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Sample records for agammaglobulinemia

  1. Agammaglobulinemia

    Science.gov (United States)

    ... with agammaglobulinemia develop infections again and again. Common infections include ones that are due to bacteria such as Haemophilus influenzae , pneumococci ( Streptococcus pneumoniae ), and staphylococci. Common sites of infection ...

  2. Evolving practice: X-linked agammaglobulinemia and lung transplantation.

    Science.gov (United States)

    Barnes, S; Kotecha, S; Douglass, J A; Paul, E; Hore-Lacey, F; Stirling, R; Snell, G I; Westall, G P

    2015-04-01

    X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD). PMID:25736826

  3. Neutropenia Associated with X-Linked Agammaglobulinemia

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    Aghamohammadi Asghar

    2009-03-01

    Full Text Available X-linked Agammaglobulinemia (XLA is a hereditary immunodeficiency, characterized by an early onset of recurrent bacterial infections, hypogammaglobulinemia and markedly reduced B lymphocytes number. In order to determine the association of neutropenia among Iranian patients with XLA, hospital records of 30 patients with confirmed XLA in Children Medical Center Hospital, were reviewed. Eight out of 30 XLA patients (26.7% developed neutropenia during the course of the disease. In two patients, episodes of neutropenia were identified before or at the time of diagnosis of XLA. Other six patients whom were not visited regularly and did not receive periodical immunoglobulin replacement therapy experienced neutropenia after diagnosis of XLA. Neutropenia in XLA is mainly associated with infection and is resolved with intravenous immunoglobulin replacement and antibiotics therapy.

  4. JOINT DISEASE IN CHILDREN WITH X-LINKED AGAMMAGLOBULINEMIA

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    Lidija Kareva

    2013-11-01

    Full Text Available Patients with X-linked agammaglobulinemia (XLA are prone to recurrent bacterial infections due to low levels of immunoglobulins. Clinical symptoms include recurrent bacterial otitis media, bronchitis, pneumonia, meningitis, skin infection and arthritis.In the majority of cases arthritis can be shown to be caused by infection, but also aseptic arthritis and autoimmune diseases may be present. Monoarthritis and oligoarthritis is usual pattern, although polyarthritis may occur. This paper presents diagnostic and therapeutic problems in our patients with agammaglobulinemia and arthritis.

  5. [A case of agammaglobulinemia with chronic enteroviral meningomyelitis].

    Science.gov (United States)

    Ito, N; Kokubo, Y; Narita, Y; Naito, Y; Kuzuhara, S

    1996-02-01

    We report a 30-year-old man with agammaglobulinemia and chronic aseptic meningomyelitis. The patient was diagnosed as having X-linked recessive agammaglobulinemia at 4 years of age and gammaglobulin supplementation was started. He had TIA-like episodes several times since 25 years of age. He developed difficulty in micturition and impotence at 29 years of age. Neurological examination revealed bilateral deafness, contracture of knee joints, slight weakness and areflexia in the lower extremities, Babinski sign and dysuria. There was sensory disturbance in the lower extremity on the left. There was not consciousness disturbance or meningeal irritation sign. The cerebrospinal fluid findings included pleocytosis and increase in protein. Enterovirus RNA was detected in the cerebrospinal fluid by the modified polymerase chain reaction (PCR) method. MRI of lower spinal cord showed syrinx formation in the lumbosacral cord and CT of the brain showed bilateral temporal lobe atrophy and temporoparietal subdural fluid collection on the left. 123I-IMP SPECT showed decrease in the cerebral blood flow in the whole brain. EEG showed diffuse slow activity, suggesting the subclinical encephalopathy. Chronic enteroviral meningoencephalitis with agammaglobulinemia (CEMA) is one of the complications of agammaglobulinemia. However, myelitis without apparent encephalopathy is very rare. To our knowledge, there have been no reports of spinal sylinx formation in CEMA. PMID:8752685

  6. Membranoproliferative Glomerulonephritis and X-Linked Agammaglobulinemia: An Uncommon Association

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    Vasco Lavrador

    2014-01-01

    Full Text Available Introduction. X-linked agammaglobulinemia (XLA is a primary immunodeficiency characterized by agammaglobulinemia requiring replacement treatment with immunoglobulin. The association of XLA and membranoproliferative glomerulonephritis (MPGN is unexpected and, to our knowledge, only one case was previously published. Case Report. The authors report the case of a 10-year-old boy with family history and prenatal diagnosis of XLA, treated from birth with intravenous immunoglobulin replacement therapy. He presented with pneumonia, macroscopic hematuria, nephrotic proteinuria, hypoalbuminemia, and hypercholesterolemia with normal renal function and serum complement levels. Renal histology showed immune complex mediated MPGN. He was started on high dose prednisolone and ramipril and switched to weekly subcutaneous immunoglobulin. After a 4-month treatment, hematuria and proteinuria significantly improved and prednisolone was gradually tapered without relapse. Conclusion. The pathogenic process underlying MPGN development in this patient is unknown but residual humoral immunity might play an important role. Thus, this case highlights the risk of autoimmune disorders among patients with XLA.

  7. Casereport - Agalactia of mare, agammaglobulinemia and arthritis in foal

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    Spasojević Jovan

    2014-01-01

    Full Text Available Lactation is physiological state of the organism and the final process of the female reproductive cycle. Milk in the first days after birth (colostrum, in addition to the necessary nutrients contains antibodies, with whose ingesting only a newborn individual receives passive immunity that protects it from various infections over time. Mammary gland dysfunction and a lack of breast milking is called agalactia. Due to the occurrence of agalactia in mother, newborn animal is denied of intake of colostrum in its body. Thus prevents ingestion of nutrients and passive immunity, which results in the occurrence of various diseases especially infectious etiology. This paper describes the treatment of agammaglobulinemia in foal after ascertaining the occurrence of primary agalactia in mare. There is described the possibility of substitution, ie. benefits of breast milk substitutes, and the procedure of diagnosis and treatment of carpal arthritis in foal.

  8. Discordant phenotype in siblings with X-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Bykowsky, M.J.; Veksler, K.S.; Sullivan, K.E. [Children`s Hospital, Philadelphia, PA (United States)] [and others

    1996-03-01

    X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency caused by a defect in a B-cell-specific signaling molecule, Btk. There has been little concordance of phenotype with genotype in this disorder, and defects in Btk cause immunodeficiencies that range from mild impairment to complete inability to produce antibodies. The factors modifying the phenotype of XLA are not understood. The current study is the first description of two male siblings with identical T{sup 134}{yields}C mutations in the translation initiation ATG of Btk who have different clinical phenotypes as well as different laboratory phenotypes. The proband lacks immunoglobulins and B cells and has recurrent infections, while the elder, affected brother has normal levels of IgG and IgM and very few infections. Both have undetectable levels of Btk kinase activity in circulating mononuclear cells. Complete sequencing of Btk gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. This description provides unequivocal evidence that the phenotype of XLA is influenced by factors additional to the Btk gene. 39 refs., 3 figs., 3 tabs.

  9. Pseudomonas aeruginosa septic shock associated with ecthyma gangrenosum in an infant with agammaglobulinemia

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    ALMEIDA João Fernando Lourenço de

    2002-01-01

    Full Text Available Ecthyma gangrenosum (EG due to Pseudomonas aeruginosa is a rare and invasive infection that can be associated with agammaglobulinemia. The cornerstone of the treatment is based on prompt recognition with appropriate antibiotic coverage and intravenous immunoglobulin. The authors report a case of EG emphasizing the clinical and therapeutic aspects of this condition.

  10. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Allen, R.C.; Nachtman, R.G.; Belmont, J.W.; Rosenblatt, H.M.

    1994-01-01

    Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19[sup +] peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLA demonstrated >95% skewing of X inactivation in peripheral blood CD19[sup +] cells but not in CD19[sup [minus

  11. High-throughput sequencing reveals an altered T cell repertoire in X-linked agammaglobulinemia

    OpenAIRE

    Ramesh, Manish; Simchoni, Noa; Hamm, David; Cunningham-Rundles, Charlotte

    2015-01-01

    To examine the T cell receptor structure in the absence of B cells, the TCR β CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V–J combinations, derived from both productive and nonproductive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cel...

  12. A Child with X-Linked Agammaglobulinemia and Enthesitis-Related Arthritis

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    Sukesh Sukumaran

    2011-01-01

    Full Text Available X-linked agammaglobulinemia (XLA is a primary immune deficiency characterized by recurrent bacterial infections and profoundly depressed serum immunoglobulin levels and circulating mature B cells. We describe a 12-year-old boy with XLA and enthesitis-related arthritis (ERA. To date, there has been a paucity of reports of noninfectious inflammatory arthritis in children with XLA. This case illustrates that functional B cells and/or immunoglobulin are not required for ERA pathogenesis. In addition, this case suggests a possible link between immune deficiency, immune dysregulation, and rheumatic illness.

  13. Agammaglobulinemia in a Patient with Smith-Lemli-Opitz Syndrome: Case Report

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    H. Halik Akar

    2016-02-01

    Full Text Available Smith-Lemli-Opitz syndrome (SLO is a rare autosomal recessive (AR inherited genetic disorder characterized by multiple congenital anomalies, microcephaly, muscular hypotonia, and severe developmental delay. The deficiency of 7-dehydrocholesterol reductase enzyme leads to this syndrome. Patients with SLO display recurrent respiratory infections due to secondary muscular hypotonia which leads to decreased motility and respiratory effort. In this study, we report a 1-year-old boy with SLO presented with recurrent urinary infections and chronic diarrhea with Klebsiella pneumonia positivity in the rectal swabs. The patient had also markedly decreased immunoglobulin G (IgG between 50-100 g/dl. In follow-up of patient, markedly clinical improvement was observed with intravenous immunoglobulin (IVIG replacement. With this study, we would like to draw attention; recurrent infections may indicate primary immunodeficiencies such as agammaglobulinemia in patients with SLO.

  14. X-Linked Agammaglobulinemia Presenting with Secondary Hemophagocytic Syndrome: A Case Report

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    Can Ozturk

    2013-01-01

    Full Text Available Introduction. Coincidence of X-linked agammaglobulinemia (XLA and secondary hemophagocytic syndrome (sHS is atypical. Both diseases are rare and pathogenesis of the latter one is not clearly known. Case Presentation. A 5-year-old boy was diagnosed both with XLA and sHS. However, in his history, he did not have severe and recurrent infections. Bruton tyrosine kinase (BTK gene mutation was present (c.1581_1584delTTTG. To the best of the authors’ knowledge, coincidence of XLA and sHS had not been reported in the literature before. Conclusion. Patients with XLA are extremely vulnerable to recurrent bacterial infections. The diagnosis of XLA with sHS at any time of life is both an interesting and challenging situation without history of recurrent bacterial infections.

  15. Mutations of Bruton's tyrosine kinase gene in Brazilian patients with X-linked agammaglobulinemia

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    V.D. Ramalho

    2010-09-01

    Full Text Available Mutations in Bruton's tyrosine kinase (BTK gene are responsible for X-linked agammaglobulinemia (XLA, which is characterized by recurrent bacterial infections, profound hypogammaglobulinemia, and decreased numbers of mature B cells in peripheral blood. We evaluated 5 male Brazilian patients, ranging from 3 to 10 years of age, from unrelated families, whose diagnosis was based on recurrent infections, markedly reduced levels of IgM, IgG and IgA, and circulating B cell numbers <2%. BTK gene analysis was carried out using PCR-SSCP followed by sequencing. We detected three novel (Ala347fsX55, I355T, and Thr324fsX24 and two previously reported mutations (Q196X and E441X. Flow cytometry revealed a reduced expression of BTK protein in patients and a mosaic pattern of BTK expression was obtained from mothers, indicating that they were XLA carriers.

  16. Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model

    DEFF Research Database (Denmark)

    Bestas, Burcu; Moreno, Pedro M D; Blomberg, K Emelie M;

    2014-01-01

    X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense...... engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct......, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we...

  17. PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT

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    Fernanda Aimée NOBRE

    2015-10-01

    Full Text Available SUMMARY We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection.

  18. Relapsing Campylobacter jejuni Systemic Infections in a Child with X-Linked Agammaglobulinemia

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    Paola Ariganello

    2013-01-01

    Full Text Available X-linked agammaglobulinemia (XLA is a primary immunodeficiency of the humoral compartment, due to a mutation in the Bruton tyrosine kinase (BTK gene, characterized by a severe defect of circulating B cells and serum immunoglobulins. Recurrent infections are the main clinical manifestations; although they are especially due to encapsulated bacteria, a specific association with Campylobacter species has been reported. Here, we report the case of a boy with XLA who presented with relapsing Campylobacter jejuni systemic infections. His clinical history supports the hypothesis of the persistence of C. jejuni in his intestinal tract. Indeed, as previously reported, XLA patients may become chronic intestinal carriers of Campylobacter, even in absence of symptoms, with an increased risk of relapsing bacteraemia. The humoral defect is considered to be crucial for this phenomenon, as well as the difficulties to eradicate the pathogen with an appropriate antibiotic therapy; drug resistance is raising in Campylobacter species, and the appropriate duration of treatment has not been established. C. jejuni should always be suspected in XLA patients with signs and symptoms of systemic infection, and treatment should be based on antibiogram to assure the eradication of the pathogen.

  19. The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Rohrer, J.; Parolini, O. [St. Jude Children`s Research Hospital, Memphis, TN (United States); Conley, M.E. [St. Jude Children`s Research Hospital, Memphis, TN (United States)]|[Univ. of Tennessee College of Medicine, Memphis, TN (United States); Belmont, J.W. [Baylor College of Medicine, Houston, TX (United States)

    1994-12-31

    It has recently been demonstrated that mutations in the gene for Bruton`s tyrosine kinase (BTK) are responsible for X-linked agammaglobulinemia. Southern blot analysis and sequencing of cDNA were used to document deletions, insertions, and single base pair substitutions. To facilitate analysis of BTK regulation and to permit the development of assays that could be used to screen genomic DNA for mutations in BTK, the authors determined the genomic organization of this gene. Subcloning of a cosmid and a yeast artificial chromosome showed that BTK is divided into 19 exons spanning 37 kilobases of genomic DNA. Analysis of the region 5{prime} to the first untranslated exon revealed no consensus TATAA or CAAT boxes; however, three retinoic acid binding sites were identified in this region. Comparison of the structure of BTK with that of other nonreceptor tyrosine kinases, including SRC, FES, and CSK, demonstrated a lack of conservation of exon borders. Information obtained in this study will contribute to understanding of the evolution of nonreceptor tyrosine kinases. It will also be useful in diagnostic studies, including carrier detection, and in studies directed towards gene therapy or gene replacement. 29 refs., 2 figs., 2 tabs.

  20. Females with a disorder phenotypically identical to X-linked agammaglobulinemia

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    Conley, M.E. (Univ. of Tennessee College of Medicine, Memphis (United States)); Sweinberg, S.K. (Children' s Hospital of Philadelphia, PA (United States))

    1992-03-01

    Clinical and laboratory findings in two girls with a disorder phenotypically indistinguishable from typical X-linked agammaglobulinemia (XLA) are described. To examine the possibility that subtle defects in the X chromosome might explain the findings, detailed genetic studies were performed on one of these patients. Cytogenetic studies showed a normal 46XX karyotype. Southern blot analysis of her DNA showed that she had inherited a maternal and a paternal allele at sites flanking the locus for typical XLA at Xq22, making a microdeletion or uniparental disomy unlikely. To determine whether both of her X chromosomes could function as the active X, somatic-cell hybrids that selectively retained the active X were produced from her activated T cells. A normal random pattern of X inactivation was seen. Of 21 T-cell hybrids, 3 retained both X chromosomes, 7 had one X as the active X, and 11 had the other X as the active X. The authors have interpreted these studies as indicating that there is an autosomal recessive disorder that is phenotypically identical to XLA.

  1. Recurrent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults

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    Tsuchiya Shigeru

    2001-04-01

    Full Text Available Abstract Background X-linked agammaglobulinemia (XLA is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood. Methods Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, Results Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT, resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain. Conclusions This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients.

  2. B lymphocytes from X-linked agammaglobulinemia. Delayed expression of light chain and demonstration of Lyonization in carriers.

    OpenAIRE

    Schwaber, J; Payne, J.; Chen, R.

    1988-01-01

    We report an unusual phenotype of B cells in a patient with X-linked agammaglobulinemia (XLA), and cellular evidence for Lyonization of B cells from his mother and sister. The patient has a failure of B cell maturation at the stage of early B lymphocytes, associated with production of D(mu delta) H chain. The phenotype of his B cells includes: (a) limitation to expression of the mu and delta H chain isotypes, (b) production of mu and delta H chains of reduced size and (c) delayed expression o...

  3. X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature

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    Krishnaswamy Guha

    2008-06-01

    Full Text Available Abstract Background Common variable immune deficiency (CVID, one of the most common primary immunodeficiency diseases presents in adults, whereas X-linked agammaglobulinemia (XLA, an inherited humoral immunodeficiency, is usually diagnosed early in life after maternal Igs have waned. However, there have been several reports in the world literature in which individuals have either had a delay in onset of symptoms or have been misdiagnosed with CVID and then later found to have mutations in Bruton's tyrosine kinase (BTK yielding a reclassification as adult-onset variants of XLA. The typical finding of absent B cells should suggest XLA rather than CVID and may be a sensitive test to detect this condition, leading to the more specific test (Btk mutational analysis. Further confirmation may be by mutational analyses. Methods The records of 2 patients were reviewed and appropriate clinical data collected. BTK mutational analysis was carried out to investigate the suspicion of adult-presentation of XLA. A review of the world literature on delayed diagnosis of XLA and mild or "leaky" phenotype was performed. Results 2 patients previously diagnosed with CVID associated with virtual absence of CD19+ B cells were reclassified as having a delayed diagnosis and adult-presentation of XLA. Patient 1, a 64 yr old male with recurrent sinobronchial infections had a low level of serum IgG of 360 mg/dl (normal 736–1900, IgA Patient 2, a 46 yr old male with recurrent sinopulmonary infections had low IgG of 260 mg/dl, low IgA Conclusion These two cases represent an unusual adult-presentation of XLA, a humoral immunodeficiency usually diagnosed in childhood and the need to further investigate a suspicion of XLA in adult males with CVID particularly those associated with low to absent CD19+ B cells. A diagnosis of XLA can have significant implications including family counseling, detecting female carriers, and early intervention and treatment of affected male

  4. Mutational analysis of Btk, the defective gene in X-linked agammaglobulinemia

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    Conley, M.E.; Fitch-Hilgenberg, M.E.; Rohrer, J. [St. Jude Children`s Research Hospital, Memphis, TN (United States)

    1994-09-01

    Recent studies have shown that X-linked agammaglobulinemia (XLA), a disorder of B cell development, is due to mutations in an scr-like cytoplasmic tyrosine kinase, Btk. Thus far, mutations in this gene have been identified by sequencing of cDNA. To permit the detection of mutations in genomic DNA, we determined the structure of Btk and identified 19 exons in 37 kb of DNA. PCR primers were designed to amplify each exon with its splice sites. Two overlapping PCR products were employed for exons longer than 230 base pairs. Single strand conformation polymorphism (SSCP) analysis was used to screen genomic DNA from 30 unrelated families presumed to carry a mutation in Btk. It was possible to amplify DNA in every reaction from every patient. None of the DNA samples demonstrated more than one aberrant SSCP pattern. Twenty three mutations were detected in 25 families. Seven point mutations resulting in amino acid substitutions were seen. An additional 7 base pair substitutions gave rise to premature stop codons. Two splice defects were noted. Small insertions or deletions, all resulting in frameshifts and premature stop codons were seen in eight patients. One patient had an A to G transition in the ATG start codon. Two mutations, both at CpG dinucleotides, were seen in more than one family. Haplotype analysis, using CA repeats closely linked to Btk, demonstrated that the mutations in these families arose independently. We conclude from these studies that the mutations in Btk in patients with XLA are highly variable. Large deletions are uncommon, although small 1 to 4 bp insertions or deletions constitute as many as one third of the mutations. Further analysis of patients with amino acid substitutions will permit structure/function correlations.

  5. Recurrent pyogenic meningitis in a 17-year-old: A delayed presentation of X-linked agammaglobulinemia with growth hormone deficiency

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    Girish R Sabnis

    2011-01-01

    Full Text Available We report an adolescent male with X-linked agammaglobulinemia (XLA and recurrent episodes of pyogenic meningitis. The workup for proportionate short stature revealed isolated growth hormone deficiency. This patient highlights the delayed presentation of the XLA variant and the need to consider primary immunodeficiency in patients with recurrent serious infections, irrespective of age.

  6. Linkage analysis and physical mapping near the gene for x-linked agammaglobulinemia at Xq22

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    Parolini, O.; Lassiter, G.L.; Henry, M.J.; Conley, M.E. (Univ. of Tennessee College of Medicine, Memphis (United States) St. Jude Children' s Research Hospital, Memphis, TN (United States)); Hejtmancik, J.F. (National Inst. of Health, Bethesda, MD (United States)); Allen, R.C.; Belmont, J.W. (Baylor College of Medicine, Houston, TX (United States)); Barker, D.F. (Univ. of Utah, Salt Lake City (United States))

    1993-02-01

    The gene for x-linked agammaglobulinemia (XLA) has been mapped to Xq22. No recombinations have been reported between the gene and the prob p212 at DXS178; however, this probe is informative in only 30-40% of women and the reported flanking markers, DXS3 and DXS94, and 10-15 cM apart. To identify additional probes that might be useful in genetic counseling, we examined 11 polymorphisms that have been mapped to the Xq21.3-q22 region in 13 families with XLA. In addition, pulsed-field gel electrophoresis and yeast artificial chromosomes (YACs) were used to further characterize the segman of DNA within which the gene for SLA must lie. The results demonstrated that DXS366 and DXS442, which share a 430-kb pulsed-field fragment, could replace DXS3 as proximal flanking markers. Probes at DXS178 and DXS265 identified the same 145-kb pulsed-field fragment, and both loci were contained within a 200-kb YAC identified with the probe p212. A highly polymorphic CA repeat (DCS178CA) was isolated from one end of this YAC and used in linkage analysis. Probes at DXS101 and DXS328 shared several pulsed-field fragments, the smallest of which was 250 kb. No recombinations were seen between XLA and the DXS178-DXS265-DXS178CA complex, DXS101, DXS328, DXS87, or the gene for proteolipid protein (PLP). Key crossovers, when combined with the linkage data from families with Alport syndrome, suggested the following order of loci: cen-DXS3-DXS366-DXS442-(PLP, DXS101, DXS328, DXS178-DXS265-DXS178CA complex, XL)-(DXS87, DXS94)-DXS327-(DXS350, DXS362)-tel. Our studies also limit the segment of DNA within which the XLA gene must lie to the 3- to 4-cM distance between DCS442 and DXS94 and they identify and orient polymorphisms that can be used in genetic counseling not only for XLA but also for Pelizaeus-Merzbacher disease (PLP deficiency), Alport syndrome (COL4A5 deficiency), and Fabry disease ([alpha]-galactosidase A difficiency). 31 refs., 5 figs., 2 tabs.

  7. "Screening of the Bruton Tyrosine Kinase (BTK Gene Mutations in 13 Iranian Patients with Presumed X-Linked Agammaglobulinemia "

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    "Asghar Aghamohammadi

    2004-12-01

    Full Text Available X-linked agammaglobulinemia (XLA is an immunodeficiency caused by mutations in the Bruton tyrosine kinase (Btk gene. In order to identify the mutations in Btk gene in Iranian patients with antibody deficiency, 13 male patients with an XLA phenotype from 11 unrelated families were enrolled as the subjects of investigation for Btk mutation analysis using PCR-SSCP followed by sequencing. Five different mutations were identified in 5 patients from 5 unrelated families. Three mutations had been reported previously including TTTG deletion in intron 15 (4 bps upstream of exon 16 boundary, nonsense point mutation (1896G>A that resulted in a premature stop codon (W588X in kinase domain, and nucleotide alteration in invariant splice donor site of exon12 (IVS12+1G>A. While 2 novel missense mutations (2084A>G, 1783T>C were identified leading to amino acid changes (I651T, Y551H. The results of this study further support the notion that molecular genetic testing represents an important tool for definitive and early diagnosis of XLA and may allow accurate carrier detection and prenatal diagnosis.

  8. Mutación de novo en el gen BTK en agammaglobulinemia ligada a X. Reporte de un caso del estado Mérida, Venezuela

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    Liliana Aboultaif Aboultaif

    2013-09-01

    Full Text Available Las inmunodeficiencias primarias (IDPs son un conjunto de enfermedades caracterizadas por defectos en el desarrollo y/o función del sistema inmune debido a anomalías genéticas en cualquiera de sus componentes. Las deficiencias de anticuerpos son las IDPs más comunes y dentro de estas la agammaglobulinemia congénita representa el 10%, siendo un 85% ligada al cromosoma X, existiendo también formas autosómicas recesivas. La agammaglobulinemia ligada a X (ALX consiste en la ausencia casi absoluta de linfocitos B, ocasionando incapacidad de sintetizar anticuerpos y una alta susceptibilidad a la adquisición de infecciones, con respuesta a vacunas disminuida o ausente. Se presenta el caso de un escolar masculino de 8 años de edad quien desde los 5 meses presentó infecciones a repetición principalmente por bacterias extracelulares encapsuladas. Estudios paraclínicos revelaron hipogammglobulinemia persistente con subpoblación de linfocitos B muy disminuida y conservación de linfocitos T en sangre periférica. El estudio molecular reportó la mutación R525X en el exón 16 del gen TirosinKinasa de Bruton (BTK en el paciente y su madre, más no en la abuela, lo que confirmó el diagnóstico de ALX y permitió concluir que se trataba de una mutación de novo en la madre. Actualmente recibe tratamiento con Inmunoglobulina por vía endovenosa, disminuyendo la frecuencia y severidad de episodios infecciosos. El diagnóstico precoz a través del reconocimiento de las señales de alarma de las IDPs, junto al tratamiento adecuado y vigilancia constante constituyen la mejor herramienta para el adecuado manejo de los pacientes con IDPs, logrando una disminución de los procesos infecciosos e inflamatorios y sus secuelas, así como también mejorar la calidad de vida y supervivencia. De novo mutation in BTK gene in X-linked agammaglobulinaemia. A case report in Mérida, Venezuela Abstract The Primary Immunodeficiencies (PIDs are a group of diseases

  9. Mutation analysis of the gene encoding Bruton`s tyrosine kinase in a family with a sporadic case of X-linked agammaglobulinemia reveals three female carriers

    Energy Technology Data Exchange (ETDEWEB)

    Hagemann, T.L.; Kwan, Sau-Ping [Rush Medical School, Chicago, IL (United States); Assa`ad, A.H. [Children`s Hospital Medical Center, Cincinnati, OH (United States)

    1995-11-06

    Bruton`s tyrosine kinase (Btk) has been identified as the protein responsible for the primary immunodeficiency X-linked agammaglobulinemia (XLA). We and others have cloned the gene for Btk and recently reported the genomic organization. Nineteen exons were positioned within the 37 kb gene. With the sequence data derived from our genomic map, we have designed a PCR based assay to directly identify mutations of the Btk gene in germline DNA of patients with XLA. In this report, the assay was used to analyze a family with a sporadic case of XLA to determine if other female relatives carry the disease. A four base-pair deletion was found in the DNA of the affected boy and was further traced through three generations. With the direct identification of the mutations responsible for XLA, we can now diagnose conclusively the disease and identify the immunologically normal female carriers. This same technique can easily be applied to prenatal diagnosis in families where the mutation can be identified. 34 refs., 3 figs.

  10. X-Linked Agammaglobulinemia (XLA)

    Science.gov (United States)

    ... viral infections but are very susceptible to chronic viral infections such as hepatitis and polio. They usually lack or have very small tonsils. Diagnosis People with XLA have extremely low numbers of ...

  11. Detection of a novel mutation in the SRC homology domain 2 (SH2) of Bruton`s tyrosine kinase and direct female carrier evaluation in a family with x-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Schuster, V.; Seidenspinner, S.; Wolfgang Kreth, H. [Univ. of Wuerzburg (Germany)

    1996-05-03

    X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disease with a block in differentiation from pre-B to B cells resulting in a selective defect in the humoral immune response. Affected males have very low concentrations of serum immunoglobulins leading predominantly to recurrent bacterial infections beginning at age 6 to 18 months. The gene responsible for XLA was identified recently to encode a cytoplasmatic tyrosine kinase (Bruton`s tyrosine kinase, BTK). We have analyzed the BTK gene in a large family in which two brothers presented with the severe phenotype of XLA. Genomic DNA of affected boys and from healthy relatives was amplified by PCR with primers specific for the putative promoter region and for all 19 exons, including flanking intron boundaries, and subsequently screened for mutations using single strand conformation polymorphism (SSCP) analysis. Altered single strand band patterns were found using primers specific for exon 10, 15, and 18. Direct cycle-sequencing of these BTK segments detected two known polymorphisms in intron 14 and in exon 18. Sequencing of exon 10 from two boys with XLA demonstrated a novel point mutation in the SH2 domain of BTK. Direct identification of healthy female carriers in three generations was performed by amplification mutagenesis using PCR with a modified first primer. This method can easily be applied also to prenatal diagnosis. 25 refs., 3 figs.

  12. Genetics Home Reference: X-linked agammaglobulinemia

    Science.gov (United States)

    ... Modell Foundation: National Primary Immunodeficiency Resource Center National Organization for Rare Disorders : ... V, Aiba Y, Shurtleff SA, Kurosaki T. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin Exp Immunol. ...

  13. Mutation pattern in the Bruton's tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia

    DEFF Research Database (Denmark)

    Vorechovský, I; Luo, L; Hertz, Jens Michael;

    1997-01-01

    mutations were associated with diminished levels of BTK mRNA expression, except for a frameshift mutation in exon 17 and two nonsense mutations in exon 2, indicating that these cases are not confined to penultimate exons. One amino acid substitution (R28H) was found in the pleckstrin homology domain...

  14. Four mutations in SH2 and SH3 domains of Bruton`s tyrosine kinase (BTK) resulting in classic X-linked agammaglobulinemia (XLA)

    Energy Technology Data Exchange (ETDEWEB)

    Chen, S.H.; Zhang, M.; Zhu, Q.; Scott, C.R.; Och, H.D. [Univ. of Washington, Seattle, WA (United States)

    1994-09-01

    XLA is an X-linked immunodeficient disease in man resulted from mutations in the BTK gene. BTK contains a unique amino-region of unknown function, SH2 and SH3 (src homology) domains, and a carboxyl-terminal kinase (SH1) domain. We have studied the normal genomic organizations of the SH2 and SH3 domains and found the regions containing 6 exons are about 3000 bp in length. We also carried out sequence analyses of cDNA and genomic DNA of XLA patients to identify mutations. Four of fourteen families with XLA were found to have mutations within the regions. (1) A point mutation G to T in codon 240 resulted in a stop codon. (2) A transition mutation (g to a) at first nucleotide of intron 8 resulted in exon 8 skipping, missing 21 codons and shorter polypeptide but with normal kinase activity and ATP binding ability. (3) An a to t transversion at one of the invariant dinucleotides (ag) of the 3{prime} end of intron 11 resulted in alternative splicing at a position 13 nucleotides downstream from the normal one. The mutation produced mRNA with 13 nucleotide deletion and presumably resulted in a frameshift at codon 372 leading to a stop codon at 398. (4) A 16 nucleotide duplication (1248 to 1263 of the cDNA sequence) consistently present in mRNA of three brothers with XLA. However, genomic sequence of patient DNA of the regions did not reveal the anormaly. The observation that mutations within SH2 and SH3 causing severe B-cell defects typical for XLA suggests that these two domains are crucial for the function of BTK, possibly by regulating the interaction of cytoplasmic proteins involved in signal transduction.

  15. Immune Disorder HSCT Protocol

    Science.gov (United States)

    2016-01-09

    Immune Deficiency Disorders:; Severe Combined Immunodeficiency; Chronic Granulomatous Disease; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Hyper-IgM; DiGeorge Syndrome; Chediak-Higashi Syndrome; Common Variable Immune Deficiency; Immune Dysregulatory Disorder:; Hemophagocytic Lymphohistiocytosis; IPEX; Autoimmune Lymphoproliferative Syndrome; X-linked Lymphoproliferative Syndrome

  16. Analysis of Clinical Presentations of Bruton Disease: A Review of 20 Years of Accumulated Data from Pediatric Patients at Severance Hospital

    OpenAIRE

    Chun, Jin-Kyong; Lee, Taek Jin; Song, Jae Woo; Linton, John A.; Kim, Dong Soo

    2008-01-01

    Purpose X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disease caused by a mutation in the Bruton tyrosine kinase (BTK) gene resulting in defective B cell differentiation. Because it is a relatively rare disorder, it is difficult for clinicians to have a comprehensive understanding of XLA due to a lack of exposure to the disease. Clinical presentations of patients with XLA were analyzed and discussed to improve care plans. Materials and Methods During a 20 year period, from J...

  17. Recurrent pneumonia caused by genetic immunodeficiency: a prophylactic and rehabilitative approach

    OpenAIRE

    Renata Cristina de Angelo Calsaverini Leal; Érika Cristina Pavarino Bertelli; Zaida Aurora Sperli Geraldes Soler

    2007-01-01

    Recurrent infections are a consequence of a series of genetic diseases characterized by deficiency in the immunological response. One of these diseases is the agammaglobulinemia, which is characterized by the basic defect in the maturation of lymphocytes B. The carrier of this kind of immunodeficiency, which is linked to the X (XLA) chromosome, has had primary pneumonias that have evolved into secondary pneumonias (chronic lungs with sequelae) after the third or fourth year of life. The clini...

  18. Current Perspectives on Primary Immunodeficiency Diseases

    OpenAIRE

    M. Eric Gershwin; Arvind Kumar; Teuber, Suzanne S.

    2006-01-01

    Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune man...

  19. Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst

    OpenAIRE

    Cerbone, Manuela; Wang, Jun; van der Maarel, Silvère M.; D’Amico, Alessandra; d’Agostino, Antonio; Romano, Alfonso; Brunetti-Pierri, Nicola

    2012-01-01

    The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agammaglobulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown...

  20. Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

    OpenAIRE

    Weemaes, Corry; van Tol, Maarten JD; Wang, Jun; van Ostaijen-Ten Dam, Monique M.; van Eggermond, Marja CJA; Thijssen, Peter E.; Aytekin, Caner; Brunetti-Pierri, Nicola; van der Burg, Mirjam; Graham Davies, E; Ferster, Alina; Furthner, Dieter; Gimelli, Giorgio; Gennery, Andy; Kloeckener-Gruissem, Barbara

    2013-01-01

    Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mu...

  1. Natural antibodies sustain differentiation and maturation of human dendritic cells

    OpenAIRE

    Bayry, Jagadeesh; Lacroix-Desmazes, Sébastien; Donkova-Petrini, Vladimira; Carbonneil, Cédric; Misra, Namita; Lepelletier, Yves; Delignat, Sandrine; Varambally, Sooryanarayana; Oksenhendler, Eric; Lévy, Yves; Debré, Marianne; Kazatchkine, Michel D.; Hermine, Olivier; Kaveri, Srini V.

    2004-01-01

    The differentiation and maturation of dendritic cells (DCs) is governed by various signals in the microenvironment. Monocytes and DCs circulate in peripheral blood, which contains high levels of natural antibodies (NAbs). NAbs are germ-line-encoded and occur in the absence of deliberate immunization or microbial aggression. To assess the importance of NAbs in the milieu on DC development, we examined the status of DCs in patients with X-linked agammaglobulinemia, a disease characterized by pa...

  2. The Effect of IVIG on Superoxide Generation in Primary Humoral Immunodeficiencies

    OpenAIRE

    Gulay Sezgin

    2016-01-01

    Primary antibody deficiency (common variable immunodeficiency, Hyper IgM, X-linked agammaglobulinemia and selective Ig A deficiency) is a group of heterogeneous diseases characterized by defective antibody production. In primary hypogammaglobulinemias, particularly in patients with common variable immunodeficiency there is an increased generation of reactive oxygen species from monocytes which may be important for both immunopathogenesis and clinical manifestations. The generation of toxic ox...

  3. Ibrutinib for B cell malignancies

    OpenAIRE

    Novero, Aileen; Ravella, Pavan M; Chen, Yamei; Dous, George; Liu, Delong

    2014-01-01

    Research over the role of Bruton’s agammaglobulinemia tyrosine kinase (BTK) in B-lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site ...

  4. PCI-32765, the First BTK (Bruton’s Tyrosine Kinase) Inhibitor in Clinical Trials

    OpenAIRE

    Brown, Jennifer R

    2013-01-01

    Ibrutinib is a potent covalent kinase inhibitor that targets BTK. BTK, or Bruton’s tyrosine kinase, is an obvious target for therapy of B cell diseases because inactivating mutations lead to B cell aplasia in humans and the disease X-linked agammaglobulinemia. Ibrutinib has modest cytotoxicity against CLL cells in vitro but also blocks trophic stimuli from the microenvironment. As with other inhibitors of the BCR pathway, ibrutinib causes rapid nodal reduction and response associated with rap...

  5. DEVELOPMENT OF REAL-TIME MULTIPLEX PCR FOR THE QUANTITATIVE DETERMINATION OF TREC'S AND KREC'S IN WHOLE BLOOD AND IN DRIED BLOOD SPOTS

    Directory of Open Access Journals (Sweden)

    M. A. Gordukova

    2015-01-01

    Full Text Available Primary immunodeficiencies (PID such as severe combined immunodeficiency (SCID and X-linked agammaglobulinemia are characterized by the lack of functional Tand B-cells, respectively. Without early diagnosis and prompt treatment children with PID suffer from severe infectious diseases, leading to their death or disability. Our purpose was developing of simple, inexpensive, high throughput technique based on the quantitative determination of TREC and KREC molecules by real-time PCR, and its validation in a group of children with a verified diagnosis of SCID and X-linked agammaglobulinemia.In this study, we developed and validated multiplex real-time PCR for the TREC’s and KREC’s quantitative analysis. We have shown that linear range of Ct changes depending on the concentrations of targets with a correlation coefficient R2 not worse than 0.98 was observed at concentrations from 109 to 5 × 104 copies per ml. The lowest amount of targets reliably detected in a reaction volume was 10 TREC’s copies, 5 KREC ‘s copies and 5 copies of internal control (IL17RA. We determined the age-depended reference values of TRECs and KRECs in whole blood in 29 boys and 27 girls with normal immunological parameters. The normal cut-offs for TRECs and KRECs were defined in dry blood spots depending on the method of extraction.The proposed method showed 100% diagnostic sensitivity and specificity in the studied group. The method can be proposed as a screening tool for the diagnosis of SCID and X-linked agammaglobulinemia both in whole blood and in the dry blood spots. The further investigation is required with larger number of samples. 

  6. [Satisfactory evolution of a patient diagnosed in childhood with Bruton's disease].

    Science.gov (United States)

    Román Jiménez, María Guadalupe; Yamazaki Nakashimada, Marco Antonio; Blancas Galicia, Lizbeth

    2010-01-01

    Bruton's agammaglobulinemia is a primary immunodeficiency with a disease onset during the first months of age, when the maternal serum immunoglobulin levels decrease. It is characterized by recurrent infections and agammaglobulinemia. We report the case of a 6-year-old male patient with third-degree consanguinity, product of a third pregnancy and complete immunization scheme. He had a history of oral candidiasis at the age of 3 months, chicken pox at the age of 7 months, and two episodes of complicated bronchopneumonia at the age of 1 year and 6 years. He was admitted to the hospital because of fever and cough. Examination of the chest showed rales and right basilar hypoventilation, and a blood cell count revealed leukocytosis and neutrophilia. The diagnosis of pneumonia was made. He was treated with IV antibiotics. Serum immunoglobulins were reported to be low (IgM 55 mg/dL, IgA 0.9 mg/dL, and IgG 199 mg/dL). With these findings the clinical diagnosis of X-linked agammaglobulinemia (ALX) was concluded. A molecular test was performed fining a BTK gene confirming the diagnosis of Bruton's disease. Therapy with intravenous IgG was started every 21 days. During his evolution, he presented three episodes of rhinosinusitis, one of suppurative otitis media, and four events of pneumonia that required 37 days of hospitalization. After hospital discharge, the patient was free of infections and he returned to his daily activities. In cases of recurrent and severe respiratory infections in children, we must consider primary immunodeficiency disease in the differential diagnosis, mainly antibiotic deficiency. Early diagnosis and treatment improves the survival and quality of life in these patients. PMID:21854727

  7. Inhibition of IgE-mediated Secretion from Human Basophils with a Highly Selective Bruton’s Tyrosine Kinase, Btk, Inhibitor

    OpenAIRE

    MacGlashan, Donald; Honigberg, Lee; Smith, Ashley; Buggy, Joseph; Schroeder, John T.

    2011-01-01

    The study of receptor-mediated signaling in human basophils is often limited by the availability of selective pharmacological agents. The early signaling reaction mediated by FcεRI aggregation is thought to require the activity of Bruton’s tyrosine kinase (btk), an enzyme that has been identified as important in B cells signaling because mutations lead to X-linked agammaglobulinemia. This study uses the btk selective irreversible inhibitor, PCI-32765, to explore the role of btk in a variety o...

  8. Current Perspectives on Primary Immunodeficiency Diseases

    Science.gov (United States)

    Kumar, Arvind; Teuber, Suzanne S.; Gershwin, M. Eric

    2006-01-01

    Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis. PMID:17162365

  9. Current Perspectives on Primary Immunodeficiency Diseases

    Directory of Open Access Journals (Sweden)

    Arvind Kumar

    2006-01-01

    Full Text Available Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis.

  10. [High-dose intravenous immunoglobulin treatment].

    Science.gov (United States)

    Taneichi, Hiromichi; Miyawaki, Toshio

    2011-03-01

    Intravenous immunoglobulin treatment was introduced as replacement therapy for patients with congenital agammaglobulinemia. For the last three decades, high-dose intravenous immunoglobulin (HD-IVIg) has been used for autoimmune diseases and systemic inflammatory diseases, such as idiopathic thrombocytopenic purpura, Kawasaki disease, myasthenia gravis and Guillain-Barré/syndrome. Although the immunomodulatory mechanisms of HD-IVIg remains unclear. Its use in many other diseases have been expected. Acute encephalitis/encephalopathy is a complex neurological syndrome associated with significant morbidity and mortality. The pathogenicity of brain dysfunction is still unknown. This review provides an overview and discussion of mechanisms that may be responsible for HD-IVIg effects in acute encephalitis/encephalopathy. PMID:21400848

  11. Molecular and genetic basis of X-linked immunodeficiency disorders

    Energy Technology Data Exchange (ETDEWEB)

    Puck, J.M. (National Center for Human Genome Research, Bethesda, MD (United States))

    1994-03-01

    Within a short time interval the specific gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and severe combined immunodeficiency (XSCID), have been identified. These represent the first human disease phenotypes associated with each of three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B cell-specific intracellular tyrosine kinase; HIGM, by mutations in the TNF-related CD40 ligand, through which T cells deliver helper signals by direct contact with B cell CD40; and XSCID, by mutations in the [gamma] chain of the lymphocyte receptor for IL-2. Each patient mutation analyzed to date has been unique, representing both a challenge for genetic diagnosis and management and an important resource for dissecting molecular domains and understanding the physiologic function of the gene products.

  12. Advances in human genetics

    Energy Technology Data Exchange (ETDEWEB)

    Harris, H.; Hirschhorn, K. (eds.)

    1993-01-01

    This book has five chapters covering peroxisomal diseases, X-linked immunodeficiencies, genetic mutations affecting human lipoproteins and their receptors and enzymes, genetic aspects of cancer, and Gaucher disease. The chapter on peroxisomes covers their discovery, structure, functions, disorders, etc. The chapter on X-linked immunodeficiencies discusses such diseases as agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, animal models, linkage analysis, etc. Apolipoprotein formation, synthesis, gene regulation, proteins, etc. are the main focus of chapter 3. The chapter on cancer covers such topics as oncogene mapping and the molecular characterization of some recessive oncogenes. Gaucher disease is covered from its diagnosis, classification, and prevention, to its organ system involvement and molecular biology.

  13. A 6. 5-Mb yeast artificial chromosome contig incorporating 33 DNA markers on the human X chromosome at Xq22

    Energy Technology Data Exchange (ETDEWEB)

    Vetrie, D.; Kendall, E.; Coffey, A.; Hassock, S.; Collins, J.; Todd, C.; Bobrow, M.; Bentley, D.R. (Paediatric Research Unit, London (United Kingdom)); Lehrach, H. (Imperial Cancer Research Fund, London (United Kingdom)); Harris, A. (John Radcliffe Hospital, Oxford (United Kingdom))

    1994-01-01

    The Xq22 region of the human X chromosome contains genes for a number of inherited disorders. Sixty-nine yeast artificial chromosome clones have been isolated and assembled into a 6.5-Mb contig that contains 33 DNA markers localized to this region. This contig extends distally from DXS366 to beyond DXS87 and includes the genes involved in X-linked agammaglobulinemia (btk), Fabry disease (GLA), and Pelizaeus-Merzbacher disease (PLP). The order of markers in this contig is consistent with the known genetic and physical mapping information of Xq22. This cloned material provides a source from which to isolate other genes located in this part of the X chromosome. 45 refs., 2 figs., 2 tabs.

  14. DNA Banking of Primary Immunodeficiency Disorders in Iran

    Directory of Open Access Journals (Sweden)

    "Anna Isaian

    2006-12-01

    Full Text Available Primary immunodeficiency disorders are a heterogeneous group of genetic disorders, with different modes of inheritance, consisting of more than 100 different types. We constructed the DNA banking of primary immunodeficiency disorders for the first time in Iran. The DNA of 31 immunodeficient patients and their families (total of 92 samples were collected, as the first step for construction of DNA banking. DNA was isolated from whole blood by salting out method. Among our patients, Common variable immunodeficiency was the most common disorder, followed by X-linked agammaglobulinemia, Ataxia-telangiectasia, Chronic granulomatous disease, Severe combined immunodeficiency, Hyper IgM syndromes, and Leukocyte adhesion defects. DNA banking is a useful method for further detection of mutation in immunodeficient patients and prenatal diagnosis for presence or absence of the disorder in the fetus which can be confirmed by molecular genetics testing.

  15. Toll-like receptor signaling in primary immune deficiencies.

    Science.gov (United States)

    Maglione, Paul J; Simchoni, Noa; Cunningham-Rundles, Charlotte

    2015-11-01

    Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are specific for susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Dampening of TLR responses is seen for TLRs 2 and 4 in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome, and for most TLRs in adenosine deaminase deficiency. PMID:25930993

  16. THE CLINICAL SPECTRUM OF RESPIRATORY DISEASES IN PATIENTS WITH PRIMARY ANTIBODY DEFICIENCY

    Directory of Open Access Journals (Sweden)

    A. Aghamohammadi

    2000-08-01

    Full Text Available Primary Humoral Immunodeficiencies (PHID are currently increasingly being recognized. Patients with PHID frequently show respiratory complications.The objectives of the study is to determine the clinical spectrum of respiratory diseases in patients with PHID."We extracted data from the clinical files of patients with PHID, diagnosed according to WHO criteria. We encountered 125 patients (84 males, with the diagnosis of primary antibody deficiency including common-variable immunodeficiency (64 pts, x-linked agammaglobulinemia (29 pts, IgA deficiency (20 pts, IgG-subc!ass deficiency (8 pts, and hyper-IgM syndrome (4 pts. The mean age of the patients at the time of study was 11 years. In the evolution of their disease, 92 cases (73.6% developed upper respiratory tract infections, among which acute otitis media (68 pts, 54.4%, sinusitis (61 pts, 48.8%, and pharyngitis (12 pts, 10.4% were found to be the most frequent. Among the lower respiratory tract infections, pneumonia was the most common occurance (91 pts, 72.8%. The other lower respiratory tract complications were: bronchiectasis (22 pts, 17.6%, bronchitis (8 pts, tuberculosis (6 pts, lung abscess (4 pts, and Pneumocystis carinii pneumonia (2 pts.Respiratory infections constitute the most common presenting symptom of patients with primary humoral immunodeficiency. There may be some differences in the type and frequency of infections in each of these disorders.

  17. Otological findings in pediatric patients with hypogammaglobulinemia.

    Directory of Open Access Journals (Sweden)

    Marzieh Tavakol

    2014-06-01

    Full Text Available The main clinical presentation of patients with primary antibody deficiency (PAD incorporates upper respiratory tract infections comprising otitis media, sinusitis and pneumonia. This study was designed to investigate clinical and paraclinical otological complications in major types of PAD. A cross sectional study was conducted on 55 PAD patients with diagnosis of selective IgA deficiency, common variable immunodeficiency (CVID, X-linked agammaglobulinemia (XLA, and hyper IgM syndrome. All patients underwent otological examinations, audiometry, and auditory brain stem response. Otological complications were detected in 54.5% of PAD patients. Conductive hearing loss was the main finding amongst PID patients (73.3% followed by sensorineural hearing loss which was present in 8 cases. Otitis media with effusion (21.8%, chronic otitis media (27.2%, tympanosclerosis with intact tympanic membrane (5.4% and auditory neuropathy (3.6% were most important found complications. CVID and XLA patients with prophylactic usage of antibiotics had lower rate of audiological complications (p=0.04 and otitis media with effusion (p=0.027. As our results showed, asymptomatic otological findings were not rare in PAD patients; therefore, a systematic otological investigation is recommended as an integral part of the management and follow-up of these patients.

  18. Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation.

    Directory of Open Access Journals (Sweden)

    Rita R Barbosa

    Full Text Available IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17 share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID, defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21(lowCD38(low. Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.

  19. Newborn Screening for Primary Immunodeficiencies: Focus on Severe Combined Immunodeficiency (SCID and Other Severe T-Cell Lymphopenias

    Directory of Open Access Journals (Sweden)

    Stephan Borte

    2015-12-01

    Full Text Available Primary immunodeficiencies (PID are congenital disorders of immune competence, which are mainly characterized by a pathological susceptibility to infection. More than 240 PID disease entities have been defined so far, accounting for a broad spectrum of clinical symptoms and severity. Severe PID are increasingly becoming appreciated as a relevant health problem, and diagnostic procedures and screening profiles to allow earliest possible diagnosis on a population scale have already been developed in the USA and few European countries. The most severe PID are characterized by significant mortality in the first years of life, as well as serious morbidity with irreversible organ damage. This applies in particular to PID that are defined by the absence or functional anergy of T-lymphocytes (severe combined immunodeficiency; SCID or B-lymphocytes (e.g., X-linked agammaglobulinemia; XLA. A strategy to improve the outcome of severe PID by prompt diagnosis and immediate adequate treatment is screening newborns for the presence of T and B cells.

  20. Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst

    Science.gov (United States)

    Cerbone, Manuela; Wang, Jun; Van der Maarel, Silvère M.; d’Amico, Alessandra; d’Agostino, Antonio; Romano, Alfonso; Brunetti-Pierri, Nicola

    2012-01-01

    The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agammaglobulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café-au-lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases. PMID:22786748

  1. Characterization of a human isolate of Tritrichomonas foetus (cattle/swine genotype) infected by a zoonotic opportunistic infection.

    Science.gov (United States)

    Suzuki, Jun; Kobayashi, Seiki; Osuka, Hanako; Kawahata, Daisuke; Oishi, Tsuyoshi; Sekiguchi, Koji; Hamada, Atsuo; Iwata, Satoshi

    2016-05-01

    Tritrichomonas species flagellates (IMC strain) were isolated from the biliary tract of an individual who had developed cholecystitis as a complication of acquired agammaglobulinemia. Sequence analysis of Tritrichomonas sp. (IMC clone 2 (cl2)) was performed for several genetic regions including the ITS1-5.8S rDNA-ITS2 region, the cysteine protease (CP)-1, CP-2 and CP-4 to CP-9 genes, and the cytosolic malate dehydrogenase 1 gene. In addition to comparison of the variable-length DNA repeats in the isolate clone with those in T. foetus (Inui cl2) and the T. mobilensis (U.S.A.: M776 cl2) reference strains, this analysis showed that the Tritrichomonas sp. (IMC cl2) was T. foetus (cattle/swine genotype). Injection of T. foetus (IMC cl2) directly into the livers of CBA mice resulted in liver abscess formation on Day 7. Moreover, inoculation via orogastric intubation caused infection in the cecum on Day 5 in CBA mice co-infected with Entamoeba histolytica (HM-1: IMSS cl6). T. foetus (IMC cl2) was able to grow in YI-S medium for over 20 days, even at 5°C. These results indicate that the T. foetus isolate is able to survive in the feces and edible organ meat of the definitive host for a prolonged period of time, and it is possible that the parasite could infect humans. PMID:26685985

  2. Infectious diseases

    International Nuclear Information System (INIS)

    Central nervous system infections represents a group of life-threatening diseases that present a formidable challenge to physicians. Despite the development of effective antimicrobial agents and modern surgical techniques, significant mortality and morbidity with CNS infections persist. Since the introduction of computed tomography, there is evidence of a marked decrease in mortality among patients with brain abscesses, although the morbidity has not changed significantly. CT correlation with pathology of the various CNS infections may aid in earlier diagnosis and bring about further disease in morbidity and mortality. Infections reach the brain or meninges mainly by two routes: (1) hematogenous dissemination from a distant infective focus to the meninges, corticomedullary junction, and choroid plexus; (2) direct extension by bony erosion for an adjacent focus of suppuration (otitis, mastoidits, sinusitis), by transmission along anaostomotic veins from the face, scalp, and orbits, and by transmission along cranial nerves following neurosurgery or traumatic craniocerebral wounds. Certain external factors serve to enhance the risk of intracranial infections, such as radiation; immunosuppressive or steroid therapy; cyanotic congenital heart disease; systemic illness such as diabetes mellitus, alcoholism, or cirrhosis; leukemia, lymphoma, or agammaglobulinemia; severe body stress; midline bony fusion defects; surgical or traumatic craniocerebral injury; and pulmonary or other systemic infections

  3. "The spectrum of primary immunodeficiency disorders in Iran "

    Directory of Open Access Journals (Sweden)

    "Aghamohammadi A

    2002-07-01

    Full Text Available Epidemiological studies have shown wide geographical and racial variation in the prevalence and patterns of immunodeficiency disorders. To determine the frequency of primary immunodeficiencies (PID in Iran, the Iranian primary Immunodeficiencies Registry (IPIDR was organized in 1999. the diagnosis of immunodeficiency in our patients was based on standard criteria. The patient’s data were extracted, by using a uniform questionnaire from their hospital records. Three hundred and twenty eight patients with PID have been registered in our registry till 2000. Among these patients, the following frequencies were found: predominantly antibody deficiency in 48.48% of patients (n=159, T-cell disorders in 25.91% (n=85, phagocytic disorders in 24.7% (n=81, and complement deficiencies in 0.91% (n=3. Common variable immunodeficiency was the most frequent disorder (n=73, followe by chronic granulomatous disease (n=55, ataxia telangiectasia (n=39, x-linked agammaglobulinemia (n=35, selective IgA deficiency (n=34. This study reveals that antibody deficiencies are the most frequent diagnosed primary immunodeficiency disorder in our patients, which is similar to that observed in other registries. A comparative study shows some differences between our results and other registries

  4. Radiographic findings in immunodeficiency

    International Nuclear Information System (INIS)

    This paper reviews the chest radiographs and high-resolution CT (HRCT) scans in patients with immunodeficiency disorders and define the role of HRCT. Thirty-three cases were retrospectively graded according to the consensus of two radiologists. Patients with HIV seropositivity and asthma were excluded. HRCT was performed in 12 cases with standard techniques. Diagnoses included common variable hypogammaglobulinemia (n = 19), X-linked agammaglobulinemia (n = 4), chronic mucocutaneous candidiasis (n = 4), and selective immunoglobulin g deficiencies (n = 2). Chest radiographs showed bronchiectasis in 11 of 33 cases with a predominant lower lobe distribution (82%). Nodules were present in six cases and mucus plugs in four cases. HRCT showed bronchiectasis in nine of 12 cases; in five of these nine cases, bronchiectasis was not apparent on chest radiographs. Other HRCT findings included segmental air trapping (four of 12), mucus plugs (three of 12), hazy consolidation (four of 12), nodules (five of 12), and bronchiolectasis (two of 12). Therapy was altered in seven of 12 cases in which HRCT was performed. Most pertinent to clinical management were the presence of a thymoma (n = 1) and severe focal of diffuse bronchiectasis

  5. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.

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    Bonnie K Harrington

    Full Text Available Acalabrutinib (ACP-196 is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL. First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR was 25% (5/20 with a median progression free survival (PFS of 22.5 days. Clinical benefit was observed in 30% (6/20 of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL.

  6. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Allen, R.C.; Zoghbi, H.Y.; Moseley, A.B.; Rosenblatt, H.M.; Belmont, J.W. (Baylor College of Medicine, Houston (United States))

    1992-12-01

    The human androgen-receptor gene (HUMARA; GenBank) contains a highly polymorphic trinucleotide repeat in the first exon. The authors have found that the methylation of HpaII and HhaI sites less than 100 pb away from this polymorphic short tandem repeat (STR) correlates with X inactivation. The close proximity of the restriction-enzyme sites to the STR allows the development of a PCR assay that distinguishes between the maternal and paternal alleles and identifies their methylation status. The accuracy of this assay was tested on (a) DNA from hamster/human hybrid cell lines containing either an active or inactive human X chromosome; (b) DNA from normal males and females; and (c) DNA from females showing nonrandom patterns of X inactivation. Data obtained using this assay correlated substantially with those obtained using the PGK, HPRT, and M27[beta] probes, which detect X inactivation patterns by Southern blot analysis. In order to demonstrate one application of this assay, the authors examined X inactivation patterns in the B lymphocytes of potential and obligate carriers of X-linked agammaglobulinemia. 42 refs., 5 figs., 1 tab.

  7. Close linkage of the locus for X chromosome-linked severe combined immunodeficiency to polymorphic DNA markers in Xq11-q13

    Energy Technology Data Exchange (ETDEWEB)

    de Saint Basile, G.; Arveiler, B.; Oberle, I.; Malcolm, S.; Levinsky, R.J.; Lau, Y.L.; Hofker, M.; Debre, M.; Fischer, A.; Griscelli, C.; Mandel, J.L.

    1987-11-01

    The gene for X chromosome-linked severe combined immunodeficiency (SCID), a disease characterized by a block in early T-cell differentiation, has been mapped to the region Xq11-q13 by linkage analysis with restriction fragment length polymorphisms. High logarithm of odds (lod) scores were obtained with the marker 19.2 (DXS3) and with the marker cpX73 (DXS159) that showed complete cosegregation with the disease locus in the informative families analyzed. Other significant linkages were obtained with several markers from Xq11 to q22. With the help of a recently developed genetic map of the region, it was possible to perform multipoint linkage analysis, and the most likely genetic order is DXS1-(SCID, DXS159)-DXYS1-DXYS12-DXS3, with a maximum multipoint logarithm of odds score of 11.0. The results demonstrate that the SCID locus (gene symbol IMD4) is not closely linked to the locus of Bruton's agammaglobulinemia (a defect in B-cell maturation). They also provide a way for a better estimation of risk for carrier and antenatal diagnosis.

  8. A novel Tth111I restriction fragment length polymorphism (RFLP) allows tracing of X-chromosome inactivation in the (Xid) hetrozygote

    Energy Technology Data Exchange (ETDEWEB)

    Shanmugam, V.; Sell, W.; Saha, B.K. [Emory Univ. of School of Medicine, Atlanta, GA (United States)] [and others

    1996-02-01

    The X-linked immunodeficiency (Xid) in CBA/N mice serves as a model for the X-linked agammaglobulinemia (XLA) syndrome in man. X-chromosome inactivation in F{sub 1} heterozygotes derived from CBA/N (X{sup xid}/X{sup xid}) and B6.Pgk-1a (X{sup +}/Y) was investigated by monitoring the methylation status of the individual Pgk-1 alleles, Pgk-1b and Pgk-1a, respectively, using a novel Tth111I RFLP. Results indicate that in circulating B lymphocytes of female heterozygotes, only the X chromosomes carrying the normal alleles (X{sup +}) are active (nonrandom inactivation of the X chromosome), whereas in non-B cells both the X chromosomes (X{sup +} and X{sup xid}) are active (random inactivation of the X chromosome). These results were further confirmed by direct evaluation of transcription of the Btk gene, the gene mutated both in Xid and in XLA. 36 refs., 2 figs., 2 tabs.

  9. Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease

    Directory of Open Access Journals (Sweden)

    Suzanne Skoda-Smith

    2009-12-01

    Full Text Available Suzanne Skoda-Smith, Troy R Torgerson, Hans D OchsSeattle Children’s Research Institute and Department of Pediatrics, University of Washington, Seattle, WashingtonAbstract: Antibody deficiency is the most frequently encountered primary immunodeficiency disease (PIDD and patients who lack the ability to make functional immunoglobulin require life-long replacement therapy to prevent serious bacterial infections. Human serum immunoglobulin manufactured from pools of donated plasma can be administered intramuscularly, intravenously or subcutaneously. With the advent of well-tolerated preparations of intravenous immunoglobulin (IVIg in the 1980s, the suboptimal painful intramuscular route of administration is no longer used. However, some patients continued to experience unacceptable adverse reactions to the intravenous preparations, and for others, vascular access remained problematic. Subcutaneously administered immunoglobulin (SCIg provided an alternative delivery method to patients experiencing difficulties with IVIg. By 2006, immunoglobulin preparations designed exclusively for subcutaneous administration became available. They are therapeutically equivalent to intravenous preparations and offer patients the additional flexibility for the self-administration of their product at home. SCIg as replacement therapy for patients with primary antibody deficiencies is a safe and efficacious method to prevent serious bacterial infections, while maximizing patient satisfaction and improving quality of life.Keywords: subcutaneous immunoglobulin, primary immunodeficiency disease, antibody deficiency, X-linked agammaglobulinemia, common variable immune deficiency

  10. High Production of IL-18 by Dendritic Cells Induced by Sera from Patients with Primary Antibody Deficiency

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    Maryam Nourizadeh

    2007-06-01

    Full Text Available Predominantly antibody deficiencies are a category of primary immunodeficiency diseases, whichconsist of several rare disorders such as common variable immunodeficiency (CVID and X-linked agammaglobulinemia (XLA. We evaluated the effects of CVID and XLA patients’ sera as a source of microenviromental factors on maturation and function of monocyte-derived DCs.Blood was collected from 10 CVID and 5 XLA patients before immunoglobulin replacementtherapy and also from 8 healthy volunteers in order to obtain necessary sera for this study. Monocyte derived DCs were generated from blood cells obtained from healthy volunteers in the presence of GM-CSF, IL-4 and 10% serum concentrations from cases and controls. Immature DCs were incubated with monocyte conditioned medium (MCM and TNF-α in order to generate mature DCs. Interleukin 18 (IL-18 production by CD40L-activated mature DCs was measured after 24 hours of culture in vitro.IL-18 production by DCs generated in the presence of CVID and XLA patients’ sera were6.75±2.59 and 7.08±1.75 ng/ml, respectively, which were significantly higher than normal serumconditioned DCs (3.55±0.68 ng/ml.These results suggest that the sera of patients with predominantly antibody deficiencies maycontain soluble factor(s that can induce a significant increase in IL-18 production by DCs.

  11. Human protein kinase C lota gene (PRKC1) is closely linked to the BTK gene in Xq21.3

    Energy Technology Data Exchange (ETDEWEB)

    Mazzarella, R.; Jones, C.; Schlessinger, D. [Washington Univ. School of Medicine, St. Louis, MO (United States)] [and others

    1995-04-10

    The human X chromosome contains many disease loci, but only a small number of X-linked genes have been cloned and characterized. One approach to finding genes in genomic DNA uses partial sequencing of random cDNAs to develop {open_quotes}expressed sequence tags{close_quotes} (ESTs). Many authors have recently reported chromosomal localization of such ESTs using hybrid panels. Twenty ESTs specific for the X chromosome have been localized to defined regions with somatic cell hybrids, and 12 of them have been physically linked to markers that detect polymorphisms. One of these ESTs, EST02087, was physically linked in a 650-kb contig to the GLA ({alpha}-galactosidase) gene involved in Fabry disease. A comparison of this contig with a 7.5-Mb YAC contig indicated that this gene is also within 250 kb of the src-like protein-tyrosine kinase BTK (X-linked agammaglobulinemia protein-tyrosine kinase) gene in Xq21.3. 14 refs., 1 fig.

  12. Acciones inmunofarmacológicas de las inmunoglobulinas intravenosas

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    Amaury Noda

    2001-03-01

    Full Text Available Se ha recorrido un largo camino en la comprensión de los mecanismos de acción relativos a la infusión de preparados de inmunoglobulinas intravenosas desde los días donde un crudo de fracción II de Cohn obtenido de plasma humano fue administrado intramuscularmente a pacientes aquejados de agammaglobulinemia de Brutton, hasta nuestros días. Debemos hacer una distinción entre los mecanismos de acción al nivel del patógeno que provoca la enfermedad, de aquellos al nivel de una enfermedad dada provocada por la reacción del huésped contra el patógeno. El efecto de supresión de las inmunoglobulinas intravenosas en las respuestas autoinmunes abre nuevas perspectivas terapéuticas y permite un nuevo acercamiento a la comprensión de los mecanismos básicos que explican la autoinmunidad patológica.

  13. Molecular genetic analysis of X-linked hypogammaglobulinemia and isolated growth hormone deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, D.M.; Kurman, C.C.; Staudt, L.M. [Univ. of Brescia (Italy)] [and others

    1995-09-01

    In 1980 the clinical syndrome of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA/GHD) was described. XLA/GHD patients have reduced serum levels of Ig and normal cell-mediated immunity, and thus resemble patients with Bruton`s X-linked agammaglobulinemia (XLA). However, XLA/GHD patients also have isolated GHD. Mutations and deletions in the Bruton`s tyrosine kinase gene (BTK) are responsible for Bruton`s XLA. We investigated BTK gene expression in an XLA/GHD patient from the family originally described by Northern analysis, cDNA sequencing, and Western analysis of protein production using mAb to BTK. BTK mRNA was normal in size and abundance, and the mRNA sequence was normal over the coding region, except for a single silent mutation. BTK protein was present in normal amounts in PBMC of this patient. Thus, at the molecular level, XLA/GHD is a different disease entity from Bruton`s XLA. These results suggest that undescribed genes critical for B cell development and growth hormone production exist on the X chromosome. 17 refs., 4 figs.

  14. ADVERSE EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN THERAPY IN PATIENTS WITH ANTIBODY DEFICIENCY

    Directory of Open Access Journals (Sweden)

    A. Aghamohammadi

    2003-09-01

    Full Text Available Long-term intravenous immunoglobulin (IVIG infusion is an effective treatment for children with humoral immunodeficiencies, already be complicated by systemic ad¬verse effects. In order to determine the adverse effects of intravenous immunoglobulin inpatients with antibody deficiency, 45 immunodeficientpatients receiving intravenous immunoglobulin were studied during a 36-month period at Children's Medical Center. The investigated group included 25 patients with common variable immunodeficiency, 14 patients with X-linked agammaglobulinemia and 6 patients with IgG subclass defi¬ciency. A total of fifty adverse effects occurred through 955 infusions (5.2%. The most frequent immediate adverse effects were mild (40 infusions out of 955 in 22 cases, including: chills, flushing, fever, nausea and headache. Three patients experienced mod¬erate effects (10 infusions out of 955 such as rash, severe headache, joint pain and chest tightness. None of the effects was anaphylactic type. It can be concluded that intravenous immunoglobulin is generally a well-tolerated medical agent for patients with antibody deficiency, but all patients should be monitored by a physician who is familiar with its indications, risks, adverse effects and their appropriate management.

  15. Basic and clinical immunology

    Science.gov (United States)

    Chinen, Javier; Shearer, William T.

    2003-01-01

    Progress in immunology continues to grow exponentially every year. New applications of this knowledge are being developed for a broad range of clinical conditions. Conversely, the study of primary and secondary immunodeficiencies is helping to elucidate the intricate mechanisms of the immune system. We have selected a few of the most significant contributions to the fields of basic and clinical immunology published between October 2001 and October 2002. Our choice of topics in basic immunology included the description of T-bet as a determinant factor for T(H)1 differentiation, the role of the activation-induced cytosine deaminase gene in B-cell development, the characterization of CD4(+)CD25(+) regulatory T cells, and the use of dynamic imaging to study MHC class II transport and T-cell and dendritic cell membrane interactions. Articles related to clinical immunology that were selected for review include the description of immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked agammaglobulinemia; the mechanism of action, efficacy, and complications of intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in HIV pathogenesis and vaccine development. We also reviewed two articles that explore the possible alterations of the immune system caused by spaceflights, a new field with increasing importance as human space expeditions become a reality in the 21st century.

  16. Recurrent pneumonia caused by genetic immunodeficiency: a prophylactic and rehabilitative approach

    Directory of Open Access Journals (Sweden)

    Renata Cristina de Angelo Calsaverini Leal

    2007-06-01

    Full Text Available Recurrent infections are a consequence of a series of genetic diseases characterized by deficiency in the immunological response. One of these diseases is the agammaglobulinemia, which is characterized by the basic defect in the maturation of lymphocytes B. The carrier of this kind of immunodeficiency, which is linked to the X (XLA chromosome, has had primary pneumonias that have evolved into secondary pneumonias (chronic lungs with sequelae after the third or fourth year of life. The clinical and rehabilitative quest for prophylaxis against the XLA immunodeficiency is accomplished in order to avoid the evolution of the bacterial infection into sequelae and loss of pulmonary function, which propitiates the recurrence of the disease and deteriorates the life quality of the patient. Forty cases of recurrent respiratory infections were studied. Some of them were associated with primary respiratory diseases without investigation of serum immunoglobulins and some were not. Casuistics was performed according to data from medical records with pertinent treatments collected from January 1997 to September 2004 at the Specialized Physiotherapy Center. Age average was 2.7 years of life. It is statistically impossible to precise results concerning only the immunosuppressed patients due to the lack of specific diagnosis. That is explained by the fact that recurrent XLA pneumonias may be attributed to the gastroesophageal reflux disease or to bronchial asthma. However, the improved results showed by the pulmonary function as preventive strategy were attributed to the respiratory physiotherapy, since intravenous immunoglobulin replacement therapies were not performed. Respiratory physiotherapy acts as a supportive factor in the healing process and occupies a fundamental role in the prophylaxis against recurrent respiratory clinical features, especially those of obstructive and secretionary characteristics.

  17. Inmunodeficiencias humorales: Un estudio en tres Centros de Inmunología Clínica de adultos en la Ciudad de Buenos Aires

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    Diego S. Fernández Romero

    2011-08-01

    Full Text Available Las inmunodeficiencias humorales (IDH comprenden a un grupo de enfermedades caracterizadas por la imposibilidad de desarrollar una respuesta inmune efectiva mediada por anticuerpos. Estos pacientes presentan infecciones, principalmente por bacterias extracelulares capsuladas, del tracto respiratorio. El objetivo de nuestro estudio fue describir las características clínicas de una población de 128 pacientes derivados con sospecha o diagnóstico de IDH a tres centros para inmunodeficiencias de adultos, asistidos entre junio de 2004 y diciembre de 2009. Tres (2.3% consultaron por infecciones recurrentes en una sola oportunidad sin datos suficientes para su adecuada clasificación y fueron excluidos del estudio. De los 125 pacientes restantes, en 21 (16.8% se descartó IDH, en 8 (6.4% se diagnosticó inmunodeficiencia humoral secundaria (IDHS y en 96 (76.8% inmunodeficiencia humoral primaria (IDHP. Las causas de IDHS fueron: en un caso enfermedad renal, en uno uso de fenitoína, dos casos: gammapatía monoclonal y en 4 linfoma B. Las causas de las 96 IDHP fueron: 57 inmunodeficiencia común variable, 12 agammaglobulinemia ligada al cromosoma X, 10 deficiencia selectiva de IgA, 7 deficiencia de IgG1, 3 síndrome hiper-IgM, 3 deficiencia de IgM, 2 síndrome linfoproliferativo ligado al cromosoma X, un síndrome de Good y una deficiencia funcional de anticuerpos. Sesenta y siete pacientes estaban en seguimiento en el momento de la finalización del estudio, 25 de ellos estaban en seguimiento al iniciarse el estudio. De los 58 pacientes en seguimiento con indicación de tratamiento sustitutivo con gammaglobulina, 54 se encontraban en tratamiento al finalizar el estudio. En cuatro pacientes no se pudo confirmar el diagnóstico de IDHP.

  18. Btk29A-mediated tyrosine phosphorylation of armadillo/β-catenin promotes ring canal growth in Drosophila oogenesis.

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    Noriko Hamada-Kawaguchi

    Full Text Available Drosophila Btk29A is the ortholog of mammalian Btk, a Tec family nonreceptor tyrosine kinase whose deficit causes X-linked agammaglobulinemia in humans. The Btk29AficP mutation induces multiple abnormalities in oogenesis, including the growth arrest of ring canals, large intercellular bridges that allow the flow of cytoplasm carrying maternal products essential for embryonic development from the nurse cells to the oocyte during oogenesis. In this study, inactivation of Parcas, a negative regulator of Btk29A, was found to promote Btk29A accumulation on ring canals with a concomitant increase in the ring canal diameter, counteracting the Btk29AficP mutation. This mutation markedly reduced the accumulation of phosphotyrosine on ring canals and in the regions of cell-cell contact, where adhesion-supporting proteins such as DE-cadherin and β-catenin ortholog Armadillo (Arm are located. Our previous in vitro and in vivo analyses revealed that Btk29A directly phosphorylates Arm, leading to its release from DE-cadherin. In the present experiments, immunohistological analysis revealed that phosphorylation at tyrosine 150 (Y150 and Y667 of Arm was diminished in Btk29AficP mutant ring canals. Overexpression of an Arm mutant with unphosphorylatable Y150 inhibited ring canal growth. Thus Btk29A-induced Y150 phosphorylation is necessary for the normal growth of ring canals. We suggest that the dissociation of tyrosine-phosphorylated Arm from DE-cadherin allows dynamic actin to reorganize, leading to ring canal expansion and cell shape changes during the course of oogenesis.

  19. A conditional form of Bruton's tyrosine kinase is sufficient to activate multiple downstream signaling pathways via PLC Gamma 2 in B cells

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    Witte Owen N

    2001-06-01

    Full Text Available Abstract Background Bruton's tyrosine kinase (Btk is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-γ2 (PLCγ2 and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCγ2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCγ2-deficient DT40 B cell line. Results Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCγ2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCγ2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK and c-Jun NH2-terminal kinase (JNK mitogen-activated protein kinase (MAPK pathways, and apoptosis. In DT40 B cells deficient for PLCγ2, Btk:ER activation failed to induce the signaling events described above with the consequence that the cells failed to undergo apoptosis. Conclusions These data suggest that Btk:ER regulates downstream signaling pathways primarily via PLCγ2 in B cells. While it is not known whether activated Btk:ER precisely mimics activated Btk, this conditional system will likely facilitate the dissection of the role of Btk and its family members in a variety of biological processes in many different cell types.

  20. Oral and Dental Health Status in Patients with Primary Antibody Deficiencies

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    Ghasem Meighani

    2011-12-01

    Full Text Available Primary antibody deficiencies (PAD are a group of immune system disorders, associated with decreased levels of secretory and protective immunoglobulins. Because of the important role of immunoglobulins in the protection  of oral cavity, patients with PADs  are more susceptible to dental caries or oral manifestations.This study was performed  to investigate the oral and dental manifestations of PADs patients. In this study, 33 patients with PADs (21 common variable immunodeficiency, 8 X- linked agammaglobulinemia and 4 hyper IgM syndrome and 66 controls were examined; the number of decayed, missed and filled teeth (DMFT were investigated.Aphthous  was the most frequent manifestation in PADs patients (38.7%, which wassignificantly16.7% higher than  the  controls  (p=0.03. The  patients  with  PADs  showed significantly higher presentation of other oral and dental manifestations, including herpes sores, candidiasis tonsillitis, gingivitis, calculus, enamel hypoplasia and other ulcerations. The mean DMFT scores were 6.15±3.6 and 1.93±0.4 in PADs patients and controls, respectively (p<0.001. Although the patients with common variable immunodeficiency had higher means of DMFT in comparison with other groups of PADs, this difference was not statistically significant.This study showed significantly higher frequency of oral and dental manifestations in the patients with PADs  compared to controls. Therefore, regular examination of oral cavity could be suggested in this group of immunodeficient patients.

  1. Dynamic Allostery Mediated by a Conserved Tryptophan in the Tec Family Kinases.

    Directory of Open Access Journals (Sweden)

    Nikita Chopra

    2016-03-01

    Full Text Available Bruton's tyrosine kinase (Btk is a Tec family non-receptor tyrosine kinase that plays a critical role in immune signaling and is associated with the immunological disorder X-linked agammaglobulinemia (XLA. Our previous findings showed that the Tec kinases are allosterically activated by the adjacent N-terminal linker. A single tryptophan residue in the N-terminal 17-residue linker mediates allosteric activation, and its mutation to alanine leads to the complete loss of activity. Guided by hydrogen/deuterium exchange mass spectrometry results, we have employed Molecular Dynamics simulations, Principal Component Analysis, Community Analysis and measures of node centrality to understand the details of how a single tryptophan mediates allostery in Btk. A specific tryptophan side chain rotamer promotes the functional dynamic allostery by inducing coordinated motions that spread across the kinase domain. Either a shift in the rotamer population, or a loss of the tryptophan side chain by mutation, drastically changes the coordinated motions and dynamically isolates catalytically important regions of the kinase domain. This work also identifies a new set of residues in the Btk kinase domain with high node centrality values indicating their importance in transmission of dynamics essential for kinase activation. Structurally, these node residues appear in both lobes of the kinase domain. In the N-lobe, high centrality residues wrap around the ATP binding pocket connecting previously described Catalytic-spine residues. In the C-lobe, two high centrality node residues connect the base of the R- and C-spines on the αF-helix. We suggest that the bridging residues that connect the catalytic and regulatory architecture within the kinase domain may be a crucial element in transmitting information about regulatory spine assembly to the catalytic machinery of the catalytic spine and active site.

  2. The Effect of IVIG on Superoxide Generation in Primary Humoral Immunodeficiencies

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    Gulay Sezgin

    2016-01-01

    Full Text Available Primary antibody deficiency (common variable immunodeficiency, Hyper IgM, X-linked agammaglobulinemia and selective Ig A deficiency is a group of heterogeneous diseases characterized by defective antibody production. In primary hypogammaglobulinemias, particularly in patients with common variable immunodeficiency there is an increased generation of reactive oxygen species from monocytes which may be important for both immunopathogenesis and clinical manifestations. The generation of toxic oxygen metabolites may contribute to inflammation and tissue damage associated with phagocytic infiltration, and play role in the pathogenesis of malignancies, autoimmune disorders, acute and chronic pulmonary diseases seen in these patients. In primary immunodeficiencies and functional antibody deficiencies, IVIG act as replacement therapy and several mechanisms of IVIG action have been postulated. In vitro studies with human granulocytes showed stimulation of respiratory burst and promotion of bacterial killing by IVIG. In adult patients with primary humoral immunodeficiency, treated with IVIG showed that IVIG does not affect superoxide generation. We investigated superoxide generation from PMNL in 35 children with hyper IgM syndrome, XLA, CVID and IgA deficiency and 13 healthy children. We also explored the effect of IVIG administration on superoxide generation from granulocytes, white cell count, absolute neutrophil count, absolute lymphocyte count and quantitative CRP levels. There was a substantial increase in superoxide generation from PMNL in patients with XLA, CVID and IgA deficiency. Comparison of the superoxide generation before, 24 hours and one week after IVIG treatment showed no difference. In patients with CVID, quantitative CRP levels before and 24 hours after IVIG revealed significant difference. Other parameters were not changed. It can be concluded that enhanced superoxide generation in patients with XLA, CVID, Ig A deficiency may result from

  3. Construction of a YAC contig and STS map spanning 2.5 Mbp in Xq25, the critical region for the X-linked lymphoproliferative (XLP) gene

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    Lanyi, A.; Li, B.F.; Li, S. [Univ. of Nebraska Medical Center, Omaha, NE (United States)] [and others

    1994-09-01

    X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability in Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia or B-cell lymphoma. The XLP gene lies within a 10 cM region in Xq25 between DXS42 and DXS10. Initial chromosome studies revealed an interstitial, cytogenetically visible deletion in Xq25 in one XLP family (43-004). We estimated the size of the Xq25 deletion by dual laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mbp of DNA sequences. To further delineate the deletion we performed a series of pulsed field gel electrophoresis (PFGE) analyses which showed that DXS6 and DXS100, two Xq25-specific markers, are missing from 45-004 DNA. Five yeast artificial chromosomes (YACs) from a chromosome X specific YAC library containing sequences deleted in patient`s 43-004 DNA were isolated. These five YACs did not overlap, and their end fragments were used to screen the CEPH MegaYAC library. Seven YACs were isolated from the CEPH MegaYAC library. They could be arranged into a contig which spans between DXS6 and DXS100. The contig contains a minimum of 2.5 Mbp of human DNA. A total of 12 YAC end clone, lambda subclones and STS probes have been used to order clones within the contig. These reagents were also used in Southern blot and patients showed interstitial deletions in Xq25. The size of these deletions range between 0.5 and 2.5 Mbp. The shortest deletion probably represents the critical region for the XLP gene.

  4. Health-Related Quality of Life in Primary Immune Deficient Patients

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    "Habibeh Mozaffari

    2006-03-01

    Full Text Available The primary immunodeficiency (PI disorders are abnormalities in development and maturation of the immune system. Individuals with PI disease may experience frequent infections, which limit their abilities to exhibit physical and psychological well-being secondary to their illness. In this survey we compared health-related quality of life of primary immune deficient patients with healthy children. The case-control study was designed for patients with PI disease who were referred to Children Medical Center in 2004-2005. Demographic information was taken and Pediatric Quality Of Life (PEDQOL questionnaire were filled for 50 PI patients and 100 healthy children. The mean age in PI patients was 12.62± 3.65 (range from 8 to 18 years and in the control group was 11.04± 3.3 years. In PI patients 68% were male and 32% female .Most patients with PI disease had a diagnosis of common variable immunodeficiency (54% or X-linked agammaglobulinemia (24%. Patients with PI disease had great limitations in physical functioning and psychological well-being (p<0.001 and p<0.001 respectively compared with children without a chronic health condition. Patients had lower PEDQOL scores in all age groups compared with normal sample (p<0.001. Long duration of disease significantly correlated with low psychological score. (r = -3.23. P= 0.03 Children with PI disease experience poorer health related quality of life than healthy children, indicating more attention should be paid to early diagnosis and treatment of PI disease, as well as more attention to their social limitation. PI patients may need psychological consultation for better coping with their illness.

  5. Isolation of cosmid and cDNA clones in the region surrounding the BTK gene at Xq21.3-q22

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    Vorechovsky, I.; Zhou, J.N.; Hammarstroem, L. [Karolinska Institute, Huddinge (Sweden)] [and others

    1994-06-01

    A regional physical and transcription map involving yeast artificial chromosomes (YACs), cosmids, and cDNAs has been constructed for Xq21.3-q22 around the gene BTK (formerly atk or BPK) defective in X-linked agammaglobulinemia (XLA). With a positional cloning strategy employing direct cDNA selection, novel cDNAs were found to cluster in the region of approximately 100 kb flanking the XLA and {alpha}-galactosidase A loci. While these widely expressed transcripts are in the area known to contain CpG islands, a less evolutionarily conserved gene, located more than 130 kb distal of DXS178, maps to cosmid clones that could not be digested with rare-cutting restriction enzymes. The presence of transcribed sequences flanking the BTK allowed investigation of their involvement in complex XLA phenotypes. Southern blot analysis using cDNA clones isolated from this region permitted exclusion of a contiguous deletion syndrome as an underlying defect in three patients with XLA and associated growth hormone deficiency. A single XLA patient with torsion dystonia and cosegregating X-linked deafness has been found with a deletion in the 3{prime} part of BTK extending centromerically into the flanking expressed sequence DXS1274E. This suggests a possible involvement of the DXS1274E in this phenotype. The GenBank accession numbers for novel cDNA sequences are as follows: DXS1269E (L20773), DXS1271E (UO1923), DXS1273E (UO1925), and DXS1274E (UO1922). 51 refs., 4 figs., 1 tab.

  6. A Tth111I RFLP in intron 1 of the mouse Pgk-1 gene allows tracing of X chromosome inactivation

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    Shanmugan, V.; Saha, B.K. [Emory Univ. School of Medicine, Atlanta, GA (United States)

    1994-09-01

    The X-linked immunodeficiency (xid) in CBA/N mice serves as a model for the X-linked agammaglobulinemia (XLA) syndrome in humans. Like the XLA carriers, the female mice heterozygous for xid (X{sup xid}/X{sup W}) are asymptomatic. The pattern of X chromosome inactivation in the F1 heterozygotes [CBA/N (X{sup xid}/X{sup xid}) X CAST/Ei (X{sup W}/Y)] was investigated by monitoring the methylation status of the two Pgk-1 alleles. Methylation of a CpG dinucleotide in the 5{prime} region of the Pgk-1 gene was previously shown to absolutely correlate with the inactivation of the corresponding X chromosome. In order to distinguish the two alleles, the proximal end of intron 1 of the Pgk-1 gene from CBA/N and CAST/Ei was sequenced. Several nucleotide polymorphisms, including a Tth111I RFLP, were detected in close proximity of the critical CpG dinucleotide. This allowed us to devise an assay based on PCR-amplification of a target DNA encompassing the CpG site as well as the Tth111I site. Results indicate that in circulating B lymphocytes of the female heterozygote only the X-chromosome carrying the normal allele is active (non-random inactivation of the X chromosome) whereas in non-B cells both the X chromosomes are active (random inactivation of the X chromosome). These results were further confirmed by direct measurement of transcription of the two alleles (X{sup xid} and X{sup W}).

  7. Genomic organization of Bruton`s tyrosine kinase

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    Rohrer, J.; Conley, M.E. [Univ. of Tennessee, Memphis, TN (United States)

    1994-09-01

    Bruton`s tyrosine kinase (Btk), is a nonreceptor tyrosine kinase that has been identified as the defective gene in X-linked agammaglobulinemia (XLA). XLA patients have profound hypogammaglobulinemia and markedly reduced numbers of B cells while their T cell and phagocyte numbers remain normal. To determine the genomic organization of Btk, intron/exon borders were identified by sequencing cosmid DNA using cDNA primers. Nineteen exons spanning 37 kb of genomic DNA were identified. All the intron/exon splice junctions followed the GT/AG rule. The translational ATG start codon was in exon 2 which was 6 kb downstream of exon 1. Exon 19, 519 bp in length and 3.8 kb distal to exon 18, was the largest exon and included the 450 bp of the 3{prime} untranslated region. Exons 6 through 18 formed the largest cluster of exons with no intron being longer than 1550 bp. There was no apparent correlation between the exon boundaries of Btk and the functional domains of the protein or the exon boundaries of src, the nonreceptor protein tyrosine kinase prototype. The region 500 bp upstream of the presumed transcriptional start site was sequenced and found to have a G+C content of 52%. No TATA-type promoter elements in the -20 bp to -30 bp region were identified. However, at position -48 bp, a TGTGAA motif was found that bears some similarity to the TATA box. This sequence was preceded by a perfect inverted CCAAT box at position -90 bp. Three retinoic acid binding sites were also identified at positions -50 bp, -83 bp and -197 bp. Defining the genomic structure of Btk will permit us to identify regulatory elements in this gene and to identify mutations in genomic DNA of patients with XLA.

  8. CD4 T cell immunity is critical for the control of simian varicella virus infection in a nonhuman primate model of VZV infection.

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    Kristen Haberthur

    2011-11-01

    Full Text Available Primary infection with varicella zoster virus (VZV results in varicella (more commonly known as chickenpox after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles, a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax and herpes zoster (Zostavax are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have

  9. Clinical Use of Intravenous Immunoglobulin in Immunodeficient Patients

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    A Agha Mohammadi

    2000-05-01

    Full Text Available Intramuscular immunoglobulin products were first used for the prophylaxis of viral diseases, such as measles, infectious hepatitis and poliomyelitis. When the first patient with agammaglobulinemia was described by routine in 1952, it became apparent that immunoglobulin replacement therapy was the treatment of choice for this entity. The intramuscular injections remained the mode of administration for immunodeficiency patients for almost 20 years. In the late sixties it was realized that administration of higher doses of gamma globuline was clinically more effective than administering low doses. As serum levels of IgG within the normal range could not be achieved using products intended for intramuscular use, in the following decades a number of different preparations intended for intravenous use were manufactured and became available. General experience suggests that through (Preinfusion IgG levels should be maintained at 400-500 mg/dl to achieve satisfactory clinical status. The recommended dose for IVIG replacement in patients with antibody deficiency syndromes is a loading dose of 400-800 mg/kg and subsequent maintenance dose of 350-500 mg/kg every 3-4 weeks. Adverse reactions may be mild, moderate or severe. Mild adverse reactions (Headache, flushing, chills, low back pain, nausea are often associated with fast infusion rate, and respond rapidly to slowing the infusion. Moderate adverse reactions (Chest pain, wheezing, mild cyanosis, and severe adverse reactions (Bronchoconstriction, severe hypotension, collapse require the infusion to be discontinued. Antihistamines, hydrocortisone and adrenaline are used as treatment for such adverse reactions. Patients with antibody deficiency and complete absence of IgA, may develop anti-IgA after infusion of immunoglobulin containing IgA, and life-threatening anaphylaxis may occur. Such patients should receive an IgA-free preparation of immunoglobulin. To the present date on immunoglobulin preparation

  10. Solution structure of the human BTK SH3 domain complexed with a proline-rich peptide from p120cbl

    International Nuclear Information System (INIS)

    X-linked agammaglobulinemia (XLA), an inherited disease, is caused by mutations in the Bruton's tyrosine kinase (BTK). The absence of functional BTK leads to failure of B cell differentiation which incapacitates antibody production in XLA patients leading to, sometimes lethal, bacterial infections. Point mutation in the BTK gene that leads to deletion of C-terminal 14 aa residues of BTK SH3 domain was found in one patient family. To understand the role of BTK in B cell development, we have determined the solution structure of BTK SH3 domain complexed with a proline-rich peptide from the protein product of c-cbl protooncogene (p120cbl). Like other SH3 domains, BTK SH3 domain consists of five β-strands packed in two β-sheets forming a β-barrel-like structure. The rmsd calculated from the averaged coordinates for the BTK SH3 domain residues 218-271 and the p120cbl peptide residues 6-12 of the complex was 0.87 A (±0.16 A) for the backbone heavy atoms (N, C, and Cα) and 1.64 A (±0.16 A) for all heavy atoms. Based on chemical shift changes and inter-molecular NOEs, we have found that the residues located in the RT loop, n-Src loop and helix-like loop between β4 and β5 of BTK SH3 domain are involved in ligand binding. We have also determined that the proline-rich peptide from p120cbl binds to BTK SH3 domain in a class I orientation. These results correlate well with our earlier observation that the truncated BTK SH3 domain (deletion of β4, β5 and the helix-like loop) exhibits weaker affinity for the p120cbl peptide. It is likely that the truncated SH3 domain fails to present to the ligand the crucial residues in the correct context and hence the weaker binding. These results delineate the importance of the C-terminus in the binding of SH3 domains and also indicate that improper folding and the altered binding behavior of mutant BTK SH3 domain likely lead to XLA

  11. Solution structure of the human BTK SH3 domain complexed with a proline-rich peptide from p120cbl

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    Tzeng, S.-R.; Lou, Y.-C.; Pai, M.-T.; Jain, Moti L.; Cheng, J.-W. [National Tsing Hua University, Division of Structural Biology and Biomedical Science, Department of Life Science (China)

    2000-04-15

    X-linked agammaglobulinemia (XLA), an inherited disease, is caused by mutations in the Bruton's tyrosine kinase (BTK). The absence of functional BTK leads to failure of B cell differentiation which incapacitates antibody production in XLA patients leading to, sometimes lethal, bacterial infections. Point mutation in the BTK gene that leads to deletion of C-terminal 14 aa residues of BTK SH3 domain was found in one patient family. To understand the role of BTK in B cell development, we have determined the solution structure of BTK SH3 domain complexed with a proline-rich peptide from the protein product of c-cbl protooncogene (p120{sup cbl}). Like other SH3 domains, BTK SH3 domain consists of five {beta}-strands packed in two {beta}-sheets forming a {beta}-barrel-like structure. The rmsd calculated from the averaged coordinates for the BTK SH3 domain residues 218-271 and the p120{sup cbl} peptide residues 6-12 of the complex was 0.87 A ({+-}0.16 A) for the backbone heavy atoms (N, C, and C{sub {alpha}}) and 1.64 A ({+-}0.16 A) for all heavy atoms. Based on chemical shift changes and inter-molecular NOEs, we have found that the residues located in the RT loop, n-Src loop and helix-like loop between {beta}4 and {beta}5 of BTK SH3 domain are involved in ligand binding. We have also determined that the proline-rich peptide from p120{sup cbl} binds to BTK SH3 domain in a class I orientation. These results correlate well with our earlier observation that the truncated BTK SH3 domain (deletion of {beta}4, {beta}5 and the helix-like loop) exhibits weaker affinity for the p120{sup cbl} peptide. It is likely that the truncated SH3 domain fails to present to the ligand the crucial residues in the correct context and hence the weaker binding. These results delineate the importance of the C-terminus in the binding of SH3 domains and also indicate that improper folding and the altered binding behavior of mutant BTK SH3 domain likely lead to XLA.

  12. Differential evolutionary wiring of the tyrosine kinase Btk.

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    Hossain M Nawaz

    Full Text Available BACKGROUND: A central question within biology is how intracellular signaling pathways are maintained throughout evolution. Btk29A is considered to be the fly-homolog of the mammalian Bruton's tyrosine kinase (Btk, which is a non-receptor tyrosine-kinase of the Tec-family. In mammalian cells, there is a single transcript splice-form and the corresponding Btk-protein plays an important role for B-lymphocyte development with alterations within the human BTK gene causing the immunodeficiency disease X-linked agammaglobulinemia in man and a related disorder in mice. In contrast, the Drosophila Btk29A locus encodes two splice-variants, where the type 2-form is the more related to the mammalian Btk gene product displaying more than 80% homology. In Drosophila, Btk29A displays a dynamic pattern of expression through the embryonic to adult stages. Complete loss-of-function of both splice-forms is lethal, whereas selective absence of the type 2-form reduces the adult lifespan of the fly and causes developmental abnormalities in male genitalia. METHODOLOGY/PRINCIPAL FINDINGS: Out of 7004-7979 transcripts expressed in the four sample groups, 5587 (70-79% were found in all four tissues and strains. Here, we investigated the role of Btk29A type 2 on a transcriptomic level in larval CNS and adult heads. We used samples either selectively defective in Btk29A type 2 (Btk29A(ficP or revertant flies with restored Btk29A type 2-function (Btk29A(fic Exc1-16. The whole transcriptomic profile for the different sample groups revealed Gene Ontology patterns reflecting lifespan abnormalities in adult head neuronal tissue, but not in larvae. CONCLUSIONS: In the Btk29A type 2-deficient strains there was no significant overlap between transcriptomic alterations in adult heads and larvae neuronal tissue, respectively. Moreover, there was no significant overlap of the transcriptomic changes between flies and mammals, suggesting that the evolutionary conservation is confined

  13. Optimization of immunoglobulin substitution therapy by a stochastic immune response model.

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    Marc Thilo Figge

    Full Text Available BACKGROUND: The immune system is a complex adaptive system of cells and molecules that are interwoven in a highly organized communication network. Primary immune deficiencies are disorders in which essential parts of the immune system are absent or do not function according to plan. X-linked agammaglobulinemia is a B-lymphocyte maturation disorder in which the production of immunoglobulin is prohibited by a genetic defect. Patients have to be put on life-long immunoglobulin substitution therapy in order to prevent recurrent and persistent opportunistic infections. METHODOLOGY: We formulate an immune response model in terms of stochastic differential equations and perform a systematic analysis of empirical therapy protocols that differ in the treatment frequency. The model accounts for the immunoglobulin reduction by natural degradation and by antigenic consumption, as well as for the periodic immunoglobulin replenishment that gives rise to an inhomogeneous distribution of immunoglobulin specificities in the shape space. Results are obtained from computer simulations and from analytical calculations within the framework of the Fokker-Planck formalism, which enables us to derive closed expressions for undetermined model parameters such as the infection clearance rate. CONCLUSIONS: We find that the critical value of the clearance rate, below which a chronic infection develops, is strongly dependent on the strength of fluctuations in the administered immunoglobulin dose per treatment and is an increasing function of the treatment frequency. The comparative analysis of therapy protocols with regard to the treatment frequency yields quantitative predictions of therapeutic relevance, where the choice of the optimal treatment frequency reveals a conflict of competing interests: In order to diminish immunomodulatory effects and to make good economic sense, therapeutic immunoglobulin levels should be kept close to physiological levels, implying high

  14. Inmunodeficiencias humorales: Un estudio en tres Centros de Inmunología Clínica de adultos en la Ciudad de Buenos Aires Antibody deficiencies: A survey from three Clinical Immunology Centers for adults in Buenos Aires City

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    Diego S. Fernández Romero

    2011-08-01

    Full Text Available Las inmunodeficiencias humorales (IDH comprenden a un grupo de enfermedades caracterizadas por la imposibilidad de desarrollar una respuesta inmune efectiva mediada por anticuerpos. Estos pacientes presentan infecciones, principalmente por bacterias extracelulares capsuladas, del tracto respiratorio. El objetivo de nuestro estudio fue describir las características clínicas de una población de 128 pacientes derivados con sospecha o diagnóstico de IDH a tres centros para inmunodeficiencias de adultos, asistidos entre junio de 2004 y diciembre de 2009. Tres (2.3% consultaron por infecciones recurrentes en una sola oportunidad sin datos suficientes para su adecuada clasificación y fueron excluidos del estudio. De los 125 pacientes restantes, en 21 (16.8% se descartó IDH, en 8 (6.4% se diagnosticó inmunodeficiencia humoral secundaria (IDHS y en 96 (76.8% inmunodeficiencia humoral primaria (IDHP. Las causas de IDHS fueron: en un caso enfermedad renal, en uno uso de fenitoína, dos casos: gammapatía monoclonal y en 4 linfoma B. Las causas de las 96 IDHP fueron: 57 inmunodeficiencia común variable, 12 agammaglobulinemia ligada al cromosoma X, 10 deficiencia selectiva de IgA, 7 deficiencia de IgG1, 3 síndrome hiper-IgM, 3 deficiencia de IgM, 2 síndrome linfoproliferativo ligado al cromosoma X, un síndrome de Good y una deficiencia funcional de anticuerpos. Sesenta y siete pacientes estaban en seguimiento en el momento de la finalización del estudio, 25 de ellos estaban en seguimiento al iniciarse el estudio. De los 58 pacientes en seguimiento con indicación de tratamiento sustitutivo con gammaglobulina, 54 se encontraban en tratamiento al finalizar el estudio. En cuatro pacientes no se pudo confirmar el diagnóstico de IDHP.Antibody deficiency (AD comprises a group of diseases characterized by the inability to develop an effective antibody mediated immune response. These patients suffer mainly of encapsulated extracellular bacterial

  15. Clinical features of invasive pneumococcus with resistance to antimicrobial agents in Pediatric Intensive Care Unit%儿童重症监护室中侵袭性肺炎链球菌病的临床特点及耐药性分析

    Institute of Scientific and Technical Information of China (English)

    刘珺; 王荃; 曾健生; 李峥; 钱素云

    2012-01-01

    Objective To study the clinical features of invasive pneumococcus disease (IPD) with resistance to antimicrobial agents in children,and to improve the diagnosis and treatment of this disease.Methods The clinical data from 21 IPD patients younger than 13 years old were collected from January 2008 through December 2010 in Pediatric Intensive Care Unit in Beijing Children's Hospital for retrospective analysis. Specimens of blood,pleural effusion,cerebrospinal fluid and soft tissue aspirated were collected from these children,and 23 strains of streptococcus pneumonia (SP) were cultured,isolated and confirmed,and the antibiotics susceptibility to penicillin and other antibiotics of these strains were assayed.Results Among the 21 IPD children,the ratio of male to female was 0.9∶1,and the age was 5 months to 13 years,with 61.9% of them under 2 years.Of them,12 patients (57.1% ) had purulent pleurisy,and 1 (4.8% )patient had an underlying disease diagnosed to be X - linked agammaglobulinemia (XLA).There was no seasonal difference in the occurrence rate of this disease. Eight (38.1%) patients were cured,11(52.4% ) were improved,while 2 (9.5% ) patients not improved without death.There was no statistically significant difference in the annual detection rate of invasive SP (x2 =3.711,P =0.156).The incidences of penicillin-intermediate susceptibility SP (PISP) and penicillin-resistant SP (PRSP) were 47.8% and 26.1% respectively.The rate of resistance to multiple antibiotics was 91.3%.Conclusions Children aged less than 5 years,especially younger than 2 years,are prone to IPD,and purulent pleurisy and septicemia are often seen in this disease. Some patients had the underlying diseases.The complications included hemophagocytic syndrome,acute respiratory distress syndrome,septic shock,bronchial pleural fistula and so on.The multidrug resistance rate was 91.3%.It is important to put great emphasis on the monitoring antibiotics resistance to invasive