Abstract
Eight families (121 individuals) with two or more members affected with systemic lupus erythematosus (SLE) were analyzed for histocompatibility antigens (HLA-A, B, C, DR, MT, and MB) and complement antigens (C4A, C4B, and BF). These data were correlated with serological markers (antinuclear antibodies, single- and double-stranded anti-DNA, anti-SM, anti-nRNP, anti-Ro [SS-A], anti-La [SS-B], and biological false-positive tests for syphilis and clinical features. Fifteen members had SLE, and 19 had other immune diseases (subacute cutaneous lupus erythematosus, discoid lupus erythematosus, hypothyroidism, insulin-dependent diabetes mellitus, primary, Sjogren's syndrome, immune thrombocytopenic purpura, rheumatoid arthritis, and multiple sclerosis). Twenty-three healthy relatives (seroreactors) had significant titers of circulating antibodies, as did 2 of 17 spouses. There was an increased frequency of null C4 alleles in those individuals with SLE (60%) and healthy relatives (50%) as compared with spouses (24%). Multivariate analysis showed a significant association between SLE and female sex (P=.006), whereas there was no significant association revealed between female sex and other immune diseases. Patients with SLE also had a higher frequency of either C4A or C4B null alleles (P=.01) than those with immune diseases. The C4A homozygous null phenotype was more common in SLE patients than in seroreactors (P=.02). There was a higher frequency of HLA-DR2 and DR3 in individuals with SLE than in those with immune disease (P=.08), seroreactors (P=.02) and normal relatives (P =.002). One totally C4-deficient patient with SLE was identified. These families demonstrate an important association between SLE and the C4 null allele and the HLA-DR2 and DR3. These risk factors, however, cannot account for the development of disease in all individuals.
Similar content being viewed by others
References
Aarden, L. S., de Groot, E. R., and Feltkamp, T. E. W.: Immunology of DNA. III. Crithidia luciliae, a simple substrate for the determination of anti-dsDNA with the immunofluorescence technique. Ann. NY Acad. Sci. 254: 505–515, 1975
Ahearn, J. M., Provost, T. T., Dorsch, C. A., Stevens, M. B., Bias, W. B., and Arnett, F. C.: The interrelationships of HLA-DR, MB and MT phenotypes, autoantibody expression and clinical features in systemic lupus erythematosus. Arthritis Rheum. 25: 1031–1040, 1982
Alvarellos, A., Ahearn, J. M., Provost, T. T., Dorsch, C. A., Stevens, M. B., Bias, W. B., and Arnett, F. C.: Relationships of HLA-DR and MT antigens to autoantibody expression in SLE. Arthritis Rheum. 26: 1533–1535, (Letter) 1983
Arnett, F. C., Hirsch, T. J., Bias, W. B., Nishikai, M., and Reichlin, M.: The Jo-1 antibody system in myositis: Relationships to clinical features and HLA. J. Rheumatol. 8: 925–930, 1981
Arnett, F. C., Reveille, J. D., Wilson, R. W., Provost, T. T., and Bias, W. B.: Systemic lupus erythematosus: Current state of the genetic hypothesis. Semin. Arthritis Rheum. 14: 24–35, 1984
Awdeh, Z. L. and Alper, C. A.: Inherited structural polymorphism of the fourth component of human complement. Proc. Natl. Acad. Sci. U.S.A. 77: 3576–3580, 1980
Awdeh, J. 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. U.S.A. 80: 259–263, 1983
Ballow, M., McLean, R. H., and Einarson, M.: Hereditary C4 deficiency. Genetic studies and linkage to HLA. Transplant. Proc. 11: 1710–1712, 1979
Batchelor, J. R., Welsh, K. I., Tinoco, R. M., Dollery, C. T., Hughes, G. R. V., Bernstein, R., Ryan, P., Naish, P. F., Aber, G. M., Bind, R. F., and Russell, G. I.: Hydralazine-induced systemic lupus erythematosus: Influence of HLA-DR and sex on susceptibility. Lancet 1: 1107–1109, 1980
Bell, D. A. and Maddison, P. J.: Serologic subsets in systemic lupus erythematosus on examination of autoantibodies in relationship to clinical features of disease and HLA antigens. Arthritis Rheum. 23: 1268–1273, 1980
Berzofsky, R. N., Dorsch, C. A., and Stevens, M. B.: Limited anti-DNA antibody specificity in systemic lupus erythematosus. Arthritis Rheum. 20: 1320–1325, 1977
Bias, W. B., Hsu, S. H., Pollard, M. K., Harvey, J., Lotze, M., Arnett, F. C., and Stevens, M. B.: HLA-DR characterization of a Chippewa Indian subpopulation with high prevalence of rheumatoid arthritis. Hum. Immunol. 2: 155–163, 1981
Bias, W. B., Meyers, D. A., Conley, C. L., Reveille, J. D., Wilson, R. W., and Arnett, F. C.: Evidence that autoimmunity is a Mendelian dominant trait. Am. J. Hum. Genet. 35: 77 A, 1983 (abstract)
Clark, G., Reichlin, M., and Tomasi, T. B.: Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythematosus. J. Immunol. 102: 117–122, 1969
Fielder, A. H. L., Walport, M. J., Batchelor, J. R., Rynes, R. I., Black, C. M., Dodi, I. A., and Hughes, G. R. V.: Family study of the major histocompatibility. Br. Med. J. 1: 425–428, 1983
Gibofsky, A., Winchester, R. J., Patarroya, M., Fotino, M., and Kunkel, H. G.: Disease associations of the Ia-like human alloantigens: Contrasting patterns in rheumatoid arthritis and systemic lupus erythematosus. J. Exp. Med. 148: 1728–1732, 1978
Glass, D., Raum, D., Gibson, D., Stillman, J. S., and Schur, P. H.: Inherited deficiency of the second component of complement. Rheumatic disease associations. J. Clin. Invest. 58: 845–861, 1976
Hauptmann, G., Grooshans, E., and Heid, E.: Lupus érythémaoux aigus et déficits héréditaires en complément. A propos d'un cas par déficit complet en C4: Ann. Derm. Syphiligr. 101: 479–496, 1974
Holborow, E. J., Weir, D. M., and Johnson, G. D.: A serum factor in lupus erythematosus with affinity for tissue nuclei. Br. Med. J. 2: 732–737, 1957
Howard, P. F., Hochberg, M. C., Bias, W. B., Arnett, F. C., and McLean, R. H.: C4A null genes (C4A*QO) and HLA-DR2 represent independent risk factors for white systemic lupus erythematosus. Arthritis Rheum. 27: (suppl.): S62, 1984 (Abstract)
Lahita, R. G., Bradlow, L., Fishman, J., and Kunkel, H. G.: Estrogen metabolism in systemic erythematosus. Patients and family members. Arthritis Rheum. 25: 843–846, 1982
Lippman, S., Arnett, F. C., Conley, C. L., Meyers, D., and Bias, W. B.: Genetic factors predisposing to autoimmune diseases: Autoimmune hemolytic anemia, chronic thrombocytopenic purpura and systemic lupus erythematosus. Am. J. Med. 73: 827–840, 1982
Mascart-Lemone, F., Hauptmann, G., Goetz, J., Duchateau, J., Delesprese, G., Vray, B., and Dab, I.: Genetic deficiency of C4 presenting with recurrent infections and an SLE-like illness. Am. J. Med. 75: 295–304, 1983
Mattioli, M. and Reichlin, M.: Heterogeneity of RNA protein antigens reactive with sera of patients with systemic lupus erythematosus. Description of a cytoplasmic nonribosomal antigen. Arthritis Rheum. 17: 421–429, 1974
Mauff G., Alper, C. A., and Awdeh, Z.: Statement on the nomenclature of human C4 allotypes. Immunobiology 164: 184–191, 1983
McLean, R. H., Kennedy, T. L., and Ballow, M.: Increased frequency of factor B fast variant (Bf*F) in idiopathic nephrotic syndrome. Dis. Markers 1: 25–32, 1983
McLean, R. H., Wyatt, R. J., and Julian, B. A.: Complement phenotypes in glomerulonephritis: Increased frequency of homozygous null C4 phenotypes in IgA nephropathy and Henoch-Schönlein purpura. Kidney Int. 26: 855–860, 1984
Minta, J. O., Urowitz, M. B., Gladman, D. D., Ilrizowa, T., and Biggar, W. D.: Selective deficiency of the fourth component of complement in a patient with systemic lupus erythematosus: Immunochemical and biological studies. Clin. Exp. Immunol. 45: 72–80, 1981
Nomenclature of the alternative activating pathway of complement. J. Immunol. 127: 1261–1262, 1981
Nomenclature of complement. Bulletin of the World Health Organization 39: 935–138, 1968
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. U.S.A. 75: 5165–5169, 1978
Provost, T. T., Arnett, F. C., and Reichlin, M.: Homozygous C4 deficiency, lupus erythematosus, and anti-Ro(SS-A) antibodies. Arthritis Rheum. 26: 1279–1282, 1983
Reinertsen, J. L., Klippel, J. H., Johnson, A. H., Steinberg, A. D., Decker, J. L., and Mann, D. L.: Blymphocyte alloantigens associated with systemic lupus erythematosus. Arthritis Rheum. 299: 515–518, 1978
Schaller, J. G., Gilliland, B. G., Ochs, H. D., Leddy, J. P., Agodoa, L. C. Y., and Rosenfeld, S. I.: Severe systemic lupus erythematosus with nephritis in a boy with deficiency of the fourth component of complement. Arthritis Rheum. 20: 1519–1525, 1977
Schur, P. H.: Complement and lupus erythematosus. Arthritis Rheum. 25: 793–798, 1982
Sontheimer, R. D., Maddison, P. J., Reichlin, M., Jordon, R. E., Stastney, P., and Gilliam, J. N.: Serologic and HLA associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus erythematosus. Ann. Intern. Med. 97: 664–671, 1982
Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., McShane, D. J., Rothfield, N. F., Schaller, J. G., Talal, N., and Winchester, R. J.: The 1982 revised criteria for the classification of systemic erythematosus. Arthritis Rheum. 25: 1271–1277, 1982
Tappeiner, G., Scholz, S., Linert, J., Albert, E., and Wolff, K.: Hereditary deficiency of the fourth component of complement: Study of a family. Inserm 80: 399–404, 1978
Tappeiner, G., Hinter, H., Scholz, S., Albert, E., Linert, J., and Wolff, K.: Systemic lupus erythematosus in hereditary deficiency of the fourth component of complement. J. Am. Acad. Dermatol. 7: 66–79, 1982
Weitkamp, L. R. and Lamm, L. U.: Report of the committee on the genetic constitution of chromosome 6. Cytogenet. Cell Genet. 32: 130–143, 1982
Wilson, J. G., Wong, W. W., Schur, P. H., and Fearon, D. T.: Mode of inheritance of decreased C3b receptors on erythrocytes of patients with systemic lupus erythematosus. N. Engl. J. Med. 307: 981–986, 1982
Wilson, R. W., Provost, T. T., Bias, W. B., Alexander, E. L., Edlow, D. W., Hochberg, N. C., Stevens, M. B., and Arnett, F. C.: Sjogren's syndrome influence of multiple HLA-D region alloantigens on clinical and serologic expression. Arthritis Rheum., in press, 1985
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Reveille, J.D., Arnett, F.C., Wilson, R.W. et al. Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus. Immunogenetics 21, 299–311 (1985). https://doi.org/10.1007/BF00430796
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00430796