Coeliac disease and C4A*QO: an association secondary to HLA-DR3.
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Biomedical subjects
Publications and source records attributed to C Rittner.
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Red cells, serum and plasma samples of 20 individuals, selected for their C4 allotypes, were distributed from Bonn to five laboratories, for investigation of their Chido (Ch) and Rodgers (Rg) determinants. One anti-Ch (M.H.) and one anti-Rg(Prest.) were distributed, but the individual laboratories also used their own reagents and their own typing methods. There was general agreement in interpretation of the majority of samples. Partial inhibition for Ch and Rg was detected. Two samples gave anomalous results; one sample with C4 A1,3 BQO, QO had Ch determinants on the red cells and in plasma (partial inhibition), and another sample with C4 A3,4 B5, QO apparently lacked Ch determinants on the red cells and in plasma. Heterogeneity of anti-Ch and anti-Rg was suggested in testing red cells, perhaps, reflecting a quantitative effect. This heterogeneity was confirmed by inhibition studies. The capacity of some reagents to detect partial inhibition probably reflects qualitative as well as quantitative differences.
The genetically determined polymorphism of the fourth component of human complement was further extended with the aid of a panel of human allo-anti-C4 sera, anti-Rodgers and anti-Chido. These antisera were found previously to react with the alpha-chains of the C4 molecules controlled by the C4A and C4B loci, respectively. We analyzed a number of new and rare C4 allotypes, and found that they generally followed the expected pattern. Some interesting exceptions, however, were found. The alpha-chain of the allotype C4A1 was found to react with anti-Chido, unlike all other C4A allotypes. Also the C4B5 allotype could be subdivided into two subtypes on the basis of their reaction with anti-Rodgers. They were tentatively named B5Rg+ and B5Rg-. Moreover, the B5Rg+ subtype reacted not only with anti-Rodgers but also with some anti-Chido sera, indicating for the first time that Chido and Rodgers determinants are present on the same allotype.
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52 symptomatic (SPB) and 64 asymptomatic (APB) pigeon breeders were investigated for the HLA-A, -B, -C, -DR; C2, C3, C4 and Bf systems, and C3, C4 and factor B serum concentrations. HLA-DR3 and Bf S frequencies were significantly higher in the SPB than the APB group. Mean factor B concentrations were lower in the SPB than in the APB group. A positive two-way association between HLA-DR3 and the disease was found. It is concluded that a gene or genes responsible for type III and IV allergic reactions leading to the disease is associated with HLA-DR3. The increase of Bf S allotype and low mean factor B concentrations, however, can be explained by the strong linkage disequilibrium between BfS and HLA-DR3.
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The major histocompatibility complex(MHC)-linked fourth component of complement (C4) shows a high degree of polymorphism in several animal species. In man C4 polymorphism was detected by distinct charge differences of the variants. O'Neill et al. showed that this C4 polymorphism was controlled by two closely linked genetic loci, F (C4A) and S (C4B) and these results were extended by Awdeh et al. with an improved typing method. Biochemical analysis of human C4 has revealed that it consists of three polypeptide chains, alpha, beta and gamma. In all reports so far on the molecular analysis of human C4, no molecular weight differences between the A and B locus-encoded molecules have been noticed. Here we demonstrate that the C4A and C4B locus-encoded alpha-chains have a molecular weight (MW) of 96,000 and 94,000, respectively, presenting for the first time a molecular basis for the difference between all C4A and C4B variants tested. Even rare variants that are difficult to allocate to the A or B locus on the basis of charge differences could be identified as C4A or C4B variants in this way, thereby providing new insights into the relationships between the C4A and C4B loci.
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In this review article, recent evidence is presented that some diseases like insulin-dependent diabetes mellitus, multiple sclerosis, and idiopathic membranous nephropathy, which are primarily associated with HLA-D,DR, are also related to the rare C2, C4, and Factor B alleles. Circumstantial evidence is available that at least some of these rare variants may be functionally deficient. Based on the concept of functionally interacting gene clusters, mutant complement genes may lead to impaired effector mechanisms in virus neutralization or lysis of virus-infected cells. Other mechanisms such as alteration of vascular permeability may be involved in the development of proliferative retinopathy and familial hypertension. In lepromatous lepra, an impaired cell-mediated lysis of M. leprae may be related to the hemolytically inactive C4F1 allelic product.
One hundred and sixty-seven blood donors, 26 families with 72 offspring and 12 motherchild couples were studied for the phosphoglycolate phosphatase polymorphism. In hemolysates, the isozymes are stable for at least five weeks. The distribution of observed phenotypes in the population study did not diverge from the expected values according to Hardy-Weinberg law. In the family study, the formal genetic model of three alleles--PGP1, PGP2 and PGP3 at one autosomal locus-could be confirmed. Among 33 individuals from a Mongoloid population PGP1 was observed in 100%. This observation lead us to the conclusion, based also on recent data in Negroid populations (Barker and Hopkinson 1978), that phosphoglycolate phosphatase may be a more recent polymorphism of Caucasoid populations. Linkage studies with the hp alpha locus an chromosome 16 resulted in 19 meiotic divisions of 4 informative families in a lod score peak of 0.23 at theta 0.25 being inconclusive. The inclusion of the PGP system in paternity testing is also discussed.
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In 24 highly selected cases of disputed paternity a chromosome expertise (karyotyping with Q banding) was performed. These included 11 cases with one man and 13 cases with two men alleged. Among the latter both men were related (brothers, father and son) in five cases; in one case the father of the mother was involved. In seven cases a definite judgement could be achieved on the disputed relationship. In most other cases the assumed true father had been investigated while having no informative karyotype. It is concluded that karyotyping should be performed when an exclusion can be expected. In addition, in all informative cases the positive information towards paternity should be included in calculations of probability of fatherhood according to Essen-Möller.
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The results of a study of the polymorphism of the sixth component of human complement by means of isoelectric focusing in polyacrylamide gels with subsequent C-dependent lysis in an agarose overlay containing C6 deficient rabbit serum are reported. The allele frequencies obtained (C6A = 0.613, C6B = 0.379, C6R = 0.008) are in good agreement with those previously published. The mode of inheritance in 47 families with 173 offspring as well as 26 mother-child combinations is in agreement with a formal genetical model: "C6A, C6B, C6A1 and C6B1 at an autosomal locus". The inclusion of this system into a blood group expertise in Germany can be recommended.
The polymorphism of the second component of human complement was studied by means of isoelectric focusing in polyacrylamide gels with subsequent complement-dependent lysis of sensitized sheep erythrocytes in an agarose overlay containing C2-deficient or normal human serum. In a material of 289 unrelated individuals the following gene frequencies were observed: C21=0.965 and C22=0.035. The rare phenotype C2 2 (=C2 B) could be seen once in a child of a C2 1--2 heterozygous mother. The investigation of the C2/HLA relationship revealed a very close linkage: Among 62 informative meiotic divisions one recombination between HLA-B and C2 was found (i.e. 1.61%); in addition, C2(2) was significantly associated with HLA-B15 and -Cw3. In a family with an HLA-B/D(DR) crossover C2 segregated together with HLA-D(DR). This supports the assumption of a C2 structural locus outside HLA-B, probably near HLA-D(DR).
This study was undertaken to get more insight into the previously suggested heterogeneity of the HLA--DW3 cluster. Preliminary evidence of DW3 heterogeneity was derived from results of intrafamilial mixed lymphocyte culture tests (MLC) where cells of apparently homozygous offspring revealed unexpected stimulations of one of the parents' cells. Therefore, 15 different homozygous typing cells (HTCs) of DW3 specificity were tested against 43 HLA-DW3 heterozygous individuals. The response patterns of the 43 HLA-DW3 heterozygous cells toward 13 HTCs leads to the definition of at least three groups of DW3 stimulating cells. According to these patterns, four groups of responding cells could be classified. These results were confirmed by a MLC checkerboard experiment running all DW3-HTCs against each other. Discussing all possible explanations for these observations, the authors conclude that the existence of DW3 subtypes having some properties in common is the most likely interpretation of the results obtained. Family segregation studies will be needed to define the genotypic situation of the DW3 cluster.