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)

Cell-to-cell signal exchange during antigen presentation deeply influences the profile and extent of the immune response. Together with the TCR/MHC-mediated signal, accessory signals are provided to the T cell by the antigen-presenting cell (APC), through specific receptor-ligand interactions that represent indispensable costimulation for T-cell activation and survival. The main costimulatory pathways are the B7 family members and the CD40-CD154 receptor-ligand pair. B7-1 and B7-2 costimulate T-cells by binding to CD28. Their binding is prevented by the neoexpression of CTLA4, a CD28 homologue that can deliver a negative signal. Another CD28-like molecule, called ICOS (inducible costimulator), has been described and binds B7RP-1, a third member of the B7 family, but not B7-1 and B7-2. The CD40-CD154 interaction works as a two way costimulatory system by triggering activation signals to both T-cell and APCs. Its importance is highlighted by the discovery that mutations of the CD154 gene are responsible for a severe human immunodeficiency. Disruption of the natural costimulatory interaction was highly effective for prevention and treatment in several experimental models of autoimmune disease and transplant rejection. This review focuses on the most significant advances in understanding the physiopathological events involving costimulatory molecules, and their impact on renal diseases and transplantation.
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PMID:Lymphocyte costimulatory receptors in renal disease and transplantation. 1193 30

No genetic defect is known to cause common variable immunodeficiency (CVID), a heterogeneous human disorder leading to adult-onset panhypogammaglobulinemia. In a search for CVID candidate proteins, we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced. The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS-/- mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation.
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PMID:Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. 1257 56

The deepened knowledge of co-stimulatory mechanisms within the immunological synapse and the emerging biological principles governing B cell homeostasis provide a plethora of new possibilities to selectively block or enhance immune responses. These mechanisms are highly relevant to the development of new treatment modalities for autoimmune diseases. Here we review approaches to antagonise members of the CD28-B7 superfamily as well as the TNF receptor ligand superfamily members, BAFF and APRIL, and their corresponding receptors on B cells (BAFF-R, TACI and BCMA). The proof of principle that such manipulations have indeed profound consequences for the human immune response comes from genetically manipulated mouse models, and, more importantly, from human immunodeficiency syndromes. Thus, the recent discovery of deletions in the ICOS, BAFF-R and TACI genes leading to disturbances in late B cell differentiation and hypogammaglobulinaemia underline the potential impact of targeting these molecules for therapeutic strategies in autoimmune disorders.
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PMID:Molecules involved in T-B co-stimulation and B cell homeostasis: possible targets for an immunological intervention in autoimmunity. 1618 41

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Patients have recurrent bacterial infections and an increased risk of developing autoimmune diseases, lung damage, and selected cancers. Since 2003, four genes have been shown to be mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19. Heterozygous mutations in TNFRSF13B are also associated with CVID, whereas the other three genes are purely recessive. Recent genetic linkage studies have also identified possible loci for dominant CVID genes on chromosomes 4q, 5p and 16q. These findings markedly improved the genetic diagnosis of CVID and point towards new strategies for future genetic studies. In addition, some CVID genes might be relevant to more common diseases such as asthma and stroke.
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PMID:Deconstructing common variable immunodeficiency by genetic analysis. 1746 61

Common Variable Immunodeficiency (CVID) is the most prevalent human primary immunodeficiency requiring medical attention. Until recently the only known genetic defect specific to CVID was ICOS deficiency that accounts for about 1% of the patients analyzed. Mutations in the TNFR family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), which mediates isotype switching in B cells, were found to be present in 5% of patients with CVID. Mutations in TACI were also found in relatives of patients with CVID who suffered from IgA deficiency (IgAD) as well as in a patient with isolated IgAD. In the majority of patients described to date only one TACI allele is mutated, showing an autosomal dominant transmission of the disease. B cells from individuals with TACI mutations did not produce IgG and IgA in response to the TACI ligand, APRIL (a proliferation-inducing ligand), probably reflecting impaired isotype switching. These results suggest that TACI mutations can lead to CVID.
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PMID:TACI, isotype switching, CVID and IgAD. 1791 15

Common variable immunodeficiency (CVID) is a primary immunodeficiency that is characterized by low level of serum immunoglobulins and an increased susceptibility to infections. The patients show a variety of clinical, cellular, and immunological defects, may develop autoimmune disease, and are susceptible to malignancy. The recent identification of four genetic defects that result in the CVID phenotype demonstrates that the genetic basis of CVID is highly variable. The responsible gene products include, ICOS, TACI, BAFF-R, CD19. Insufficiency of each molecule disrupts B cell maturation, function and differentiation at a different stage. Despite the elucidation of responsible genes, the molecular mechanisms leading to the immune defects are still yet to be understood. In this paper, we overview the molecular basis of CVID, and will provide some data on how the defect leads to autoimmunity.
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PMID:Common variable immunodeficiency. 1831 Oct 38

A 43 year old female patient presented for recurrent bacterial lower respiratory infections. A research for immunodeficiency status revealed total hypogammaglobulinemia, reduced IgG1, IgG2, IgG3 subclass levels, and low number of B lymphocytes (CD19+). Common Variable Immunodeficiency (CVID) 11.2 category was diagnosed according to recent criteria of primary immunodeficiencies (PID). Further immunological study consisting of genetic polymorphism of genes relating to differentiation, activation and function of B cells (ICOS, BAFF receptor BCMA and TACI) was performed, which did not reveal any related mutations. T cell parameters and Th1/Th2 cytokine network did not show any disturbances. It is postulated that probable endstage B cell differentiation defects should be investigated. The patient receives IVIGs replacement thereafter and the rate and severity of infections have significantly improved.
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PMID:Genetic polymorphism study of regulatory B cell molecules and cellular immunity function in an adult patient with Common Variable Immunodeficiency. 1892 49

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14-18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.
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PMID:The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. 1902 May 30

The most prevalent primary immunodeficiency is common variable immunodeficiency (CVID). Mutations have been described in four genes, ICOS, CD19, BAFF-R and TNFRSF13B (encoding TACI), together associated with 10-15% of CVID cases. We investigated a family with CVID and identified the heterozygous C104R TNFRSF13B mutation in two of the three index-children with CVID, a mother with selective immunoglobulin A deficiency, a mother with recurrent infections and a healthy grandfather. Remarkably, we did not find the TNFRSF13B mutation in the third index-child with CVID, despite his hypogammaglobulinaemia and decreased response to unconjugated pneumococcal vaccine. This family illustrates that TNFRSF13B mutations induce disease susceptibility rather than cause disease directly. Apparently, other genetic or environmental factors, still to be identified, contributed to the development of CVID in this family. Consequently, TNFRSF13B mutations must be interpreted with caution in the clinical setting.
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PMID:TACI mutations and disease susceptibility in patients with common variable immunodeficiency. 1921 May 17

Sophisticated genetic tools have made possible the identification of the genes responsible for most well-described immunodeficiencies in the past 15 years. Mutations in Btk, components of the pre-B cell and B cell receptor (lambda5, Igalpha, Igbeta), or the scaffold protein BLNK account for approximately 90% of patients with defects in early B cell development. Hyper-IgM syndromes result from mutations in CD40 ligand, CD40, AID, or UNG in 70-80% of affected patients. Rare defects in ICOS or CD19 can result in a clinical picture that is consistent with common variable immunodeficiency, and as many as 10% of patients with this disorder have heterozygous amino acid substitutions in TACI. For all these disorders, there is considerable clinical heterogeneity in patients with the same mutation. Identifying the genetic and environmental factors that influence the clinical phenotype may enhance patient care and our understanding of normal B cell development.
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PMID:Primary B cell immunodeficiencies: comparisons and contrasts. 1930 39


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