SEARCH · PubMed Health

Results for “Complement C4a”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 793 records · Page 44Linked to original sources

PubMed1990

DQw7 and the C4B null allele in rheumatoid arthritis and Felty's syndrome.

DQ beta and C4 null alleles have been defined in patients with rheumatoid arthritis, Felty's syndrome, and in control subjects. Comparison of DR4 positive subjects shows that rheumatoid disease without extra-articular features has no preferential associations with either DQ beta or C4 null variants. In Felty's syndrome there are significant associations with both the class II major histocompatibility complex (MHC) DQw7 allele (86% of DR4 positive patients with Felty's syndrome and 53% of DR4 positive controls) and the class III MHC C4B null allele (50% of patients with Felty's syndrome and 20% of DR4 positive controls). DQw7 and the C4B null allele are in linkage disequilibrium and the B44-Bf *S-C4A*3-C4B*Q0-DR4-DQw7 haplotype accounts for five of 24 DR4 positive haplotypes assigned in subjects with Felty's syndrome. The results were not accounted for by articular disease severity and suggest that articular and extra-articular forms of rheumatoid disease may be immunogenetically heterogeneous.

Alleles↗

PubMed1985

C4 uremic variant: an acquired C4 allotype.

The major histocompatibility complex (MHC)-linked complotype region includes alleles for B, C2, and C4 loci. These loci are closely linked to each other and to HLA-DR on chromosome 6. The duplicated C4 loci, C4A and B, are especially polymorphic. In seven patients with renal insufficiency, we observed a C4 variant with electrophoretic mobility between C4B2 and C4B3. Four of these patients were detected during a study of MHC markers in membranoproliferative glomerulonephritis. Complete complotype and HLA data from families of five of the seven patients demonstrated that the variant was not inherited. The pattern was revealed by immunofixation electrophoresis and also by C4-specific hemolytic overlay. In serial plasma specimens taken from one patient, the C4 variant appeared only after the patient became uremic. However, the variant could not be produced in normal plasma after incubation with C4-depleted uremic plasma. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions of immunoprecipitated C4 from these patients showed C4A and C4B alpha chains of normal molecular mass; incompletely processed forms of C4 were not observed. We believe that this variant is probably acquired in the presence of uremia and may represent the C4B2.9 allele found by Wank and co-workers in many patients with glomerulonephritis. Family studies are mandatory to distinguish genetic variants from acquired alterations in the C4 phenotype.

Alleles↗

PubMed1995

Familial anticardiolipin antibodies and C4 deficiency genotypes that coexist with MHC DQB1 risk factors.

OBJECTIVE: To investigate the familial basis of antiphospholipid antibodies by studying putative risk factors at the C4 and MHC class II loci. METHODS: Autoimmune diseases, anticardiolipin (aCL) and other autoantibodies were studied in 38 first and 2nd degree family members of 3 index cases selected for primary antiphospholipid syndrome (APS) and 33 controls. C4 protein phenotyping and restriction fragment length polymorphism analysis of C4 and MHC class II loci were performed. RESULTS: Nineteen family members (46%) had autoimmune diseases or autoantibodies; aCL were present in 10 family members, 4 of whom had primary APS. Each family had 2 or more subjects with aCL. Among 22 independent haplotypes in family members, there was a high frequency of C4A and C4B deficiency alleles (0.41 vs 0.18 in 66 controls, p = 0.03) and a strong trend toward an increase in MHC DQB1 putative risk factors that share the TRAELDT structural domain. This DQB1 structural domain was present in 4/5 different haplotypes that contained a C4B deficiency genotype; however, neither of 2 different haplotypes with a C4A deletion (one being a common ancestral haplotype) contained this DQB1 putative risk factor. Among the 10 family members who had aCL, 10/20 haplotypes contained a C4 deficiency genotype; moreover, the DQB1 putative risk factor was present in all 16 MHC haplotypes that did not contain a C4A deletion. CONCLUSION: In these families, expression of an autoimmunity trait as aCL antibody appears to be associated with the coexistence of C4 deficiency alleles with DQB1 alleles that contain the TRAELDT structural domain.

Adolescent↗

PubMed1991

Immunogenetic heterogeneity in rheumatoid disease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets.

Genetic variants at DRB1 (Dw subtypes), DQB, and C4 loci were compared in rheumatoid disease subjects with or without the extra-articular feature of Felty's syndrome or major vasculitis. DR4 positive subjects with rheumatoid arthritis alone showed no preferential associations with DQB or Dw variants or with C4 null alleles. Felty's subjects showed associations with the DQB encoded DQw7 allele and with the C4B null allele but no preferential associations with any Dw subtype of DR4. By contrast DR4 +ve rheumatoid-vasculitic subjects showed associations with the Dw14 as well as with DQw7 and the C4A null allele. These different MHC associations in different clinical disease subsets show that rheumatoid disease is immunogenetically heterogeneous and suggest that MHC genes outside the DRB1 locus may also influence susceptibility or modify expression of the rheumatoid disease process.

Alleles↗

PubMed1998

Systemic lupus erythematosus in three ethnic groups: I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset. LUMINA Study Group. Lupus in minority populations, nature versus nurture.

OBJECTIVE: To study the relative impact of immunogenetic versus socioeconomic factors on systemic lupus erythematosus (SLE) at disease onset/presentation. METHODS: Medical records regarding SLE onset/ presentation were abstracted on 229 SLE patients who were enrolled in a prospective lupus outcome study. Patients were grouped in equivalent proportions of Caucasians, African Americans, and Hispanics. HLA-DRB1, DQA1, and DQB1 oligotyping, as well as C4 and CR1 allotyping, were carried out by standard methods. In addition to these genetic factors, data on ethnicity, age at SLE onset, monthly income, level of education, and home ownership were entered into stepwise logistic or stepwise multiple linear regression models as independent variables, and each specific clinical feature (neurologic, renal, and cardiovascular disease due to SLE), as well as the total Systemic Lupus Activity Measure (SLAM) score and physician's global assessment of disease activity at disease onset, were entered as dependent variables. RESULTS: HLA-DRB1*0301 (DR3), DRB1*1503 (DR2), and DRB1*08 (DR8) alleles were more frequently found in Caucasians, African Americans, and Hispanics, respectively. Hispanics were more likely to have cardiac and renal disease, as well as a higher physician's global assessment of disease activity. African Americans were more likely to have neurologic disease, renal disease, and a higher SLAM score. Those with less education had a higher SLAM score. Patients with HLA-DRB1*01 had less renal disease and a lower SLAM score. Those with C4A*3 alleles had a higher SLAM score and a higher physician's global assessment of disease activity. CONCLUSION: Both genetic and socioeconomic determinants, as well as other factors associated with Hispanic and African-American ethnicity, affect the presentation of SLE.

Adolescent↗

PubMed1984

Partial C4 deficiency in subacute sclerosing panencephalitis.

In an immunogenetic study, 23 subacute sclerosing panencephalitis (SSPE) patients and their families were studied for the HLA region markers HLA-A, B, C, DR, BF, C2, C4A, C4B, GLO I, and PGM3. In addition, C3, C4, and factor B serum levels were determined. A highly significant association of C4A QO with SSPE was found. Furthermore, two rare haplotypes, C4A QOB QO, two C4ACh+ allotypes, and four Ch partial inhibitors were detected, which possibly impair the function of the C4 molecules. HLA-DR5 was increased. In addition, a number of rare HLA-A, C, B, DR haplotypes were observed. It is postulated that rare C4 molecular deficiency might be a predisposing factor in the pathogenesis of SSPE.

Complement C4↗

PubMed1991

DNA analysis in a MHC heterozygous patient with complete C4 deficiency--homozygosity for C4 gene deletion and C4 pseudogene.

Virtually all cases of inherited C4 deficiency appear to be caused by homozygosity for rare MHC haplotypes carrying combined defects of genes coding for the C4A and C4B isotypes. The present analysis concerned a C4-deficient patient with two different MHC haplotypes, [HLA-A2, B40, SC00, DR6] and [HLA-A30, B18, F1C00, DR3]. Digestion of genomic DNA from the patient with Taq I and probing with a 5' cDNA C4 probe and a CYP21-specific probe gave only a 7.0-kb and a 3.7-kb band, respectively. The analysis of restriction fragment length polymorphism in family members showed that both C4-deficient haplotypes contained a C4 pseudogene at the C4 locus I and a CYP21 gene together with a deletion of the C4B gene and the adjacent CYP21P gene. None of the C4 pseudogenes contained C4A- or C4B-specific nucleotide sequences as judged from hybridization studies of polymerase chain reaction products. The findings illustrate the high degree of polymorphism in C4 genes and that both gene deletions and presence of a C4 pseudogene are common as reasons for C4 null alleles. The rare C4 double null alleles appear to have arisen in different MHC haplotypes independently.

Adolescent↗

PubMed1983

Potentiation of the anaphylatoxins in vivo using an inhibitor of serum carboxypeptidase N (SCPN). I. Lethality and pathologic effects on pulmonary tissue.

Carboxypeptidase N (EC 3.4.12.7) (SCPN) is a plasma enzyme that efficiently inactivates the anaphylatoxins C3a and C4a and significantly reduces C5a spasmogenic activity by removing the C-terminal arginyl residue from each of these factors. The arginine analog DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (SCPN-INH) is a potent competitive inhibitor of SCPN with a Ki for this carboxypeptidase in serum of 2 x 10(-9) M. Therefore, we have used the SCPN inhibitor to potentiate biologic activity of the anaphylatoxins in vivo. Infusion via the carotid artery of about 40 mg of SCPN-INH into each of 8 adult guinea pigs inactivated the SCPN for at least 3 hours and caused no measurable toxic effects. When cobra venom factor (CVF) is infused into guinea pigs, it activates the alternative pathway of complement, thereby generating the anaphylatoxins C3a and C5a. Ordinarily, infusion of CVF is nonlethal, because the generated anaphylatoxins are rapidly converted to C3a des Arg and C5a des Arg by SCPN. However, CVF (200 micrograms) plus SCPN-INH delivered intravenously in 5 animals induced a lethal reaction in less than 5 minutes. The authors conclude that the lethal effect is due largely to the anaphylatoxins. Histologic sections of the lungs from treated animals show dramatic structural changes consistent with peripheral small airway constriction, bronchial constriction, and vasoconstriction of small muscular arteries. Also, cell aggregates are present in blood vessels. Other histologic changes include severe congestion, pulmonary edema, and an interstitial infiltrate of mononuclear cells. Large doses of chlorpheniramine prevent this lethal reaction. Lethality is apparently attributable to asphyxia and is dependent on the level of CVF administered: eg, 100 micrograms CVF was not lethal in 4 animals given SCPN inhibitor, although signs of respiratory distress were observed. On histologic examination of lungs from guinea pigs given CVF and SCPN-INH, the features are similar to those described when anaphylatoxins are instilled into guinea pig lungs. Intravenous application of purified C3a plus SCPN-INH also proved lethal in 3 of the 6 animals challenged. This is the first evidence that the C3a anaphylatoxin can elicit a lethal response.

Anaphylatoxins↗

PubMed1985

Immunofixation for C2 typing: C2 allotypes in Spaniards in relation to HLA, Bf and C4.

C2 typing is performed by immunofixation with anti-C2 antiserum instead of by a hemolytic overlay. This method gives sharp band definition, is less cumbersome than the hemolytic overlay, gel files are easily made, and it also enables one to describe putative new nonhemolytic variants. C2 allele frequencies were studied in a sample of the normal Spanish population and were found to be similar to other Caucasoids. HLA-Bw62,-Cw3, and -DR4 were significantly associated with C2 B. Concordantly, the only C2*B extended HLA haplotype found in family material was Bw62-Cw3-Bw6-(DR4)-Bf*S-C2*B-C4A*3 B*2-(GLO*1). C4A*4 B*2 and C4A*4 B*4 are not found within the same haplotype together with C2*B and Bw62 or Bw22 respectively, nor do other C2*B haplotypes occur with common HLA-B alleles. These results may favour the hypothesis that the Bw62-C2*B haplotype is produced by one mutation arising in the Bw62-C2*C haplotype and that subsequent crossovers can explain other C2*B haplotypes (including Bw22-C2*B).

Alleles↗

PubMed1988

Major histocompatibility complex genes in systemic lupus erythematosus, Sjögren's syndrome, and polymyositis.

Current concepts about the roles of human leukocyte antigen (HLA) and complement genes in predisposing to connective tissue diseases are reviewed. Precise localization of disease conferring alleles and epitopes is confounded by two major phenomena: (1) clinical and serologic heterogeneity of the diseases and associations of several different HLA alleles with different and often overlapping autoantibody responses; and (2) linkage disequilibrium of many potentially relevant gene loci located on the disease-associated HLA haplotypes. Using molecular genetic tools in serologically homogeneous patient populations, and across racial lines, the Ro (SS-A) and la (SS-B) autoantibody responses in systemic lupus erythematosus and Sjögren's syndrome appear to associate most strongly with HLA-DQ alleles, whereas the anti-Jo-1 autoantibody in myositis correlates best with HLA-DRw52. A gene deletion of C4A within HLA predisposes to systemic lupus erythematosus in both white and black patients.

Alleles↗

PubMed1990

C3, BF and C4 polymorphisms in Tunisians.

The C3, BF, C4A and C4B polymorphisms were studied in a Tunisian population sample. The allelic frequencies for C3 were S = 0.844 and F = 0.148, and for BF, S = 0.535, F = 0.331, SO7 = 0.075 and F1 = 0.041. The most frequent C4 alleles were A3 and B1 followed in a decreasing order by A2, B2 and the A and B null alleles. The results indicate that the Tunisian population is intermediate between the Caucasian and Arab populations with some trace admixture of African Blacks.

Complement C3↗

PubMed1990

Molecular analysis of the IGHA and MHC class III region genes in one family with IgA and C4 deficiencies.

We report molecular studies in 2 IgA-deficient persons. One of them had an unusual association with an acute lymphoblastic leukaemia; his sister was also IgA deficient and shared an HLA haplotype and a complotype known to be associated to IgA deficiencies. The 2 IgA-deficient siblings also had low C4 serum levels due to C4A*Q0 allele. We showed that both defects were transmitted independently in the family. Molecular analysis revealed no major structural defects of the IGHA coding and switch regions, whereas a broad C4A-21-OHA deletion was responsible for the C4A*Q0 phenotype. These results confirm previous data showing that IgA deficiencies seem to be, in most cases, a regulatory defect rather than a structural defect of the coding IGHA region itself. These data were further supported by another molecular study in a patient with a recurrent Landry-Guillain-Barre syndrome who showed total absence of serum IgA and sIgA+B cells with no major structural defect of the IGHA region.

Adolescent↗

PubMed1995

Sharing of MHC haplotypes among patients with systemic lupus erythematosus from unrelated Caucasian multicase families: disease association with the extended haplotype [HLA-B8, SC01, DR17].

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease often clustered in families. We investigated the association between MHC haplotypes and SLE in multicase Caucasian families. METHODS: Ten consecutive families with 2 or more patients with SLE, in total 27 patients among 66 individuals, were studied. MHC haplotypes were determined by typing for HLA-A, B, C, DR, and DQ by serological and DNA methods. Complotypes were determined by protein typing and C4 gene polymorphism by DNA analysis. RESULTS: Fifty-four independent MHC haplotypes were found. Ten of the 31 haplotypes in the patients with SLE were examples of the extended haplotype [HLA-B8,SC01,DR17]. Six of these were found in 2 or more patients with SLE within the same family. All the 14 SLE sib-pairs in the families shared at least one haplotype and in 9 of the sib-pairs the shared haplotype was [HLA-B8,SCO1,DR17]. Three SLE associated haplotypes were [HLA-B7,SC31,DR15]. Four of the 27 patients with SLE were C4A deficient. Two C2 deficient siblings were homozygous for the haplotype [HLA-B18,S042,DR15]. CONCLUSION: We demonstrate that a very limited number of MHC haplotypes are associated with familial SLE. The haplotype [HLA-B8,SCO1,DR17] was closely related with the disease. There was no evidence suggesting familial SLE constitutes a disease subset. Determination of MHC haplotypes in multicase families is of value for assessment of disease susceptibility.

Adult↗

PubMed1988

Major histocompatibility complex associations with systemic lupus erythematosus.

This study focused on clinical subsets within systemic lupus erythematosus (SLE) in order to identify more homogeneous patient groups in which to define disease susceptibility gene(s). Analysis of the major histocompatibility complex gene products and genes with major histocompatibility complex class II and class III locus-specific probes and oligonucleotide probes for selected human leukocyte antigen DQ-beta alleles showed significant increases of human leukocyte antigen DR2 and the rare DQ-beta allele DR2-DQw1.AZH in the lupus nephritis patients compared with lupus patients without renal disease (relative risk = 8.3). C4A null was detected in one third of all of the SLE patients. In two thirds of the C4A null patients this was due to a DR3-associated C4A gene deletion. The remaining third may have a regulatory defect and this was DR2-associated. DR4 was significantly decreased in the nephritis patients in comparison with the non-renal SLE patients (relative risk = 0.3). A novel DQ-beta gene has been sequenced from two SLE patients that has not been observed in the normal population. Potential implications of these findings are discussed.

Complement C2↗

PubMed2004

Identification of two new C4 alleles by DNA sequencing and evidence for a historical recombination of serologically defined C4A and C4B alleles.

Nucleotide polymorphisms of the C4 genes were investigated by direct sequencing of seven different homozygous typing cells from the 10IHW panels. Two novel sequences were identified within the C4d region of the C4 genes. Our sequencing analyses extend previous findings suggesting that a recombination hot spot is likely to have occurred between codon positions 1157 and 1186 within the C4d region. The classification of electrophoretically defined C4A and C4B alleles can be further subtyped by sequencing. Because the central major histocompatibility complex region that carries various copies of the C4 gene has been associated with a range of disorders; further analysis at the sequence level within the C4 locus may provide informative genetic markers for the investigation of disease-associated polymorphisms.

Alleles↗

PubMed1987

Serositis with autoimmune endocrinopathy: clinical and immunogenetic features.

Twenty patients with autoimmune endocrinopathies experienced 45 episodes of pleural and/or pericardial serositis. Seventeen of these patients were women and 15 had clinical or serologic evidence of 2 or more endocrinopathies. Idiopathic primary hypoadrenalism (10 cases), Graves' disease (8 cases), Hashimoto's disease (4 cases), atrophic thyroiditis with hypothyroidism (3 cases), idiopathic primary hypogonadism (3 cases), transient thyroiditides (2 cases), and type I diabetes mellitus (1 case) were diagnosed at a mean age of 24 years. Serositis recurred after asymptomatic intervals of months to years even in patients treated for endocrine dysfunction. Fourteen of 16 Caucasians had circulating immune complexes, including all 9 patients with a C4AQ0 (C4A null) phenotype and including all 12 patients with HLA antigens B8 and DR3, antigens associated with systemic lupus and with autoimmune endocrinopathies. Serositides associated with autoimmune endocrinopathies can occur with chest pain, fever, and exudative effusions in young Caucasian women with the HLA B8 DR3 C4AQ0 phenotype. These serositides may have a common pathophysiologic mechanism.

Adolescent↗

PubMed1983

Association of Sjögren's syndrome with C4 deficiency, defective reticuloendothelial function and circulating immune complexes.

A case of Sjögren's syndrome with the sicca complex is presented which was associated with persistently low or absent C4 levels, high levels of circulating immune complexes and abnormal reticuloendothelial clearance of damaged or IgG antibody sensitized autologous red blood cells (RBCs). Investigation of normal relatives of the patient revealed low C4 levels and abnormal reticuloendothelial clearance of damaged or sensitized RBCs. HLA, A, B, DR typing revealed a high incidence of the HLA B8, DR3 haplotype and of homozygous null alleles at the C4A locus in the family members. These results suggest that the C4 deficiency and the abnormal reticuloendothelial function in the patient was in part genetically determined and may have predisposed to the development of Sjögren's syndrome. These findings serve to emphasize the possible importance of abnormal macrophage function in the pathogenesis of Sjögren's syndrome and suggest that further investigation of these aspects may increase understanding of this disease.

Antigen-Antibody Complex↗

PubMed1988

Antigenic determinants of human C4, Rodgers and Chido.

The duplicated genes, C4A and C4B, are located within the major histocompatibility complex on chromosome 6 and each exhibits a high degree of polymorphism expressed as both electrophoretic and antigenic variation (Rg/Ch). Eight high-frequency antigens and one low-frequency antigen have been defined by immune human polyspecific antisera in haemagglutination inhibition assays. Close association exists between different C4 allotypes and the antigens they express. Normally, C4A expresses Rg and C4B has Ch but rare reverse associations exist. Nucleotide sequences of the C4d region from C4 allotypes of known antigenic status have demonstrated four polymorphic sites that correlate with the antigens, which, in a structural model, are seen to be conformational or sequential epitopes. The observed interrelationships of the antigens on C4 allotypes accommodated by the model suggest that the electrophoretic variation is located outside the C4d region. The molecular genetics of C4 are also considered as part of the polymorphism.

Amino Acid Sequence↗