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Combined Heterozygous Deficiency of the Classical Complement Pathway Proteins C2 and C4

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Abstract

Genetic deficiencies of components of the classical pathway of complement activation are associated with an increased risk for the development of autoimmune and immune complex-mediated diseases. In the present study we report on the molecular and clinical features associated with combined heterozygous C4 and C2 deficiency in 15 individuals investigated within six families. Approximately 30% of the individuals manifested SLE or another autoimmune condition. Heterozygous C2 deficiency was related to a 28-bp deletion in the C2 gene (C2 deficiency type I), in most cases within the HLA-A25 B18 C2Q0 BfS C4A4B2 DR2 haplotype. Among 13 partial C4-deficient haplotypes transmitted, 8 carried C4A*Q0 alleles and 5 C4B*Q0 alleles. In seven cases the C4A*Q0 alleles were associated with a deletion of the C4A/CYP21P genes within the HLA-B8 C2C BfS C4AQ0B1 DR3 haplotype. In three cases, the C4B*Q0 allele was associated with a deletion of the C4B/CYP21P genes within the HLA-B18 C2C BfF1 C4A3BQ0 DR3 haplotype. In the other cases, C4A*Q0 or C4B*Q0 was dependent on as yet uncharacterized defects in the C4 gene or in C4 gene expression. In view of the relatively high frequency of heterozygous C4 deficiency in the normal Caucasian population, the expected frequency of the combined deficiency should approximate 0.001.

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REFERENCES

  1. Atkinson JP: Complement deficiency. Predisposing factor to autoimmune syndromes. Am J Med 85 (Suppl. 6A):45–47, 1988

    Google Scholar 

  2. Hauptmann G, Tappeiner G, Schifferli JA: Inherited deficiency of the fourth component of human complement. In Immunodeficiencies, FS Rosen, M Seligmann (eds). Chur, Harwood Academic, 1993, pp 253–266

    Google Scholar 

  3. Fielder AHL, Walport MJ, Batchelor JR, Rynes RI, Black CM, Dodi IA, Hughes GRV: Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: Importance of null alleles of C4A and C4B in determining disease susceptibility. Br Med J 286:425–428, 1983

    Google Scholar 

  4. Fan Q, Uring-Lambert B, Weill B, Menkes CJ, Delpech M: Complement component C4 deficiencies and gene alterations in patients with systemic lupus erythematosus. Eur J Immunogenet 20:11–21, 1993

    Google Scholar 

  5. Reveille JD: The molecular genetics of systemic lupus erythematosus and Sjögren's syndrome. Curr Op Rheumatol 4:644–656, 1992

    Google Scholar 

  6. Ruddy S: Component deficiencies 3. The second component. In Hereditary and Acquired Complement Deficiencies in Animals and Man, Progress in Allergy, Vol 39, K Rother, U Rother (eds). Basel, Karger, 1986, pp 250–266

    Google Scholar 

  7. Sullivan KE, Petri MA, Schmeckpeper BJ, McLean RH, Winkelstein JA: Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus. J Rheumatol 21:1128–1133, 1994

    Google Scholar 

  8. Truedsson L, Alper CA, Awdeh ZL, Johansen P, Sjöholm AG, Sturfelt G: Characterization of type I complement C2 deficiency MHC haplotypes. Strong conservation of the complotype/HLA-B-region and absence of disease association due to linked class II genes. J Immunol 151:5856–5863, 1993

    Google Scholar 

  9. Carroll MC, Campbell RD, Porter RR: Mapping of steroïd 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, 1985

    Google Scholar 

  10. Carroll MC, Campbell RD, Bentley DR, Porter RR: A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2, and factor B. Nature 307:237–241, 1984

    Google Scholar 

  11. Alper CA, Awdeh ZL, Yunis EJ: Frequency of the C2 deficiency gene among normal Caucasians. Complement 4:125, 1987

    Google Scholar 

  12. Alper CA, Raum D, Karp S, Awdeh ZL, Yunis EJ: Serum complement (“supergenes”) of the major histocompatibility complex in man (complotypes). Vox Sang 45:62–67, 1983

    Google Scholar 

  13. Awdeh ZL, Raum D, Yunis EJ, Alper CA: Extended HLA/complement allele haplotypes: Evidence for T/t-like complex in man, Proc Natl Acad Sci USA 80:259–263, 1983

    Google Scholar 

  14. Dawkins RL, Christiansen FT, Kay PH, Garlepp MJ, McCluskey J, Hollingsworth PN, Zilko PJ: Disease associations with complotypes, supratypes and haplotypes. Immunol Rev 70:5–22, 1983

    Google Scholar 

  15. Taïeb A, Hehunstre JP, Goetz J, Surlève Bazeille JE, Fizet D, Hauptmann G, Maleville J: Lupus erythematosus panniculitis with partial genetic deficiency of C2 and C4 in a child. Arch Dermatol 122:576–582, 1986

    Google Scholar 

  16. Johnson CA, Densen P, Hurford RK, Colten HR, Wetsel RA: Type I human complement C2 deficiency. A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing. J Biol Chem 13:9347–9353, 1992

    Google Scholar 

  17. Barba G, Rittner C, Schneider P: Genetic basis of human complement C4A deficiency. Detection of a point mutation leading to non expression. J Clin Invest 91:1681–1686, 1993

    Google Scholar 

  18. Tan EM, Cohen AS, Fries JF, Masi AT, McShanes DJ. Rothfield NF, Schaller JG, Talal N, Winchester RJ: The 1992 revised criteria for the classification of systemic lupus erythematosus. Arth Rheum 25:1271–1277, 1982

    Google Scholar 

  19. Kazatchkine M, Hauptmann G, Nydegger U: Techniques du complément. In Techniques en Immunologie. Paris, INSERM, 1985

    Google Scholar 

  20. Ngan BY, Gelfand EW, Minta JO: A simple one-step hemolytic assay for C2 with C2-deficient human serum. J Immunol 118:736–741, 1977

    Google Scholar 

  21. Uring-Lambert B, Gas S, Goetz J, Mauff G, Goldman SF, Frössler M, Bender K, Hauptmann G: Detection of the genetic polymorphism of human C2 (native protein and C2a fragment) by immunoblotting after polyacrylamide gel isoelectric focusing. Complement 2:185–192, 1985

    Google Scholar 

  22. Terasaki PI, McClelland JD: Microdroplet assay of human serum cytotoxins. Nature 204:998–1000, 1964

    Google Scholar 

  23. Gross-Bellard M, Oudet P, Chambon P: Isolation of high molecular weight DNA from mammalian cells. Eur J Biochem 36:32–38. 1973

    Google Scholar 

  24. Schneider PM, Carroll MC, Alper CA, Rittner C, Whitehead AS, Yunis EJ, Colten HR: Polymorphism of the human complement and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications and size variants. J Clin Invest 78:650–657, 1986

    Google Scholar 

  25. Schneider PM: C4DNA RFLP reference typing report. Complement Inflamm 7:218–224, 1990

    Google Scholar 

  26. Kumar A, Kumar P, Schur PH: DR3 and non DR3 associated complement component C4A deficiency in systemic lupus erythematosus. Clin Immunol Immunopathol 60:55–64, 1991

    Google Scholar 

  27. Cambon-de-Mouzon A, Ohayon E, Hauptmann G, Sevin A, Abbal M, Sommer E, Vergnes H, Ducos J: HLA-A, B, C, DR antigens. Bf, C4 and glyoxalase I (GLO) polymorphisms in French basques with insulin-dependent diabetes mellitus (IDDM). Tissue Antigens 19:366–379, 1982

    Google Scholar 

  28. Braun L, Schneider PM, Giles CM, Bertrams J, Rittner C: Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus. J Exp Med 171:129–140, 1990

    Google Scholar 

  29. Partanen J, Campbell RD: Restriction fragment analysis of nondeleted complement C4 null genes suggests point mutations in C4A null alleles, but gene conversion in C4B null alleles. Immunogenetics 30:520–523, 1989

    Google Scholar 

  30. Hauptmann G, Tongio MM, Goetz J, Mayer S, Fauchet R, Sobel A, Griscelli C, Berthoux F, Rivat C, Rother U: Association with the C2 deficiency genes (C2*Q0) with the C4A*4, C4B*2 genes. J Immunogenet 9:127–132, 1982

    Google Scholar 

  31. Lachmann PJ, Walport MJ: Deficiency of the effector mechanisms of the immune response and autoimmunity. In Auto-immunity and Autoimmune Disease, Ciba Foundation Symposium, D Evered, J Whelan (eds). London, Churchill-Livingstone, pp 129–149, 1987

    Google Scholar 

  32. Dawkins RL, Degli-Esposti MA, Abraham LJ, Zhang WJ, Christiansen FT: Conservation and polymorphism of the MHC in relation to immune responses and autoimmune disease. In Molecular Evolution of the MHC, J Klein, D Klein (eds). New York, Springer, 1991, pp 391–402

    Google Scholar 

  33. Maillet F, Fremeaux-Bacchi V, Uring-Lambert B, Kazatchkine MD: Assessment of complement activation in clinical samples. Comparison of immunochemical and functional measurements of complement components with quantitation of activation fragments. J Immunol Meth 156:171–178, 1992

    Google Scholar 

  34. Moulds JM, Warner NB, Arnett FC: Complement component C4A and C4B levels in systemic lupus erythematosus: Quantitation in relation to C4 null status and disease activity.J Rheumatol 20:443–447, 1993

    Google Scholar 

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Authors and Affiliations

  1. Laboratoire de Recherches en Immunologie, Université Louis Pasteur, Strasbourg, France

    Dominique Hartmann, Alice Meyer, Georges Hauptmann & Beatrice Uring-Lambert

  2. Service d'Immunologie, INSERM U430, and Université Pierre et Marie Curie, Hôpital Broussais, Paris, France

    Veronique Fremeaux-Bacchi, Laurence Weiss, Jacques Blouin & Michel Kazatchkine

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  1. Dominique Hartmann
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  2. Veronique Fremeaux-Bacchi
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  3. Laurence Weiss
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  4. Alice Meyer
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  6. Georges Hauptmann
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  7. Michel Kazatchkine
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  8. Beatrice Uring-Lambert
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Hartmann, D., Fremeaux-Bacchi, V., Weiss, L. et al. Combined Heterozygous Deficiency of the Classical Complement Pathway Proteins C2 and C4. J Clin Immunol 17, 176–184 (1997). https://doi.org/10.1023/A:1027334716982

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