Inherited Deficiencies of the Complement System

  • Noorbibi K. Day
  • B. Moncada
  • Robert A. Good
Part of the Comprehensive Immunology book series (COMIMUN, volume 2)


In recent years, studies of genetically determined deficiencies of components of the complement (C) system have begun to yield the same crucial type of information often yielded in the past by other inborn errors of metabolism, e.g., the primary immunodeficiencies as experiments of nature. To date, the deficiencies of the complement system described in man (Tables 1 and 2) are as follows: C1-esterase inhibitor in patients with hereditary angioneurotic edema; Clq in combined immuno-deficiency states; Clr deficiencies associated with infections and a strange vascular disease with lupus-like lesions and chronic glomerulonephritis; C1s with lupus and lupus-like syndrome; C2 with systemic lupus erythematosus, lupus-like syndrome, dermatomyositis, anaphylactoid purpura, increased susceptibility to infections, Hodgkin’s disease, and discoid lupus, and recently in a patient with chronic lymphocytic leukemia and dermatitis herpetiformis; C3 with increased frequency of infections, in particular, of the pulmonary apparatus; C4 with lupus erythematosus; C5 deficiency with membranous glomerulonephritis, vasculitis, arthritis, and propensity to bacterial infections; C5 abnormality with Leiner’s syndrome, recurrent and persistent gram-negative bacterial skin disease and gastroenteritis; C6 in one individual who is apparently healthy at the moment and in another with repeated episodes of meningococcal meningitis; C7 with Raynaud’s phenomenon; C7 inactivator with apparent good health; C8 deficiency with prolonged disseminated gonococcal infection syndrome, and also in three homozygous C8-deficient siblings in a family in which xeroderma pigmentosa is also present.


Systemic Lupus Erythematosus Chronic Lymphocytic Leukemia Complement System Paroxysmal Nocturnal Hemoglobinuria Dermatitis Herpetiformis 
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  1. Agnello, V., de Bracco, M. M. E., Kunkel, H. G., 1972, Hereditary C2 deficiency with some manifestations of systemic lupus erythematosus, J. Immunol. 108: 837–840.PubMedGoogle Scholar
  2. Agnello, V., Ruddy, S., Winchester, R. J., Christian, C. L., Kunkel, H. G., 1975, Hereditary C2 deficiency in systemic lupus erythematosus and acquired complement abnormalities in an unusual SLE-related syndrome, in: Immunodeficiency In Man and Animals (R. A. Good, J. Finstad, and N. W. Paul, eds.), in: Birth Defects: Original Article Ser., XI(1):312–317, Sinauer Associates, Sunderland, Massachusetts.Google Scholar
  3. Alper, C. A., Abramson, N., Johnston, R. B., Jr., Jandl, J. H., Rosen, F. S., 1970, Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3), N. Engl. J. Med. 282: 349–354.CrossRefGoogle Scholar
  4. Alper, C. A., Colten, H. R., Rosen, F. S., Rabson, A. R., Macnab, G. M., Gear, J. S. S., 1972, Homozygous deficiency of the third component of complement (C3) in a patient with repeated infections, Lancet 2: 1179–1181.PubMedCrossRefGoogle Scholar
  5. Alper,. A., Colten, H. R., Gear, J. S. S., Rabson, A. R., Rosen, F. S., 1976, Homozygous C3 deficiency. The role of C3 in antibody production, Cls-induced vasopermeability, and cobra venom reduced passive hemolysis, J. Clin. Invest. 57: 222–229.Google Scholar
  6. Ballow, M., Day, N. K., Biggar, W. D., Park, B. H., Yount, W. J., Good, R. A., 1973, Reconstitution of Clq following bone marrow transplantation in patients with severe combined immunodeficiency, Clin. Immunol. Immunopathal. 2: 28–35.CrossRefGoogle Scholar
  7. Ballow, M., Shira, J. E., Harden, L., Yang, S. Y., Day, N. K., 1975, Complete absence of the third component of complement in man, J. Clin. Invest. 56: 703–710.PubMedCrossRefGoogle Scholar
  8. Beck, P., Willis, D., Davies, G. T., Lachmann, P. J., Sussman, M., 1973, A family study of hereditary angioneurotic oedema, Q. J. Med. 42: 317–339.PubMedGoogle Scholar
  9. Blum, L., Lee, K., Lee, S. L., Barone, R., Wallace, S. L., 1976, Hereditary Cls deficiency, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 35(3)(abstract 2480 ).Google Scholar
  10. Boyer, J. T., Gall, E. P., Norman, M. E., Nilsson, U. R., Zimmerman, T. S., 1975, Hereditary deficiency of the seventh component of complement, J. Clin. Invest. 56: 905–913.PubMedCrossRefGoogle Scholar
  11. de Bracco, M. M. E., Windhorst, D., Stroud, R. M., Moncada, B., 1974, The autosomal Clr deficiency in a large Puerto Rican family, Clin. Exp. Immunol. 16: 183–188.Google Scholar
  12. Champion, R. H., Lachmann, P. J., 1969, Hereditary angio-oedema treated with e-aminocaproic acid. Br. J. Dermatol. 81: 763–5.PubMedCrossRefGoogle Scholar
  13. Cohen, G., Peterson, A., 1972, Treatment of hereditary angioedema with frozen plasma, Ann. Allergy 30: 690–692.PubMedGoogle Scholar
  14. Cooper, N. R., tenBensel, R., Kohler, P. F., 1968, Studies of an additional kindred with hereditary deficiency of the second component of human complement (C2) and description of a new method for the quantitation of C2, J. Immunol. 101: 1176–1182.PubMedGoogle Scholar
  15. Day, N. K., Good, R. A., 1975, Deficiencies of the complement system in man, in: Immunodefi-ciency in Man And Animals (R. A. Good, J. Finstad, and N. W. Paul, eds.), in: Birth Defects: Original Article Ser. XI (1): 306–311, Sinauer Associates, Sunderland, Massachusetts.Google Scholar
  16. Day, N. K., Gewurz, H., Pickering, R. J., Good, R. A., 1970, Ontogenic studies of Clq synthesis in the piglet, J. Immunol. 104: 1316–1319.PubMedGoogle Scholar
  17. Day, N. K., Geiger, H., Stroud, R., deBracco, M. M. E., Moncada, B., Windhorst, D., Good, R. A., 1972, Clr deficiency. An inborn error associated with cutaneous and renal disease. J. Clin. Invest. 51: 1102–1108.PubMedCrossRefGoogle Scholar
  18. Day, N. K., Geiger, H., McLean, R., Michael, A., Good, R. A., 1973, C2 deficiency: Development of lupus erythematosus, J. Clin. Invest. 52: 1601–1607.PubMedCrossRefGoogle Scholar
  19. Day, N. K., Geiger, H., Good, R. A., 1975a, Complement, in: Molecular Pathology ( R. A. Good, S. B. Day, and J. Yunis, eds.), pp. 115–160, Charles C. Thomas, Springfield, Illinois.Google Scholar
  20. Day, N. K., L’Esperance, P., Good, R. A., Michael, A. F., Hansen, J. A., Dupont, B., Jersild, C., 1975b, Hereditary C2 deficiency: Genetic studies and association with the HL-A system, J. Exp. Med. 141: 1464–1469.PubMedCrossRefGoogle Scholar
  21. Day, N. K., Rubinstein, P., Case, D., Walker, M. E., Tulchin, M., Good, R. A., Dupont, B., Hansen, J. A., Jersild, C., 1976a, Linkage of gene for C2 deficiency and the major histocompatibility complex (MHR) in man. Family study of a further case, Vox Sang. 31 (2): 96–102.PubMedCrossRefGoogle Scholar
  22. Day, N. K., Degos, L., Beth, M., Sasportes, M., Gharbi, R., Giraldo, G., 1976b, C8 deficiency in a family with xeroderma pigmentosum. Lack of linkage to the HL-A region, in: HLA and Disease, Vol. 58, p. 197 (abstract), INSERM, Paris.Google Scholar
  23. Donaldson, V. H., Evans, R. R., 1963, A biochemical abnormality in hereditary angioneuroticedema: absence of serum inhibitor of C′l esterase, Amer. J. Med. 35: 37–44.PubMedCrossRefGoogle Scholar
  24. Donaldson, V. H., Ratnoff, O. D., Dias da Silva, W., Rosen, F. S., 1969, Permeability increasing activity in hereditary angioneurotic edema plasma. II. Mechanism of formation and partial characterization, J. Clin. Invest. 48: 642–653.Google Scholar
  25. Donaldson, V. M., Mertee, E., Rosen, F. S., Kretschmer, K. W., Lepow, J. M., 1970, A polypeptide kinin in hereditary angioneurotic edema plasma; Role of complement in its formation, J. Lab. Clin. Med. 76: 986 (abstract).Google Scholar
  26. Douglass, M. C., Lamberg, S. I., Lorincz, A. L., Good, R. A., Day, N. K., 1976, Lupus erythematosus-like syndrome with a familial deficiency of C2, Arch. Dermatol. 112: 671–674.PubMedCrossRefGoogle Scholar
  27. Fu, S. M., Kunkel, HG., Brusman, H. P., Allen, F. M., Jr., Fotino, M., 1974, Evidence for linkage between HL-A histocompatibility genes and those involved in the synthesis of the second component of complement, J. Exp. Med. 140: 1108–1111.PubMedCrossRefGoogle Scholar
  28. Fu, S. M., Stern, R., Kunkel, H. G., Dupont, B., Hansen, J. A., Day, N. K., Good, R. A., Jersild, C., Fotino, M., 1975, LD-7a association with C2 deficiency in five of six families, in: Histocompatibility Testing 1975, Proceedings of the 6th International Histocompatibility Workshop, pp. 933–936, Munksgaard A/S, Copenhagen.Google Scholar
  29. Gabrielsen, A. E., Linna, T. J., Weitekamp, D. P., Pickering, R. J., 1974, Reduced hemolytic CI activity in serum of hypogammaglobulinemic chickens, Immunology 27: 463–468.PubMedGoogle Scholar
  30. Gewurz, H., Pickering, R. J., Naff, G. B., Snyderman, R., Mergenhagen, S. E., Good, R. A., 1969, Decreased properdin activity in acute glomerulonephritis, Int. Arch. Allergy 56: 592.CrossRefGoogle Scholar
  31. Götze, O., Miiller-Eberhard, H. J., 1971, The C3 activation system: an alternate pathway of complement activation, J. Exp. Med. 134: 90s–108s.PubMedGoogle Scholar
  32. Haines, A. L., Lepow, I. H., 1964, Studies on human C′l esterase. II. Function of purified C′l esterase in the human complement system, J. Immunol. 92: 468–478.PubMedGoogle Scholar
  33. Hauptman, G., Grosshans, E., Heid, E., 1974, Lupus erythemateux aigus et déficits héréditaires en complement. A propos d’un cas par déficit complement en C, Ann. Dermatol. Syphilgr. Paris 101: 479–495.Google Scholar
  34. Jaffee, C. J., Atkinson, J. P., Gelfand, J. A., Frank, M. M., 1975, Hereditary angioedema: the use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery, J. Allergy Clin. Immunol. 55: 386–393.CrossRefGoogle Scholar
  35. Klemperer, M. R., Woodworth, H. C., Rosen, F. S., Austen, K. F., 1966, Hereditary deficiency of the second component of complement (C′2) in man, J. Clin. Invest. 45: 880–890.PubMedCrossRefGoogle Scholar
  36. Klemperer, M. R., Austen, K. F., Rosen, F. S., 1967, Hereditary deficiency of the second component of complement (C′2) in man: further observations of a second kindred, J. Immunol. 98: 72–78.PubMedGoogle Scholar
  37. Klemperer, M. R., Rosen, F. S., Donaldson, V. H., 1969, A polypeptide derived from the second component of human complement (C2) which increases vascular permeability, J. Clin. Invest. 48 (Jan.-June): 44a–45a (abstract 142).Google Scholar
  38. Kohler, P. F., Müller-Eberhard, H. J., 1972, Metabolism of human Clq studies in hypogammaglobulinemia, myeloma and systemic lupus erythematosus, J. Clin. Invest. 51: 868–875.PubMedCrossRefGoogle Scholar
  39. Kohler, P. F., Percy, J., Campion, W. M., Smyth, C. J., 1974, Hereditary angioedema and “familial” lupus erythematosus in identical twin boys, Amer. J. Med. 56: 406–411.PubMedCrossRefGoogle Scholar
  40. Landerman, N. S., 1962, Hereditary angioneurotic edema. I. Case reports and review of the literature, J. Allergy 33: 316–329.PubMedCrossRefGoogle Scholar
  41. Landerman, N. S., Webster, M. E., Becker, E. L., Ratcliffe, H. E., 1960, Hereditary angioneurotic edema. II. Deficiency of inhibitor for serum globulin permeability factor and/or plasma kallikrein, J. Allergy 33: 330.CrossRefGoogle Scholar
  42. Laurell, A. B., Lindegren, J., Malmros, J., Martensson, A., 1969, Enzymatic and immunochemical estimation of CI esterase inhibitor in sera from patients with hereditary angioneurotic edema, Scand. J. Clin. Lab. Invest. 24: 221.PubMedCrossRefGoogle Scholar
  43. Leddy, J. P., Frank, M. M., Gaither, T., Baum, J., Klemperer, M. R., 1974, Hereditary deficiency of the sixth component of complement in man, J. Clin. Invest. 53: 544–553.PubMedCrossRefGoogle Scholar
  44. Leddy, J. P., Griggs, R. C., Klemperer, M. R., Frank, M. M., 1975, Hereditary complement (C2) deficiency with dermatomyositis, Amer. J. Med. 58: 83–91.PubMedCrossRefGoogle Scholar
  45. Lepow, I. M., 1971, Permeability producing peptide by product of the interaction of the fourth and second components of complement, in: Biochemistry of the Acute Allergic Reactions: Second International Symposium ( K. F. Austen and E. L. Becker, eds.), pp. 205–215, Blackwell Scientific Publications, London.Google Scholar
  46. Levy, R., Lepow, I. H., 1959, Assay and properties of serum inhibitor of C′l esterase, Proc. Soc. Exp. Biol. Med. 101: 608–611.PubMedGoogle Scholar
  47. Lim, D., Gewurz, A., Lint, T., Ghaze, M., Sepheri, B., Gewurz, H., 1976, Absence of the sixth component of complement in a patient with repeated episodes of meningococcal meningitis, J. Ped. 89: 42–47.CrossRefGoogle Scholar
  48. Lundh, B., Laurell, A. B., Wetterqvist, H., White, T., Granerus, G., 1968, A case of hereditary angioneurotic oedema, successfully treated with e-aminocaproic acid. Studies on C′l esterase inhibitor, C′l activation, plasminogen level and histamine metabolism, Clin. Exp. Immunol. 3: 733–745.PubMedGoogle Scholar
  49. Merritt, A. D., Petersen, B. H., Angenieta, A. B., Meyers, D. A., Brooks, G. F., Hodes, M. E., 1976, Chromosome G: Linkage of the eighth component of complement (C8) to the histocompatibility region (HLA), in: 3rd International Workshop on Human Gene Mapping. Birth Defects XII, p. 6, Baltimore Conference, The National Foundation, New York, in press.Google Scholar
  50. Miller, M. E., Nilsson, U. R., 1970, A familial deficiency of the phagocytosing enhancing activity of serum related to a C5 dysfunction of the fifth component of complement (C5), N. Engl. J. Med. 282: 354–358.PubMedCrossRefGoogle Scholar
  51. Miller, M. E., Seals, J., Kaje, R., Levitsky, L. C., 1968, A familial plasma-associated defect of phagocytosis. A new cause of recurrent bacterial infections, Lancet 2 (July): 60–63.Google Scholar
  52. Moncada, B., Day, N. K., Good, R. A., Windhorst, D. B., 1972, Lupus erythematosus-like syndrome with a familial defect of complement, N. Engl. J. Med. 286: 689–693.PubMedCrossRefGoogle Scholar
  53. Müller-Eberhard, H. J., Kunkel, H. G., 1961, Isolation of a thermolabile serum protein which precipitates y-globulin aggregates and participates in immune hemolysis, Proc. Soc. Exp. Biol. N. Y. 106: 291–295.Google Scholar
  54. O’Connell, E. J., Enriquez, P., Linman, J. W., Gleich, G. J., McDuffie, F. C., 1967, Absence of activity of first component of complement in man: Association with thymic alymphoplasia and defective inflammatory response, J. Lab. Clin. Med. 70: 715.Google Scholar
  55. Osofsky, S. G., Thompson, B. H., Lint, T. F., Gewurz, H., 1976, Hereditary deficiency of the third component of complement in a child with fever, skin rash and arthralgias and response to whole blood transfusion, J. Ped., in press.Google Scholar
  56. Osterland, C. K., Espinoza, L., Parker, L. P., Schur, P. H., 1975, Inherited C2 deficiency and systemic lupus erythematosus: Studies on a family. Ann. Intern. Med. 82: 323–328.PubMedGoogle Scholar
  57. Pensky, J., Schwick, H. G., 1969, Human serum inhibitor of C′l esterase: Identity with a2- neuraminoglycoprotein, Science 163: 698–699.PubMedCrossRefGoogle Scholar
  58. Petersen, B. H., Graham, J. A., Boroks, G. F., 1976, Human deficiency of the eighth component of complement: The requirement of C8 for serum Neisseria gonorrhoeae bactericidal activity, J. Clin. Invest. 57: 283–290.PubMedCrossRefGoogle Scholar
  59. Pickering, R. J., Good, R. A., Kelly, J. R., 1969, Replacement therapy in hereditary angioedema. Successful treatment of two patients with fresh frozen plasma, Lancet 1: 326–330.PubMedCrossRefGoogle Scholar
  60. Pickering, R. J., Naff, G. B., Stroud, R. M., Good, R. A., Gewurz, H., 1970, Deficiency of Clr in human serum; effects on the structure and function of macromolecular Cl, J. Exp. Med. 141: 803–815.CrossRefGoogle Scholar
  61. Pickering, R. J., Michael, A. F., Herdman, R. C., Good, R. A., Gewurz, H., 1971, The complement system in chronic glomerulonephritis: three newly associated aberrations, J. Pediatr. 78: 30–43.PubMedCrossRefGoogle Scholar
  62. Pondman, K. W., Stoop, J. W., Cormane, R. H., Hannema, A. J., 1968, Abnormal CI in a patient with systemic lupus erythematosus, J. Immunol. 101: 811 (abstract).Google Scholar
  63. Ratnoff, O. D., Lepow, I. H., 1963, Complement as a mediator of inflammation. Enhancement of vascular permeability by purified human C′l esterase, J. Exp. Med. 118: 681–697.PubMedCrossRefGoogle Scholar
  64. Rittner, C. H., Hauptmann, G., Grosse-Wilde, H., Grosshans, E., Tongio, M. M., Mayr, S., 1975, Linkage between HL-A (major histocompatibility complex) and genes controlling the synthesis of the fourth component of complement, in: Histocompatibility Testing 1975, pp. 945–954, Munksgaard, Copenhagen.Google Scholar
  65. Rosen, F. S., Charache, P., Pensky, J., Donaldson V., 1965, Hereditary angioneurotic edema: two genetic variants, Science 148: 957–958.PubMedCrossRefGoogle Scholar
  66. Rosenfeld, S. I., Kelly, M. E., Leddy, J. P., 1976, Hereditary deficiency of the fifth component of complement in man, J. Clin. Invest. 57: 1626–1634.PubMedCrossRefGoogle Scholar
  67. Ruddy, S., Klemperer, M. R., Rosen, F. S., Austen, K. F., Kumate, J., 1970, Hereditary deficiency of the second component of complement (C2) in man; correlation of C2 haemolytic activity with immunochemical measurements of C2 protein, Immunology 18: 943–954.PubMedGoogle Scholar
  68. Schultze, H. E., Heide, K., Haupt, H., 1962, Über ein bisher unbekanntes Saures α2-Glycoprotein, Naturwissenschaften 94: 133.Google Scholar
  69. Silverstein, A. M., 1960, Essential hypocomplementemia: report of a case, Blood 16: 1338–1341.PubMedGoogle Scholar
  70. Stecher, U. J., Thorbecke, C. J., 1967, Sites of synthesis of serum proteins produced by macro-phages in vitro, J. Immunol. 99: 643.PubMedGoogle Scholar
  71. Stern, R., Fu, S. M., Fotino, M., Agnello, V., Kunkel, H. G., 1976, Hereditary C2 deficiency: association with skin lesions resembling the discoid lesion of SLE, Arthritis Rheum. 19: 45–50.CrossRefGoogle Scholar
  72. Sussman, M., Jones, J. S., Almeida, J. D., 1973, Deficiency of the second component of complement associated with anaphylactoid purpura and presence of mycoplasma in the serum, Clin. Exp. Immunol. 14: 531–539.PubMedGoogle Scholar
  73. Torisu, M., Sonozaki, H., Inai, S., Arata, M., 1970, Deficiency of the fourth component of complement in man, J. Immunol. 104: 728–737.PubMedGoogle Scholar
  74. Wellek, B., Opferkuch, W., 1974, A case of deficiency of the seventh component of complement in man. Biological properties of a C7-deficient serum and description of a C7-inactivating principle, Clin. Exp. Immunol. 19: 223–225.Google Scholar
  75. Wild, J. H., Zvaifler, N. J., Müller-Eberhard, H. J., Wilson, C. B., 1976, Deficiency of the second component of complement (C2) in a patient with discoid lupus erythematosus, Clin. Exp. Immunol. 24: 238–248.PubMedGoogle Scholar
  76. Wolski, K. P., Schmid, F. R., Mittal, K. K., 1975, Genetic linkage between the HL-A system and a deficit of the second component (C2) of complement, Science 188: 1020–1022.PubMedCrossRefGoogle Scholar
  77. Zimmerman, T. S., Müller-Eberhard, H. J., 1971, Blood coagulation initiation by a complement- mediated pathway, J. Exp. Med. 134: 1601–1607.PubMedCrossRefGoogle Scholar
  78. Zimmerman, T. S., Arroyave, C. M., Müller-Eberhard, H. J., 1971, A blood coagulation abnormality in rabbits deficient in the sixth component of complement (C6) and its correction by purified C6, J. Exp. Med. 134: 1591–1600.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1977

Authors and Affiliations

  • Noorbibi K. Day
    • 1
  • B. Moncada
    • 2
  • Robert A. Good
    • 1
  1. 1.Sloan-Kettering Institute for Cancer ResearchNew YorkUSA
  2. 2.Universidad Autonoma de San Luis PotosiSan Luis PotosiMexico

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