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. 1996 Mar 1;97(5):1348–1354. doi: 10.1172/JCI118552

Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans.

J E Salmon 1, S Millard 1, L A Schachter 1, F C Arnett 1, E M Ginzler 1, M F Gourley 1, R Ramsey-Goldman 1, M G Peterson 1, R P Kimberly 1
PMCID: PMC507190  PMID: 8636449

Abstract

Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.

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Selected References

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  1. AboT, Tilden A. B., Balch C. M., Kumagai K., Troup G. M., Cooper M. D. Ethnic differences in the lymphocyte proliferative response induced by a murine IgG1 antibody, Leu-4, to the T3 molecule. J Exp Med. 1984 Jul 1;160(1):303–309. doi: 10.1084/jem.160.1.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson C. L., Shen L., Eicher D. M., Wewers M. D., Gill J. K. Phagocytosis mediated by three distinct Fc gamma receptor classes on human leukocytes. J Exp Med. 1990 Apr 1;171(4):1333–1345. doi: 10.1084/jem.171.4.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Antes U., Heinz H. P., Loos M. Evidence for the presence of autoantibodies to the collagen-like portion of C1q in systemic lupus erythematosus. Arthritis Rheum. 1988 Apr;31(4):457–464. doi: 10.1002/art.1780310401. [DOI] [PubMed] [Google Scholar]
  4. Blasini A. M., Stekman I. L., Leon-Ponte M., Caldera D., Rodriguez M. A. Increased proportion of responders to a murine anti-CD3 monoclonal antibody of the IgG1 class in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1993 Dec;94(3):423–428. [PMC free article] [PubMed] [Google Scholar]
  5. Clark M. R., Stuart S. G., Kimberly R. P., Ory P. A., Goldstein I. M. A single amino acid distinguishes the high-responder from the low-responder form of Fc receptor II on human monocytes. Eur J Immunol. 1991 Aug;21(8):1911–1916. doi: 10.1002/eji.1830210820. [DOI] [PubMed] [Google Scholar]
  6. Cochrane C. G., Koffler D. Immune complex disease in experimental animals and man. Adv Immunol. 1973;16(0):185–264. doi: 10.1016/s0065-2776(08)60298-9. [DOI] [PubMed] [Google Scholar]
  7. Drake C. G., Babcock S. K., Palmer E., Kotzin B. L. Genetic analysis of the NZB contribution to lupus-like autoimmune disease in (NZB x NZW)F1 mice. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4062–4066. doi: 10.1073/pnas.91.9.4062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Drake C. G., Rozzo S. J., Hirschfeld H. F., Smarnworawong N. P., Palmer E., Kotzin B. L. Analysis of the New Zealand Black contribution to lupus-like renal disease. Multiple genes that operate in a threshold manner. J Immunol. 1995 Mar 1;154(5):2441–2447. [PubMed] [Google Scholar]
  9. Dunckley H., Gatenby P. A., Hawkins B., Naito S., Serjeantson S. W. Deficiency of C4A is a genetic determinant of systemic lupus erythematosus in three ethnic groups. J Immunogenet. 1987 Aug-Oct;14(4-5):209–218. doi: 10.1111/j.1744-313x.1987.tb00383.x. [DOI] [PubMed] [Google Scholar]
  10. Edberg J. C., Kimberly R. P. Receptor specific probes for the study of Fc gamma receptor specific function. J Immunol Methods. 1992 Apr 8;148(1-2):179–187. doi: 10.1016/0022-1759(92)90171-o. [DOI] [PubMed] [Google Scholar]
  11. Frank M. M., Hamburger M. I., Lawley T. J., Kimberly R. P., Plotz P. H. Defective reticuloendothelial system Fc-receptor function in systemic lupus erythematosus. N Engl J Med. 1979 Mar 8;300(10):518–523. doi: 10.1056/NEJM197903083001002. [DOI] [PubMed] [Google Scholar]
  12. Gosselin E. J., Brown M. F., Anderson C. L., Zipf T. F., Guyre P. M. The monoclonal antibody 41H16 detects the Leu 4 responder form of human Fc gamma RII. J Immunol. 1990 Mar 1;144(5):1817–1822. [PubMed] [Google Scholar]
  13. Hamburger M. I., Lawley T. J., Kimberly R. P., Plotz P. H., Frank M. M. A serial study of splenic reticuloendothelial system Fc receptor functional activity in systemic lupus erythematosus. Arthritis Rheum. 1982 Jan;25(1):48–54. doi: 10.1002/art.1780250108. [DOI] [PubMed] [Google Scholar]
  14. Hawkins B. R., Wong K. L., Wong R. W., Chan K. H., Dunckley H., Serjeantson S. W. Strong association between the major histocompatibility complex and systemic lupus erythematosus in southern Chinese. J Rheumatol. 1987 Dec;14(6):1128–1131. [PubMed] [Google Scholar]
  15. Howard P. F., Hochberg M. C., Bias W. B., Arnett F. C., Jr, McLean R. H. Relationship between C4 null genes, HLA-D region antigens, and genetic susceptibility to systemic lupus erythematosus in Caucasian and black Americans. Am J Med. 1986 Aug;81(2):187–193. doi: 10.1016/0002-9343(86)90250-0. [DOI] [PubMed] [Google Scholar]
  16. Huang D. F., Siminovitch K. A., Liu X. Y., Olee T., Olsen N. J., Berry C., Carson D. A., Chen P. P. Population and family studies of three disease-related polymorphic genes in systemic lupus erythematosus. J Clin Invest. 1995 Apr;95(4):1766–1772. doi: 10.1172/JCI117854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hulett M. D., Hogarth P. M. Molecular basis of Fc receptor function. Adv Immunol. 1994;57:1–127. doi: 10.1016/s0065-2776(08)60671-9. [DOI] [PubMed] [Google Scholar]
  18. Indik Z., Kelly C., Chien P., Levinson A. I., Schreiber A. D. Human Fc gamma RII, in the absence of other Fc gamma receptors, mediates a phagocytic signal. J Clin Invest. 1991 Nov;88(5):1766–1771. doi: 10.1172/JCI115496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Johnson A. E., Gordon C., Palmer R. G., Bacon P. A. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum. 1995 Apr;38(4):551–558. doi: 10.1002/art.1780380415. [DOI] [PubMed] [Google Scholar]
  20. Kimberly R. P., Gibofsky A., Salmon J. E., Fotino M. Impaired fc-mediated mononuclear phagocyte system clearance in HLA-DR2 and MT1-positive healthy young adults. J Exp Med. 1983 May 1;157(5):1698–1703. doi: 10.1084/jem.157.5.1698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kimberly R. P., Parris T. M., Inman R. D., McDougal J. S. Dynamics of mononuclear phagocyte system Fc receptor function in systemic lupus erythematosus. Relation to disease activity and circulating immune complexes. Clin Exp Immunol. 1983 Feb;51(2):261–268. [PMC free article] [PubMed] [Google Scholar]
  22. McDaniel D. O., Alarcón G. S., Pratt P. W., Reveille J. D. Most African-American patients with rheumatoid arthritis do not have the rheumatoid antigenic determinant (epitope) Ann Intern Med. 1995 Aug 1;123(3):181–187. doi: 10.7326/0003-4819-123-3-199508010-00004. [DOI] [PubMed] [Google Scholar]
  23. Morel L., Rudofsky U. H., Longmate J. A., Schiffenbauer J., Wakeland E. K. Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity. 1994 Jun;1(3):219–229. doi: 10.1016/1074-7613(94)90100-7. [DOI] [PubMed] [Google Scholar]
  24. Moulds J. M., Krych M., Holers V. M., Liszewski M. K., Atkinson J. P. Genetics of the complement system and rheumatic diseases. Rheum Dis Clin North Am. 1992 Nov;18(4):893–914. [PubMed] [Google Scholar]
  25. Osborne J. M., Chacko G. W., Brandt J. T., Anderson C. L. Ethnic variation in frequency of an allelic polymorphism of human Fc gamma RIIA determined with allele specific oligonucleotide probes. J Immunol Methods. 1994 Aug 1;173(2):207–217. doi: 10.1016/0022-1759(94)90299-2. [DOI] [PubMed] [Google Scholar]
  26. Parren P. W., Warmerdam P. A., Boeije L. C., Arts J., Westerdaal N. A., Vlug A., Capel P. J., Aarden L. A., van de Winkel J. G. On the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest. 1992 Oct;90(4):1537–1546. doi: 10.1172/JCI116022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Parris T. M., Kimberly R. P., Inman R. D., McDougal J. S., Gibofsky A., Christian C. L. Defective Fc receptor-mediated function of the mononuclear phagocyte system in lupus nephritis. Ann Intern Med. 1982 Oct;97(4):526–532. doi: 10.7326/0003-4819-97-4-526. [DOI] [PubMed] [Google Scholar]
  28. Prada A. E., Strife C. F. IgG subclass restriction of autoantibody to solid-phase C1q in membranoproliferative and lupus glomerulonephritis. Clin Immunol Immunopathol. 1992 Apr;63(1):84–88. doi: 10.1016/0090-1229(92)90097-8. [DOI] [PubMed] [Google Scholar]
  29. Prada A. E., Strife C. F. IgG subclass restriction of autoantibody to solid-phase C1q in membranoproliferative and lupus glomerulonephritis. Clin Immunol Immunopathol. 1992 Apr;63(1):84–88. doi: 10.1016/0090-1229(92)90097-8. [DOI] [PubMed] [Google Scholar]
  30. Ravetch J. V., Kinet J. P. Fc receptors. Annu Rev Immunol. 1991;9:457–492. doi: 10.1146/annurev.iy.09.040191.002325. [DOI] [PubMed] [Google Scholar]
  31. Salmon J. E., Edberg J. C., Brogle N. L., Kimberly R. P. Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function. J Clin Invest. 1992 Apr;89(4):1274–1281. doi: 10.1172/JCI115712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Salmon J. E., Edberg J. C., Kimberly R. P. Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities. J Clin Invest. 1990 Apr;85(4):1287–1295. doi: 10.1172/JCI114566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Salmon J. E., Kimberly R. P., Gibofsky A., Fotino M. Defective mononuclear phagocyte function in systemic lupus erythematosus: dissociation of Fc receptor-ligand binding and internalization. J Immunol. 1984 Nov;133(5):2525–2531. [PubMed] [Google Scholar]
  34. Schreiber A. D., Rossman M. D., Levinson A. I. The immunobiology of human Fc gamma receptors on hematopoietic cells and tissue macrophages. Clin Immunol Immunopathol. 1992 Jan;62(1 Pt 2):S66–S72. doi: 10.1016/0090-1229(92)90043-n. [DOI] [PubMed] [Google Scholar]
  35. Siegert C. E., Daha M. R., Swaak A. J., van der Voort E. A., Breedveld F. C. The relationship between serum titers of autoantibodies to C1q and age in the general population and in patients with systemic lupus erythematosus. Clin Immunol Immunopathol. 1993 Jun;67(3 Pt 1):204–209. doi: 10.1006/clin.1993.1066. [DOI] [PubMed] [Google Scholar]
  36. Siegert C., Daha M., Westedt M. L., van der Voort E., Breedveld F. IgG autoantibodies against C1q are correlated with nephritis, hypocomplementemia, and dsDNA antibodies in systemic lupus erythematosus. J Rheumatol. 1991 Feb;18(2):230–234. [PubMed] [Google Scholar]
  37. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  38. Tate B. J., Witort E., McKenzie I. F., Hogarth P. M. Expression of the high responder/non-responder human Fc gamma RII. Analysis by PCR and transfection into FcR-COS cells. Immunol Cell Biol. 1992 Apr;70(Pt 2):79–87. doi: 10.1038/icb.1992.12. [DOI] [PubMed] [Google Scholar]
  39. Uwatoko S., Gauthier V. J., Mannik M. Autoantibodies to the collagen-like region of C1Q deposit in glomeruli via C1Q in immune deposits. Clin Immunol Immunopathol. 1991 Nov;61(2 Pt 1):268–273. doi: 10.1016/s0090-1229(05)80030-3. [DOI] [PubMed] [Google Scholar]
  40. Uwatoko S., Mannik M. Low-molecular weight C1q-binding immunoglobulin G in patients with systemic lupus erythematosus consists of autoantibodies to the collagen-like region of C1q. J Clin Invest. 1988 Sep;82(3):816–824. doi: 10.1172/JCI113684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Warmerdam P. A., van de Winkel J. G., Gosselin E. J., Capel P. J. Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). J Exp Med. 1990 Jul 1;172(1):19–25. doi: 10.1084/jem.172.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Warmerdam P. A., van de Winkel J. G., Vlug A., Westerdaal N. A., Capel P. J. A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding. J Immunol. 1991 Aug 15;147(4):1338–1343. [PubMed] [Google Scholar]
  43. Wener M. H., Mannik M., Schwartz M. M., Lewis E. J. Relationship between renal pathology and the size of circulating immune complexes in patients with systemic lupus erythematosus. Medicine (Baltimore) 1987 Mar;66(2):85–97. doi: 10.1097/00005792-198703000-00001. [DOI] [PubMed] [Google Scholar]
  44. Wisnieski J. J., Jones S. M. Comparison of autoantibodies to the collagen-like region of C1q in hypocomplementemic urticarial vasculitis syndrome and systemic lupus erythematosus. J Immunol. 1992 Mar 1;148(5):1396–1403. [PubMed] [Google Scholar]
  45. Yamada H., Watanabe A., Mimori A., Nakano K., Takeuchi F., Matsuta K., Tanimoto K., Miyamoto T., Yukiyama Y., Tokunaga K. Lack of gene deletion for complement C4A deficiency in Japanese patients with systemic lupus erythematosus. J Rheumatol. 1990 Aug;17(8):1054–1057. [PubMed] [Google Scholar]
  46. van de Winkel J. G., Capel P. J. Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications. Immunol Today. 1993 May;14(5):215–221. doi: 10.1016/0167-5699(93)90166-I. [DOI] [PubMed] [Google Scholar]

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