Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human B cell-negative severe combined immunodeficiency (B-SCID) is a primary immunodeficiency disease characterized by both T and B lymphocytopenia and agammaglobulinemia. Although lymphocytes of B-SCID patients express defective recombinase activity and rarely succeed in making Ag receptors, the molecular defect of the human B-SCID remains to be identified. To gain more insight into the human B-SCID defect and its effect on the Ab repertoire, we examined the Ig heavy (H) chain genes of the peripheral blood leaky B cells from three B-SCID patients. Although the number of B cells in their peripheral blood was very limited, we could obtain 41 productive VDJ recombinations from the 58 joints. The recombinations showed a grossly altered pattern characterized by short N nucleotides, short deleted nucleotides from 5' JH segments, immature JH and D segment utilization, absence of VDDJ recombination, and all but one JH segment equal to germline JH segments. Therefore, Ab repertoire of IgH chain gene in human B-SCID was limited because of restricted junctional and combinatorial diversity and few somatic mutations. Furthermore, unusually long P nucleotides were inserted in junctional sequences, which might indicate that resolution of hairpin is impaired in human B-SCID as in the murine SCID.
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PMID:Analysis of the CDR3 region of the rearranged IgH chain genes in patients with severe combined immunodeficiency and severe lymphopenia. 864 10

We report a 26 years old female with a common variable immunodeficiency diagnosed at the age of 21, with recurrent pulmonary and sinusal bacterial infections, that had a clinical and laboratory remission. At the moment of diagnosis, she had agammaglobulinemia in the protein electrophoresis, very low level of IgG and IgM and absence of IgA. Absolute counts of CD4(+) T lymphocytes were low and CD8(+) were normal. B lymphocyte count was normal. Five years later, a repeated study revealed normal levels of all these parameters, excepting IgA that continued to be undetectable. We propose that the remission could be due to a decrease in suppressor activity of T lymphocytes. There is no documented evidence of infectious factors or the use of immunological therapy that could have influenced the course of the disease.
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PMID:[Unexplained remission of common variable immunodeficiency: analysis of a clinical case]. 904 31

Seven to 22% of patients with agammaglobulinemia develop joint manifestations consisting of septic arthritis or aseptic arthritis of unclear pathogenesis. Intravenous gammaglobulin therapy seems effective on the latter condition but is burdensome and expensive. We report the case of a patient with common variable immunodeficiency and aseptic oligoarthritis in which minocycline therapy was effective in relieving the joint symptoms.
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PMID:Response to minocycline of arthritis associated with agammaglobulinemia. A case-report. 909 Jul 70

Over the past decade, a number of important advances have been made in the molecular characterization and the treatment of the primary immunodeficiency disorders. These advances include identification of the abnormal genes responsible for such syndromes as X-linked severe combined immune deficiency, several forms of autosomal severe combined immune deficiency, X-linked and autosomal agammaglobulinemia, Wiskott-Aldrich syndrome, and other primary immunodeficiency disorders. In the past year, the biologic functions of the abnormal gene products responsible for these syndromes have been better defined, and new molecular defects that lead to primary immunodeficiency disorders have also been reported. This better understanding of the molecular basis of the primary immunodeficiency disorders has led to improvement of established therapies, such as gene product replacement and stem cell transplants, and to new treatment strategies, such as gene therapy.
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PMID:The molecular basis and treatment of primary immunodeficiency disorders. 942 89

Epidemiological studies have shown wide geographical and racial variations in the prevalence and pattern of immunodeficiency diseases. As there is no national registry, very little is known of the prevalence and nature of humoral immunodeficiency in the Arabian peninsula. We report here for the first time the analysis of serum immunoglobulin (Ig) levels in 2000 consecutive patients (age, 1-80 years). They were seen over a period of 6 years and were referred to us from six district hospitals for suspected immunodeficiency, autoimmunity, allergy, or immunoglobulin dyscrasia. Forty-six were found to be immunodeficient, in whom at least one of the Ig class was low; 15 had secondary immunodeficiency. The remaining 31 cases, representing 1.5% of the population studied (giving a prevalence of 1550/100,000 hospital registered patients), were categorized into four primary humoral immunodeficiency groups: these included, in order of frequency, (i) selective IgA deficiency (45%; 700/100,000) (ii) common variable immunodeficiency (CVID) (29%; 450/100,000), (iii) agammaglobulinemia (16%; 250/100,000), and (iv) selective IgG deficiency (10%; 150/100,000). Compared with similar hospital-based surveys in the west the prevalence of humoral immunodeficiency seems to be higher in Arabs; this in part may be related to race and higher rate of consanguinity. Most patients with IgA deficiency had either infection, atopy or autoimmunity. Compared with some other races, agammaglobulinemia (X- and non-X-linked) seems to be more prevalent.
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PMID:Primary antibody deficiency in Arabs: first report from eastern Saudi Arabia. 979 29

Bruton's tyrosine kinase (Btk) plays crucial roles in B cell differentiation as well as mast cell activation through the high-affinity IgE receptor (FcepsilonRI). Defects in the btk gene lead to agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Mast cells from xid and btk null mice exhibit mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FcepsilonRI cross-linking. Recent studies demonstrated the role of Btk in a sustained increase in intracellular calcium concentrations in response to antigen receptor stimulation. Btk is also involved in the activation of stress-activated protein kinases, JNK/SAPK1/2, and thereby regulates c-Jun and other transcription factors that are important in cytokine gene activation. Regulation of the JNK/SAPK activation pathway by Btk may be related to the proapoptotic function of Btk in the programmed cell death in these hematopoietic cells.
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PMID:Functions of Bruton's tyrosine kinase in mast and B cells. 1008 May 29

Bruton's tyrosine kinase (Btk) is considered an essential signal transducer in B-cells. Mutational defects are associated with a severe immunodeficiency syndrome, X-chromosome linked agammaglobulinemia (XLA). Here we show by coimmunoprecipitation that a member of the protein kinase C (PKC) family, PKCmu, is constitutively associated with Btk. Neither antigen receptor (Ig) crosslinking nor stimulation of B-cells with phorbol ester or H(2)O(2) affected Btk/PKCmu interaction. GST precipitation analysis revealed association of the Btk pleckstrin/Tec homology domain with PKCmu. Transient overexpression of PKCmu deletion mutants as well as expression of selected PKCmu domains in 293T cells revealed that both the kinase domain and the regulatory C1 region are independently capable of binding to the Btk PH-TH domain. These data show the existence of a PKCmu/Btk complex in vivo and identify two PKCmu domains that participate in Btk interaction.
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PMID:Bruton's tyrosine kinase (Btk) associates with protein kinase C mu. 1056 98

Mutations in the Bruton's tyrosine kinase (BTK ) gene are responsible for X-linked Agammaglobulinemia (XLA), an immunodeficiency caused by a block in B cell differentiation. Non Isotopic RNAse Cleavage Assay (NIRCA), followed by sequencing was used to screen for BTK mutations in 11 Italian XLA patients. Nine novel mutations were identified: 6 missense (Y39S, L512P, L512Q, R544G, S578Y, E589K), one non-sense (Q260X), one frameshift (1599-1602del GCGC) and one in-frame insertion (2037-2038insTTTTAG), that represents the first case of premature stop codon introduction in the BTK coding frame. These data support the high molecular heterogeneity of BTK gene in XLA disease and provide new insight to the diagnosis and to the role of BTK domain in XLA and in B cell signal transduction and development. Hum Mutat 15:117, 2000.
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PMID:Identification of nine novel mutations in the Bruton's tyrosine kinase gene in X-linked agammaglobulinaemia patients. 1061 38

The Tec family is a recently emerging subfamily of non-receptor protein-tyrosine kinases (PTKs) represented by its first member, Tec. This family is composed of five members, namely Tec, Btk. Itk/Emt/Tsk, Bmx and Txk/Rlk. The most characteristic feature of this family is the presence of a pleckstrin homology (PH) domain in their protein structure. The PH domain is known to bind phosphoinositides; on this basis, Tec family PTKs may act as merge points of phosphotyrosine-mediated and phospholipid-mediated signaling systems. Many Tec family proteins are abundantly expressed in hematopoietic tissues, and are presumed to play important roles in the growth and differentiation processes of blood cells. Supporting this, mutations in the Btk gene cause X chromosome-linked agammaglobulinemia (XLA) in humans and X chromosome-linked immunodeficiency (Xid) in mice, indicating that Btk activity is indispensable for B-cell ontogeny. In addition, Tec family kinases have been shown to be involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein-coupled receptors and integrin molecules. Efforts are being made to identify molecules which interact with Tec kinases to transfer Tec-mediated signals in vivo. Candidates for such second messengers include PLC-gamma2, guanine nucleotide exchange factors for RhoA and TFII-I/BAP-135. This review summarizes current knowledge concerning the input and output factors affecting the Tec kinases.
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PMID:Tec family of protein-tyrosine kinases: an overview of their structure and function. 1064 81

Development of mammalian B-lineage cells is characterized by progression through a series of checkpoints defined primarily by rearrangement and expression of immunoglobulin genes. Progression through these checkpoints is also influenced by stromal cells in the microenvironment of the primary tissues wherein B-cell development occurs, ie, fetal liver and bone marrow and adult bone marrow. This review focuses on the developmental biology of human bone marrow B-lineage cells, including perturbations that contribute to the origin and evolution of B-lineage acute lymphoblastic leukemia and primary immunodeficiency diseases characterized by agammaglobulinemia. Recently described in vitro and in vivo models that support development and expansion of human B-lineage cells through multiple checkpoints provide new tools for identifying the bone marrow stromal cell-derived molecules necessary for survival and proliferation. Mutations in genes encoding subunits of the pre-B cell receptor and molecules involved in pre-B cell receptor signaling culminate in X-linked and non-X-linked agammaglobulinemia. A cardinal feature of these immunodeficiencies is an apparent apoptotic sensitivity of B-lineage cells at the pro-B to pre-B transition. On the other end of the spectrum is the apoptotic resistance that accompanies the development of B-lineage acute lymphoblastic leukemia, potentially a reflection of genetic abnormalities that subvert normal apoptotic programs. The triad of laboratory models that mimic the bone marrow microenvironment, immunodeficiency diseases with specific defects in B-cell development, and B-lineage acute lymphoblastic leukemia can now be integrated to deepen our understanding of human B-cell development.
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PMID:Fates of human B-cell precursors. 1089 25


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