Abstract
C4 protein variants were analyzed in 64 individuals, of which 51 were either homozygous or heterozygous for an extended major histocompatibility complex (MHC) haplotype (a fixed combination of MHC alleles). The relative amount of each C4 variant was measured by densitometric scanning of stained immunofixed electrophoretic patterns of neuraminidase- and carboxypeptidase-treated samples. The relative concentrations of C4 variants on any haplotype were stable and inherited in families. In five of the eight extended haplotypes investigated, the amount of one of the C4 variants relative to others in the same pattern was increased:[HLA-B8, SC01, DR3] and[HLA-B7, SC31, DR2] produced an approximately doubled amount of C4B1;[HLA-B18, S042, DR2] an increased amount of C4B2; and[HLA-B44, SC30, DR4] a double amount of C4A3. The extended haplotype[HLA-Bw57, SC61, DR7] gave rise to two to three times as much C4B1 as C4A6. In the extended haplotypes[HLA-B44, FC31, DR7] and[HLA-Bw62, SC33, DR4], the results did not clearly indicate differences in expression of the C4 isotypes. DNA analysis possibly supported an actual gene duplication only for the haplotype[HLA-B7, SC31, DR2]. The results suggest that, in addition to variation in the number of structural genes, other MHC-linked mechanisms may be involved in the regulation of the relative amounts of C4A or C4B protein specified by any haplotype.
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Abbreviations
- C2:
-
second component of complement
- C4:
-
fourth component of complement
References
Alper, C. A.: Inherited structural polymorphism in C2: evidence for genetic linkage between C2 and Bf.J Exp Med 144: 1111–1115, 1976
Alper, C. A., Boenisch, T., and Watson, L.: Genetic polymorphism in human glycine-rich beta-glycoprotein.J Exp Med 135: 68–80, 1972
Alper, C. A., Raum, D., Karp, S., Awdeh, Z. L., and Yunis, E. J.: Serum complement “supergenes” of the major histocompatibility complex in man (complotypes).Vox Sang 45: 62–67, 1983
Awdeh, Z. L., and Alper, C. A.: Inherited structural polymorphism of the fourth component of human complement.Proc Natl Acad Sci USA 77: 3576–3580, 1980
Awdeh, Z. L., Raum, D., and Alper, C. A.: Genetic polymorphism of human complement C4 and the detection of heterozygotes.Nature 282: 205–207, 1979
Awdeh, Z. L., Raum, D., Yunis, E. J., and Alper, C. A.: Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man.Proc Natl Acad Sci USA 80: 259–263, 1983
Awdeh, Z. L., Alper, C. A., Eynon, E., Alosco, S. M., Stein, R., and Yunis, E. J.: Unrelated individuals matched for MHC extended haplotypes and HLA-identical siblings show comparable responses in mixed lymphocyte culture.Lancet ii: 853–856, 1985
Belt, K. T., Carroll, M. C., and Porter, R. R.: The structural basis of the multiple forms of human complement component C4.Cell 36: 907–914, 1984
Bruun-Petersen, G., Lamm, L. U., Jacobsen, B. K., and Kristensen, T.: Genetics of human complement C4. Two homoduplication haplotypes C4S,C4S and C4F,C4F in a family.Hum Genet 61: 36–38, 1982
Carroll, M. C., Campbell, D., Bentley, D. R., and Porter, R.: A molecular map of the human histocompatibility complex class III region linking complement genes C4, C2 and factor B.Nature 307: 237–241, 1984
Carroll, M. C., Campbell, R. D., and Porter, R. R.: Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HLA, the major histocompatibility complex in man.Proc Natl Acad Sci USA 82: 521–525, 1985a
Carroll, M. C., Palsdottir, A., Belt, K. T., and Porter, R. R.: Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region on some chromosomes.EMBO J 4: 2547–2552, 1985b
Collier, S., Sinnott, P. J., Dyer, P. A., Price, D. A., Harris, R., and Strachan, T.: Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complementC4 gene repeats in 21-hydroxylase deficiency haplotypes.EMBO J 8: 1393–1402, 1989
Dasgupta, J. D., Relias, V., Awdeh, Z. L., Alper, C. A., and Yunis, E. J.: Two variants of DRw52, DR3, and DQw2 specificities distinguish two different DR3-bearing extended haplotypes.Hum Immunol 21: 133–142, 1988
Dunham, I., Sargent, C. A., Dawkins, R. L., and Campbell, R. D.: Direct observation of the gene organization of the complement C4 and 21-hydroxylase loci by pulsed-field gel electrophoresis.J Exp Med 169: 1803–1818, 1989
Garlepp, M. J., Wilton, A. N., Dawkins, R. L., and White, P. C.: Rearrangement of 21-hydroxylase genes in disease-associated MHC supratypes.Immunogenetics 23: 100–105, 1986
Gross-Belard, M., Oudet, P., and Chambon, P.: Isolation of high molecular weight DNA from mammalian cells.Eur J Biochem 36: 32–38, 1973
Isenman, D. and Young, J. R.: The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of the human complement component C4.J Immunol 123: 3019–3027, 1984
Kruskall, M. S., Eynon, E. E., Awdeh, Z. L., Alper, C. A., and Yunis, E. J.: Identification of HLA-B44 subtypes associated with extended MHC haplotypes.Immunogenetics 26: 216–219, 1987
Law, S. K. A., Dodds, A. W., and Porter, R. R.: A comparison of the properties of two classes, C4A and C4B, of the human complement component C4.EMBO J 3: 1819–1823, 1984
Mauff, G., Alper, C. A., Awdeh, Z., Batchelor, J. R., Bertrams, J., Bruun-Petersen, G., Dawkins, R. L., Demant, P., Edwards, J., Grosse-Wilde, H., Hauptmann, G., Klouda, P., Lamm, L., Mollenhauer, E., Nerl, C., Olaisen, B., O’Neill, G., Rittner, C., Ross, M. H., Skanes, V., Teisberg, P., and Wells, L.: Statement on the nomenclature of human C4 allotypes.Immunobiology 164: 184–191, 1983
Morell, A., Skvaril, F., Steinberg, A. G., van Loghem, E., and Terry, W. D.: Correlations between the concentrations of the four subclasses of IgG and Gm allotypes in normal human sera.J Immunol 108: 195–206, 1972
O’Neill, G. J., Yang, S. Y., and Dupont, B.: Two HLA-linked loci controlling the fourth component of human complement.Proc Natl Acad Sci USA 75: 5165–5169, 1978
Palsdottir, A., Arnason, A., Fossdal, R., and Jensson, O.: Gene organization of haplotypes expressing two different C4A allotypes.Hum Genet 76: 220–224, 1987a
Palsdottir, A., Fossdal, R., Arnason, A., Edwards, J. H., and Jensson, O.: Heterogeneity of humanC4 gene size, a large intron (6.5 kb) is present in allC4A genes and someC4B genes.Immunogenetics 25: 299–304, 1987b
Raum, D., Awdeh, Z. L., Anderson, J., Strong, L., Granados, J., Pevan, L., Giblett, E., Yunis, E. J., and Alper, C. A.: Human C4 haplotypes with duplicated C4A or C4B.Am J Hum Genet 36: 72–79, 1984
Ray, J. G., Jr., Hare, D. B., Pedersen, P. D., and Mulally, D. I.:NIAID Manual of Tissue Typing Techniques, Department of Health Education and Welfare, National Institutes of Health, Bethesda, Maryland, pp. 76–545, 1976
Rittner, C., Giles, C. M., Roos, M. H., Demant, P., and Mollenhauer, E.: Genetics of human C4 polymorphism: detection and segregation of rare and duplicated haplotypes.Immunogenetics 19: 321–333, 1984
Saito, H., Maki, R. A., Clayton, L. K., and Tonegawa, S.: Complete primary structure of the Eβ chain and gene of the mouse major histocompatibility complex.Proc Natl Acad Sci USA 80: 5520–5524, 1983
Schneider, P. M., Carroll, M. C., Alper, C. A., Rittner, C., Whitehead, A. S., Yunis, E. J., and Colten, H. R.: Polymorphism of the human complement C4 and steroid 21-hydroxylase genes.J Clin Invest 78: 650–657, 1986
Sim, E., and Cross, S. J.: Phenotyping of human complement component C4, a class-III HLA antigen.Biochem J 239: 763–767, 1986
Southern, E.: Detection of specific sequences among DNA fragments separated by gel electrophoresis.J Mol Biol 98: 503–517, 1975
Spiro, R. C., DeMartino, J. L., Boto, W., Lazarus, H., and Humphreys, R. E.: Comparison of membrane proteins of Burkitt’s lymphoma and EBV-transformed B-lymphoblastoid cell lines and Con-A activated T lymphocytes and T lymphoblastoid cell lines.Leuk Res 3: 315–327, 1979
Wescott, M. Z., Awdeh, Z. L., Yunis, E. J., and Alper, C. A.: Molecular analysis distinguishes twoHLA-DR3-bearing major histocompatibility complex extended haplotypes.Immunogenetics 26: 370–374, 1984
Whitehead, A. S., Woods, D. E., Fleischnick, E., Chin, J. E., Yunis, E. J., Katz, A. J., Gerald, P. S., Alper, C. A., and Colten, H. R.: DNA polymorphism of the C4 genes, a new marker for analysis of the major histocompatibility complex.N Engl J Med 310: 88–91, 1984
Whitehead, A. S., Truedsson, L., Schneider, P. M., Awdeh, Z. L., Fleischnick, E., Blumenthal, M., Costello, W., Gerald, P. S., Yunis, E. J., and Alper, C. A.: The distribution of human C4 DNA variants in relation to major histocompatibility complex alleles and extended haplotypes.Hum Immunol 21: 23–32, 1988
Wilson, J. G., Murphy, E. E., Wong, W. W., Klickstein, L. B., Weis, J. H., and Fearon, D. T.: Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes.J Exp Med 164: 50–59, 1986
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Truedsson, L., Awdeh, Z., Yunis, E.J. et al. Quantitative variation of C4 variant proteins associated with many MHC haplotypes. Immunogenetics 30, 414–421 (1989). https://doi.org/10.1007/BF02421172
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DOI: https://doi.org/10.1007/BF02421172