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PubMed1992

Neonatal lupus erythematosus syndrome: analysis of C4 allotypes and C4 genes in 18 families.

We examined 18 families with infants who had neonatal lupus erythematosus (NLE) syndrome to determine whether abnormalities in C4 phenotypes and genotypes were an additional risk factor for this syndrome. Fifteen of 18 mothers of infants with NLE (83%) had C4 null allotypes compared with 36% of population controls (p = less than .001). This increased frequency was due mainly to the presence of C4A null allotypes (11/18, 61%). C4 gene abnormalities, i.e., deletion or probable duplication, were present in 100% (16/16) of mothers of infants with NLE. The most common molecular genetic abnormality in mothers of infants with NLE in this study was deletion of C4A genes. Duplication of C4A and C4B loci was also commonly seen. Duplication of C4A genes was detected only in mothers of infants with complete congenital heart block (CCHB), and duplication of C4B was detected only in mothers of infants with dermatitis. No significant increase in C4A or C4B null allotypes or protein deficiencies was noted in mothers of infants with neonatal lupus when compared with anti-Ro(SS-A)-positive mothers delivered of clinically normal infants. Fathers of infants with NLE showed a trend toward increase in C4B null allotypes when compared with population controls (75%, 3/4, p = .06). The two infants with CCHB examined were C4B protein-deficient, in contrast to infants with lupus dermatitis, who had frequent C4B null allotypes but no C4B protein deficiency. C4B null allotypes were not seen in unaffected siblings of infants with NLE and in only 1 of 7 anti-Ro(SS-A)-positive mothers who delivered clinically normal infants. We conclude that inheritance of C4A null allotypes is not predictive of increased risk of neonatal lupus when present in anti-Ro(SS-A)-positive women. Examination of paternal and maternal C4 genes of additional infants with NLE, in particular those with CCHB, and of normal infants born to anti-Ro(SS-A)-positive mothers--and of the normal infants' parents--is required to determine if abnormal C4B genes are a critical factor rendering susceptibility to the NLE syndrome.

Antibodies, Antinuclear↗

PubMed1997

Cloning and functional characterization of the mouse C3a anaphylatoxin receptor gene.

The mouse anaphylatoxin C3a receptor (mC3aR) gene was isolated using a human C3aR cDNA probe. The genomic fragment contains an open reading frame of 1431 base pairs that encodes a peptide of 477 amino acids. A cDNA with identical sequence was subsequently obtained from the mouse pre-B cell line 70Z/3 by reverse transcriptase polymerase chain reaction based on sequence of the mC3aR gene. Northern blot analysis suggested expression of the mC3aR in lung and heart, and to a lesser extent, in brain, liver, muscle, kidney, and testis. The deduced amino acid sequence of the mouse C3aR is 65% identical to that of the human C3aR. Like the human receptor, mouse C3aR contains a predicted large extracellular loop of approximately 165 amino acids (residues 161-325) between the fourth and fifth transmembrane domains. This loop, however, is the least conserved structure (45% identical sequence) of all the extracellular and intracellular domains between the mouse and human C3aRs. The mouse gene product bound 125I-labeled human C3a with a Kd of 2.54 nM when expressed in the stably transfected rat basophilic leukemic cell line RBL-2H3. Bound C3a could be effectively displaced by excess quantities of unlabeled C3a, but not by C4a or C5a. C3a induced dose-dependent calcium mobilization in the transfected cells, which could be blocked by pertussis toxin treatment. These results confirm that the cloned gene encodes a functional C3aR capable of coupling to a pertussis toxin-sensitive G protein. The sequence divergence of the large extracellular loop does not appear to affect C3a binding and transmembrane signaling.

Amino Acid Sequence↗

PubMed1988

Human MHC class III (Bf, C2, C4) genes and GLO: their association with other HLA antigens and extended haplotypes in the Spanish population.

C4 allotype frequencies and their combination with factor B and C2 alleles (complotypes) were studied in a sample of the Spanish population in relation to MHC class I, class II and GLO alleles. The shorter genetic distances found for C4 between Spaniards and North Africans and the high frequency of extended HLA haplotypes (GLO 2) HLA-DR3 F1C30 HLA-B18 HLA-Cw5 (HLA-A30) and HLA-DR7 S1C21 HLA-Bw50 HLA-Cw6 are consistent with a paleo-North African ethnic origin (about 20,000 years B.C.) of a part of present Spaniards (Iberians), and with the effect of racial admixture during late Moslem invasions (from the 8th to the 15th century). The complotype null alleles C4A QO and C4B QO may be under natural selection pressure when found in cis position, since they are never in the same haplotype in families. The underestimation of these C4 null alleles' frequencies in unrelated individuals as compared to genotyped families is shown to be a very likely event and a serious hindrance for C4-disease association studies. We have not found any C4 duplications in the Spanish population; this may be due to sample size limitations or to the degree of admixture of our population. Strikingly, no positive linkage disequilibrium between C4A and C4B alleles is detected in unrelated individuals nor in families, although strong associations are maintained among Bf, C2, C4, HLA-A, HLA-B, HLA-C and HLA-DR markers. Assuming that all MHC polymorphisms have reached equilibrium, several explanations are proposed, including the possibility of no, different or additional natural selection mechanisms operating on some MHC class III genes (Bf, C2, C4 alleles combinations for most appropriate C3 convertases), as compared to those affecting class I and class II gene clusters (most advantageous immune response genes sets).

Alleles↗

PubMed1997

Major histocompatibility complex (MHC) class III genetics in two Amerindian tribes from southern Brazil: the Kaingang and the Guarani.

Population genetic studies of the major histocompatibility complex (MHC) class III region, comprising C2, BF and C4 phenotypes, and molecular genetic data are rarely available for populations other than Caucasoids. We have investigated three Amerindian populations from Southern Brazil: 131 Kaingang from Ivaí (KIV), 111 Kaingang (KRC) and 100 Guarani (GRC) from Rio das Cobras. Extended MHC haplotypes were derived after standard C2, BF, C4 phenotyping and restriction fragment length polymorphism (RFLP) analysis with TaqI, together with HLA data published previously by segregation analysis. C2 and BF frequencies corresponded to other Amerindian populations. C4B*Q0 frequency was high in the GRC (0.429) but low in the Kaingang. Unusual C4 alleles were found, viz. C4A*58, A*55 and C4B*22 (presumably non-Amerindian) and aberrant C4A*3 of Amerindian origin occurring with a frequency of 0.223 in the GRC. C4A*3 bands of homo- and heterozygous individuals carrying this variant were Rodgers 1 positive and Chido 1,3 positive, showed a C4A specific lysis type and a C4A like alpha-chain. Polymerase chain reaction studies and sequencing showed that this is based on a C4A*3 duplication with a regular C4A*3 and a partially converted C4A*0304 carrying the C4B specific epitopes Ch 6 and Ch 1,3. Associations of class III haplotypes with particular RFLP patterns were similar to those reported for Caucasoids. The previously described association between combined C4A and CYP21P deletions and the 6.4 kb TaqI fragment was not seen in these Amerindians. This fragment occurred within a regular two locus gene structure in the Kaingang, representing a "short" gene at C4 locus I. C4 and CYP21 duplications were frequently observed. The distribution of extended MHC haplotypes provides evidence for a close relationship between the KIV and KRC and a larger genetic distance between the two Kaingang groups and the GRC.

Brazil↗

PubMed1985

Oligosaccharide structure of human C4.

The oligosaccharide structure of human C4 was studied by using C4 purified from plasma and C4 secreted by human hepatoma-derived cell line, HepG2. The alpha- and beta-chains of human C4 are glycosylated, whereas the gamma-chain is devoid of carbohydrate. The alpha-chain has three complex fucosylated oligosaccharides of the biantennary type, one each on the alpha 2, alpha 3, and alpha 4 fragments. The beta-chain has a single high mannose oligosaccharide primarily of the Man9GlcNAc2 type. The approximately 2000 Mr difference between the alpha-chains of the two C4 gene products (C4A and C4B) was localized to the alpha 2 fragment and is not due to carbohydrate. Sulfation of the C4 alpha-chain was localized to the alpha 4 fragment of the alpha-chain. Hence, the Mr difference between the two gene products is likely to reside in amino acid differences. The oligosaccharide structure of three incompletely processed C4 molecules was also analyzed. These molecules have the oligosaccharide composition of the appropriate individual subunits. Therefore, intracellular proteolytic processing to the multi-chain form of C4 is not required for proper oligosaccharide processing.

Acetylglucosaminidase↗

PubMed1990

Marked shortage of C4B DNA polymorphism among insulin-dependent diabetic patients.

TaqI, BamHI and HinddIII polymorphisms of the C4 genes were studied with a 500-bp C4 cDNA probe (pAT-A153) specific for the 5' end of the gene. The restriction patterns obtained were correlated with the C4A and C4B genotypes in 35 patients suffering from insulin-dependent diabetes mellitus (IDDM), and results were compared to those from 40 healthy individuals. The controls, all Caucasian, were genotyped for HLA-A, B, C, DR, Bf, C2 and C4, together with 10 diabetics and their families; haplotypes for the other patients had been deduced using DNA and protein polymorphism, and taking into consideration linkage disequilibrium for neighbouring loci. No significant difference between genotypes at the C4A locus was seen in either population. The C4A gene deletion, associated with a C4B "short" gene (66.7%), was found mainly in the haplotype B8,Cw7,DR3,BfS,C2C, C4AQOB1, and the C4B gene deletion in the haplotype B18,Cw5,DR3,BfF1, C2C,C4A3BQO. When diabetic patients were compared with normal individuals, we observed, at the C4B locus, a decrease in the C4B "long" gene (22% vs. 49% respectively, p less than 0.001). A compensatory increase was observed in patients vs. controls for the frequency of C4BQO, both in the deleted and intact form (26% vs. 10% respectively, p less than 0.03).

Alleles↗

PubMed1989

An estimate on the frequency of duplicated haplotypes and silent alleles of human C4 protein polymorphism. I. Investigations in healthy Caucasoid families.

The frequency of duplicated and non-expressed C4 alleles was determined by segregation analysis in 31 German and five French families with altogether 274 individuals by submitting the complete data from C4 protein phenotyping, including C4 beta chains, and the other classical MHC markers to the family analysis programme (FAP). From 120 unrelated German haplotypes the following frequencies were derived for silent alleles: C4A*Q0 0.2000, C4B*Q0 0.2083, and for the total of homo- and heteroduplicated C4A resp. C4B alleles: C4"DA"* 0.1333, C4"DB"* 0.1000. The true occurrence of the duplicated C4A*2, "DB*21" haplotype, first observed in French families, was found to be 0.0250 in the German sample. While the frequency of duplicated C4 haplotypes confirms earlier estimates, the increase in the frequency of silent alleles corresponds to those assumed from investigations at the DNA level. The results demonstrate classical protein typing with inclusion of C4 beta chain types to be an indispensable and powerful tool for haplotype recognition; they support the hypothesis that deletion at one C4 locus is accompanied by duplication at the other in a majority of haplotypes.

Alleles↗

PubMed1990

Connective tissue disease in southeast Georgia. A community based study of immunogenetic markers and autoantibodies.

HLA antigens, C4 allotypes and T cell antigen receptor (TcR)beta DNA polymorphisms were determined in a community based study of connective tissue diseases (CTD). HLA-B8, DR3 and C4A null phenotypes occurred frequently in Caucasian patients with CTD, especially those with systemic lupus erythematosus (SLE), but were also more commonly found among healthy white controls of this southeast Georgia community. TcR beta gene polymorphisms also showed differential segregation patterns between patients with SLE and scleroderma. High frequencies of ANA and anti-ssDNA antibodies occurred among apparently healthy family members and local controls. Genetic factors predisposing to CTD in a community setting appear to be similar to those reported from referral centers.

Alleles↗

PubMed1990

C4 reference typing report.

Human C4 is most polymorphic at the protein level, distinction between allotypes of the C4A and C4B proteins resting on electrophoretic migration patterns and difference in hemolytic activity. The aim of the C4 reference typing has been the definition of reference variants, the assignment of rare variants, and the investigation of duplicated, deleted, or non-expressed and hybrid genes. Samples from 136 individuals, predominantly with known segregation, from 16 laboratories were investigated by standard electrophoretic techniques, for their relative hemolytic activity, reactivity with monoclonal antibodies and Rg/Ch reagents, alpha-, and beta-chain types, relative electrophoretic migration distance, as well as the C4/21-OH-TaqI RFLPs. The results were evaluated in three groups; they consisted in the definition of the eight most common C4 alleles, and the ten Rg/Ch standard phenotypes in group I. In group II twelve C4A and fourteen C4B duplications among 96 complotypes, as well as eighteen deleted/non-expressed C4A and twenty-two C4B alleles, and hybrid alleles were seen by correlation of lytic activity, electrophoretic mobility, and monoclonal and/or Rg/Ch reactivity. Group III consisted of the newly defined allotypes A 8, A 7, A 58, A 55, A 45, B 45, B 35, and B 22, furthermore of alleles subdividing the A 1/A 91, and the B 13/B 12/B 11 regions. The reference typing has allowed reclassification of the majority of described C4 allotypes and resulted in a revision of the C4 nomenclature.

Blood Grouping and Crossmatching↗

PubMed1995

Major histocompatibility complex class II and C4 alleles in Mexican Americans with systemic lupus erythematosus.

Few data exist on associations of class II and class III alleles of the major histocompatibility complex (MHC) and susceptibility to systemic lupus erythematosus (SLE) in Mexican Americans, a group of predominantly mixed Spanish and Native American ancestry. Therefore, MHC class II alleles (HLA-DRB1, DQA1, DQB1, DPA1 and DPB1 alleles) and C4 allotypes were determined in 52 Mexican American SLE patients and 105 ethnic-matched controls. HLA-DRB1*0301 and C4A*Q0 were each increased in the SLE patients, especially HLA-DRB1*0301 in those with anti-Ro/SSA autoantibodies. C4A*Q0 was associated with HLA-DRB1*0301 only in a minority of patients and controls. Anti-U1RNP antibodies were significantly associated with the presence of HLA-DQB1*0302, and the risk for the production of anti-Ro antibodies was heightened by the presence of at least three (out of four possible) DQA1 chains possessing a glutamine at position 34 and/or DQB1 chains a leucine at position 26 of their outermost domains. Thus the HLA class II and C4 null allele associations that have been noted in other ethnic groups are also found in Mexican Americans, suggesting shared susceptibility factors across ethnic lines in predisposition to SLE.

Alleles↗

PubMed2001

Evidence of a role for C4 in modulating interstitial inflammation in experimental glomerulonephritis.

Activation of C4 releases into the fluid phase a fragment of the alpha chain, C4a. Unlike the analogous fragments of C3 and C2, there is no evidence for an anaphylatoxic effect of C4a. There is actually some in vitro evidence that it could have a modulating effect on inflammation by inhibiting monocyte chemotaxis. We induced an immune complex glomerulonephritis in wild-type (WT) and C4 knock out (C4KO) mice. Although the glomerular component of the disease did not differ in the two groups of animals, there were marked differences in the accompanying tubulo-interstitial injury. Compared to WT animals, the C4KO mice had significantly more infiltrating interstitial cells (1910 vs 2720/mm(2)), foci of tubular atrophy (6.3 vs 14.8/section), and interstitial space (22 vs 30% of cortex). C4 is expressed constitutively by renal tubular epithelial cells. These data support a role for such local C4 in modulating interstitial inflammation, consistent with in vitro experiments.

Animals↗

PubMed1989

Haplotypes bearing HLA-A, -B, and -DR: Bf and C4 genes in rheumatoid arthritis families.

We have compared haplotypes bearing HLA-A, -B, -DR; Bf and C4 genes in 54 rheumatoid arthritis (RA) and 24 control families. There was no statistically significant differences in C4A or C4B gene frequencies between RA and control groups, although there were trends for C4B*Q0 to be reduced and C4B2 to be increased in DR4 positive RA compared with DR4 positive controls. The lack of any strong association between C4 variants and RA overall makes it unlikely that the association between RA and genes within the MHS represents a direct effect of variants within the C4A or C4B loci themselves. On comparison of DR4-bearing haplotypes, the haplotype B15-BfS-DR4 was increased fourfold and the B44-Bfs-DR4 haplotype was less frequent in the RA group. When C4 variants were also considered, the haplotype B44-C4B*Q0-C4A3-BfS-DR4 was nine times less frequent in RA patients than in controls. The observation that different DR4 bearing haplotypes may confer either increased or decreased susceptibility to RA suggests either that it is unlikely that DR4 itself is involved in the disease process or that specific haplotypic combinations are important. Thirty-two RA patients were HLA-DR4 negative. No single DR4 negative haplotype was found to confer significantly increased susceptibility to RA.

Arthritis, Rheumatoid↗

PubMed1995

Extended HLA haplotypes among the Bari Amerindians of the Perija Range. Relationship to other tribes based on four-loci haplotype frequencies.

Extended HLA haplotypes among Bari Amerindians living at the Perija Range on the limits between Colombia and Venezuela have been defined using serology for class I, electrophoresis and immuno-fixation for Bf and C4, and PCR-SSO for class II loci typing. Haplotypes were assigned based on family studies and gene frequencies were calculated using a subset of less related subjects selected from the genealogy. No rare class III variants were observed, but the characteristic low HLA diversity of isolated Amerindians populations present also in the Bari extends to Bf and C4. Thus there were only 22 different haplotypes segregating in families when nine loci were considered. All of them except three carried Bf*S, C4A*3, C4B*1. The null allele C4A*Q0 reached a frequency of 0.147 and was predominantly present in A24 Cw7 B39 DRB1*0411 haplotypes. In contrast to what has been reported using HLA alleles or class I haplotype frequencies and other isolated South American tribes, genetic distance estimates based on A-Cw-B-DR haplotype frequencies show a closer relationship between the two linguistically but geographically distant Venezuelan tribes, the Bari and the Warao, as compared to two culturally different Brazilian populations. The information reported here will be useful for identifying ancestral haplotypes in native peoples of America, for population comparison, and for discussing the differential influence of MHC haplotype diversity and population survival when similar data on other Amerindian tribes becomes available.

Alleles↗

PubMed1984

An unusual "morphologic" variant of BF S.

In the course of family studies of haplotypes of the alleles of the sixth chromosome loci HLA-A, C, B, D/DR, BF, C2, C4A, C4B, and glyoxalase I, we encountered an unusual BF variant. Its mobility was similar to BF F but it appeared to have a lesser intensity after straining with Coomassie Blue, and it was demonstrated by crossed immunoelectrophoresis to be present in lower concentration. It was therefore designated BF FQL. This variant was found on the haplotype HLA-A1, B17, DR7, BF*FQL, C2*C, C4A*6, C4B*1, GLO2. All other haplotypes of this type so far identified carry the BF variant BF S. Following activation of serum samples with zymosan, BF was analyzed by both agarose electrophoresis and isoelectric focusing and immunofixation. On both treatments, serum with BF SFQL produced a Ba pattern identical to that of a sample which was BF S. The Bb pattern for F and S are similar but differ from those of the rare variants BF F1 and BF S1. The Bb pattern of BF FQL was, thus, as expected, the same as BF F or BF S. Hence, we conclude that the variant is a mutant from BF S with mobility similar to BF F. The mutation seemed also to have resulted in a lower concentration of product than normal.

Chromosome Mapping↗

PubMed1986

HL-A and disease.

Of more than 500 diseases or syndromes studied for HL-A markers, more than 40 are known to be associated with an allele of class I, II, or III. Seven are linked to the HL-A region: six are recessive (idiopathic hemochromatosis, C2, C4A, and C4B deficiencies, congenital and late-onset deficiencies) and one is dominant (spinocerebellar ataxia). In addition, insulin-dependent diabetes mellitus is also linked to HL-A with more than one single locus. HL-A typing is of practical interest for diagnosis of ankylosing spondylitis by B27 antigen determination and for prevention of idiopathic hemochromatosis by genotyping of siblings of the index case. Prenatal diagnosis of 21-OH deficiency by genotyping fetal cells permits genetic counseling. Indeed, the discovery of the relationship between HL-A and disease can be considered a new approach to medical genetics. Extensive use of HL-A technology will probably allow better prediction of risk and may elucidate the mechanisms of certain diseases. For the first time the study of one single immunogenetic system may have a significant effect on public health through the possibility of wide-scale prevention.

Alleles↗

PubMed1991

C4 polymorphism and major histocompatibility complex haplotypes in IgA deficiency: association with C4A null haplotypes.

IgA-deficient individuals (n = 110) and six families comprising 9 cases of IgA deficiency were typed for HLA-A, -B, -DR, C4 and factor B. Phenotype frequencies were increased for HLA-B8 (p = 0.004), HLA-DR3 (p = 0.001) and homozygous C4AQ0 (p = 0.01) and decreased for HLA-B7 (p = 0.004), HLA-DR2 (p = 0.0001) and C4A3 (p = 0.00007) compared to controls. Homozygous C4A deficiency was found in 20% of IgA-deficient persons. As clearly suggested by investigation of families, the findings could be attributed to high prevalence of the extended major histocompatibility complex (MHC) haplotype [HLA-A1, B8, C4AQ0, C4B1, BfS, DR3] in IgA deficiency. All but 1 of the 9 IgA-deficient persons included in the family study carried this haplotype and 4 of them were homozygous. In the families, 3 persons with normal serum IgA concentrations had the same MHC haplotypes as their IgA-deficient relatives. The findings were also consistent with possible overrepresentation of other MHC haplotypes with aberrant C4 gene organization in IgA deficiency. As previously suggested, the presence of two MHC haplotypes associated with IgA deficiency appears to be a necessary but not sufficient requirement for manifestation of the condition. The putative existence of a recessive gene in the MHC with regulatory function with regard to IgA gene expression is consistent with the findings.

Complement C4↗

PubMed2003

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.

Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers of anti-nuclear autoantibodies. This AH carries a single segment characterized by no C4A gene. This null allele does not code for a functional C4A protein that likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. So, this genetic defect has been claimed to allow that an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance. The results obtained in the present study fit very well with this hypothesis. In the AH carriers the simultaneous high setting of tumor necrosis factor (TNF)-alpha may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. In conclusion, the C4 defect associated to the increased spontaneous release of TNF-alpha, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. In the majority of individuals, an autoimmune response clinically relevant will develop only in the presence of other immunological abnormalities.

Adult↗

PubMed1987

Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SC01] and [HLA-B44, DR7, FC31] which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena.

Celiac Disease↗