Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

64 members of a large kindred with inherited deficiency of the seventh component of complement, C7, were studied for plasma levels of antigenetic and functional components of complement as well as for clinical manifestations of infections and autoimmune diseases. Thirty-six individuals showed a low level of C2, C7, C8, and/or C9, including null alleles for C4A and C4B. Two subjects had a complete C7 deficiency. One of them concomitantly presented a low C2 level and a C4BQ0 allele. HLA allotyping strongly suggested C2 depression associated with a C4BQ0 allele. The 2 individuals with total absence of C7 suffered from fulminant disseminated meningococcal infections. The partial depression of one or more complement components associated with apparent good health. These results may indicate that simultaneous partial depressions of up to four complement components do not lead to clinical manifestation of infectious and autoimmune disease.
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PMID:Clinical manifestations in humans of combined C7 and C4 deficiency associated with low levels of C2, C8, and C9. 205 10

Susceptibility to autoimmune disease is associated with null alleles at one of the two genetic loci encoding complement protein C4. These two genetic loci, C4A and C4B, are highly homologous in primary structure but encode proteins with different functional activities. Expression of C4A and C4B genes is regulated by IFN-gamma in human hepatoma cells and in murine fibroblasts transformed with the respective genes. In these cell lines, IFN-gamma has a significantly greater and longer-lasting effect on expression of C4A than that of C4B. In this study we examined synthesis and regulation of C4A and C4B in peripheral blood monocytes from normal, C4A-null, and C4B-null individuals. Synthesis of C4 in human peripheral blood monocytes decreases during time in culture. IFN-gamma mediates a concentration- and time-dependent increase in steady-state levels of C4 mRNA and a corresponding increase in synthesis of C4 in normal human monocytes. LPS decreases monocyte C4 expression and completely abrogates the effect of IFN-gamma on the expression of this gene. In contrast, LPS and IFN-gamma have a synergistic effect in upregulating expression of another class III MHC gene product, complement protein factor B. The effect of LPS on constitutive and IFN-gamma-regulated C4 synthesis is probably not mediated via release of endogenous monokines IL-1 beta, TNF-alpha, or IL-6. Synthesis of C4, and regulation of its synthesis by IFN-gamma and LPS, are similar in normal, C4A-, and C4B-null individuals. These results demonstrate the synthesis of C4 at extrahepatic sites and tissue-specific regulation of C4 gene expression.
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PMID:Counterregulatory effects of interferon-gamma and endotoxin on expression of the human C4 genes. 210 12

HLA typing for A, B, and C locus antigens was performed on 70 patients with ocular cicatricial pemphigoid (OCP) and on 1849 controls. Additionally, typing for DR and DQ antigens and for the complement proteins (C2, factor B, C4A, and C4B) was performed on 63 patients and on the same control population. A significantly higher incidence of the following antigens was found in the OCP patients when compared to the control population: DR4 (43% in patients compared to 18% in controls, p = 0.0001); DR5 (41% compared to 16%, p = 0.0001); DQw3 (57% compared to 31%, p = 0.0010); A2 (60% compared to 28%, p = 0.0001); B8 (24% compared to 13%, p = 0.0086); B35 (19% compared to 9%, p = 0.0097); and B49 (7% compared to 2%, p = 0.0052). The complement types SC01, SC30, SC32, SC41, and SC42 were also significantly increased in patients compared to controls. No significant differences were found based on ethnic background, involvement of multiple mucous membranes, history of glaucoma, or deposition of specific immunoreactants in conjunctival biopsy samples. These findings may provide further insights into the pathogenesis of OCP and may help to localize a susceptibility gene for this autoimmune disease.
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PMID:Association of HLA-DR4 with ocular cicatricial pemphigoid. 265 36

The recognition of the association between complete and partial complement (C) deficiencies and immune complex-mediated diseases is of clinical and etiopathologic interest. From studies of sera deficient in C1, C4, C2, or C3, the crucial role of these complement components in promoting the solubility and clearance of immune complexes has been elucidated. Moreover, partial C4 deficiency appears to be a common risk factor for the development of systemic lupus erythematosus, with complete C4A deficiency (C4A null) being present in 10 to 15 percent and heterozygous C4A deficiency present in 50 to 80 percent of patients with systemic lupus erythematosus. Most importantly, there is an obvious pathophysiologic relationship between the function of complement relative to immune complex processing and the disease that results from their deficiency. Systemic lupus erythematosus is characterized by excessive quantities of inappropriately deposited immune complexes. More subtle complement component and receptor deficiencies are likely to be predisposing factors for autoimmune disease. The complement deficiencies provide us with a unique opportunity to investigate the origin and development of immune complex excess syndromes.
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PMID:Complement deficiency. Predisposing factor to autoimmune syndromes. 320 7

Two genes, C4A and C4B, encoding the fourth component of the complement system are linked to the HLA complex. C4 defects or C4 'null' genes can predispose to an autoimmune disease, lupus erythematosus (LE). We have used Southern blotting techniques to analyse genomic DNA from 23 patients with LE and from healthy controls, to evaluate the molecular basis of the C4 null phenotypes. In addition to the high frequencies of C4 null phenotypes and HLA-B8. DR3 antigens, confirming earlier results, we observed that among the patients both the C4A and C4B null phenotypes mostly resulted from gene deletions. Among the controls only the C4A null phenotypes were predominantly the result of gene deletions. In all cases these C4 gene deletions also extended to a closely linked pseudogene, 21-hydroxylase A (21-OHA). Altogether, 52% of the patients and 26% of the controls carried a C4/21-OHA deletion.
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PMID:C4 null phenotypes among lupus erythematosus patients are predominantly the result of deletions covering C4 and closely linked 21-hydroxylase A genes. 326 Sep 57

In a study of 32 white patients with systemic lupus erythematosus from 28 families, 60 unique chromosome 6 haplotypes were defined. The MHC extended haplotype HLA-B8, -DR3, SC01, GL02 was strongly disease-associated (0.09 patients, 0.02 controls, RR = 4.5, C.I. = 1.6-12.4, P less than 0.05), while the corresponding haplotype with the GL01 specificity was not increased in frequency (0.05 in both patients and controls). In the present data, the increase in the haplotype bearing GL02 accounted entirely for the association between HLA-DR3 and SLE. Furthermore, the phenotype of complete C4A deficiency was also strongly disease-associated (patients 0.14, controls 0.02, RR = 8.5, C.I. = 1.8-37.0, P less than 0.05). The only other MHC association in these patients was an increased occurrence of the HLA-B17, -DR7, SC61 haplotype (patients 0.07, controls 0.01, RR = 6.0, C.I. = 1.8-20.6, P corr. less than 0.05). The relationship between MHC markers and autoimmune disease appears to be a result of an association with MHC extended haplotypes and complete complement component deficiencies rather than with individual alleles. It is important that future studies include family members so that such haplotypes can be defined.
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PMID:Major histocompatibility complex extended haplotypes in systemic lupus erythematosus. 326 26

The fourth component of complement in humans is coded for by two closely linked loci, i.e., C4A and C4B, that have been positioned within the class III region of the human major histocompatibility complex along with the genes for C2, Bf, and steroid 21-OH. Both C4 loci are highly polymorphic and certain alleles, particularly the nulls, are associated with susceptibility to autoimmune disease. About one-half of the null alleles are due to a large deletion that includes both a C4 and flanking 21-OH gene. Despite the near identity of the products of the two loci, the proteins differ dramatically in their efficiency of covalent binding to antigen. The amino acid substitutions responsible for the functional differences have been identified and they are clustered relatively near the covalent binding site within the C4d region of the alpha chain. These observations support the hypothesis that the susceptibility to autoimmune disease is related to the structural variation of the C4 protein.
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PMID:Molecular genetics of the fourth component of human complement. 355 39

Genes coding for the complement proteins C2, C4A, C4B and factor B lie between HLA-D and HLA-B in HLA, the major histocompatibility complex in man. All the complement components are polymorphic, particularly C4, which has many alleles at each locus. The genetic complexity of C4 extends to the number of loci each of which may be deleted or duplicated on the chromosome. The different forms of C4 showed markedly different reactivities with small molecules and on haemolytic activity in the complement system. Surprisingly, amino acid sequences of the several allelic forms of C4 appear to be very similar, with less than 1% of residue positions being changed between alleles of C4A and C4B. These results may be relevant to the increased susceptibility to autoimmune disease which is associated with particular haplotypes of the HLA complex.
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PMID:The polymorphism of the complement genes in HLA. 387 5

The fourth component of complement (C4) in man, is coded for by two separate but closely linked loci (C4A and C4B) within the major histocompatibility region (MHC), on the short arm of chromosome 6. Like class I and II loci of this region, the C4 genes are highly polymorphic with more than 30 alleles, including null alleles, assigned to the two loci. This extensive polymorphism, based mainly on electrophoretic mobility, provides a useful marker for studies of disease susceptibility. Several disorders, including systemic lupus erythematosus and type I diabetes, show associations with C4 phenotypes. We have used the technique of Southern with a C4 specific probe to examine the genomic DNA of individuals typed for C4 by protein electrophoresis. We have identified 10.7 and 3.8 kilobase (kb) BglII restriction fragments in each of 9 unrelated individuals with a C4A6 allele, and in none of 22 unrelated individuals in whom this allele was not expressed. This clear correlation of restriction fragment length polymorphism with C4 phenotype provides a precise basis for analysis of C4 polymorphism. It is likely to be of value in clinical investigations of autoimmune disease.
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PMID:Correlation between a DNA restriction fragment length polymorphism and C4A6 protein. 631 64

The major autoantigens in Addison's disease have recently been shown to be members of the adrenal steroidogenic enzymes, such as 21OH. The genes encoding the 21OH enzyme are located in the class III segment of the MHC complex. Therefore, its identification as an autoantigen provides a novel link between MHC and susceptibility to this autoimmune disease. We have determined the MHC class II (DRB1, DQA1, DQB1, DPB1) and class III (TNF, HSP70, C4, 21OH) gene polymorphism in patients with Addison's disease. Also, we tested whether presence of autoantibodies against 21OH is associated with specific alleles in MHC. Our results show that patients with Addison's disease in association with APS2 or Addison's disease as an isolated form share highly similar MHC class II and class III alleles. A very strong association with HLA DRB1*0301, DQA1*0501, DQB1*0201, and DPB1*0101, as well as with the C4A + 21OHA gene deletion and TNFB*1 allele was observed. However, identical gene markers were observed also in controls matched for DRB1*0301, thus suggesting that the patient group did not carry MHC gene segments specific for Addison's disease. The presence of autoantibodies against 21OH was not found to be directly determined by the MHC alleles; rather it was associated with the clinical form of the disease.
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PMID:Major histocompatibility complex class II and III in Addison's disease. MHC alleles do not predict autoantibody specificity and 21-hydroxylase gene polymorphism has no independent role in disease susceptibility. 786 Mar 58


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