Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5%) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.
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PMID:A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer. 2664 13

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by disturbed antibody production and a dysregulated immune system. Aside from recurrent infections, the most common complications of CVID are autoimmune complications, particularly autoimmune cytopenias. To date, type 1 diabetes mellitus (T1D) in combination with CVID has only been described as an unusual complication in several reports, but the true incidence of T1D with CVID remains unknown. We describe 2 patients with a combination of T1D and CVID with serious impairment of antibody production. We also provide a review of the available literature. T1D-specific insulin autoantibodies and autoantibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 were not detected in either of our patients at the time of diagnosis or during the course of the disease. In both cases, T1D manifestation and diagnosis preceded the discovery of CVID by several years. Following the diagnosis of immunodeficiency and the start of immunoglobulin substitution therapy, their clinical status improved, manifesting as a lower frequency of infections and improved T1D control, with decreased glycosylated hemoglobin A1c values. Based on these reported cases, we assume that T1D might be more frequent than previously reported in patients with CVID. To verify the actual incidence of T1D among CVID patients, we searched the European Society for Immunodeficiencies Registry database, and found 25 cases of T1D in 1,671 listed CVID patients, suggesting a higher occurrence of T1D among CVID patients than previously thought. Early diagnosis and treatment of immunodeficiency improve both the prognosis and the course of CVID, reduce the frequency and severity of infections and may contribute to better management of T1D.
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PMID:Negativity for Specific Autoantibodies in Patients with Type 1 Diabetes That Developed on a Background of Common Variable Immunodeficiency. 2679 63

Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.
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PMID:Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus. 2911 88