Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1986 Nov;39(5):584–602.

Evidence that autoimmunity in man is a Mendelian dominant trait.

W B Bias, J D Reveille, T H Beaty, D A Meyers, F C Arnett
PMCID: PMC1684061  PMID: 3098096

Abstract

Family studies of autoimmune diseases are consistent with multifactorial etiology. However, familial occurrence of the autoimmune trait as defined by the presence of autoimmune disease and/or high titer autoantibody supports the hypothesis that autoimmunity is inherited as an autosomal dominant trait. Based on genetic analysis of 18 autoimmune kindreds, the population frequency of this primary autoimmune gene is approximately .10 with penetrance estimates of 92% in females and 49% in males. The estimated high penetrance of the autoimmune gene in females suggests that the interacting genetic and/or environmental factors must be numerous or ubiquitous. Sex, age, and specific major histocompatibility complex (MHC) antigens are among the genetic and physiological factors known to influence autoimmunity. A genetic model is proposed that takes these factors into account. Inherent in the hypothesis of a primary autoimmune gene is that it is epistatic to other, secondary, genes that influence the autoimmune phenotype. The genetic model further postulates that the secondary genes, including those of the MHC, confer specificity to the phenotype. The effects of the secondary genes can be modulated by gonadal steroids and, over time, may be abrogated by environmental challenges, such as viral infections.

Full text

PDF
584

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams D. D., Knight J. G. H gene theory of inherited autoimmune disease. Lancet. 1980 Feb 23;1(8165):396–398. doi: 10.1016/s0140-6736(80)90946-0. [DOI] [PubMed] [Google Scholar]
  2. Arnett F. C., Reveille J. D., Wilson R. W., Provost T. T., Bias W. B. Systemic lupus erythematosus: current state of the genetic hypothesis. Semin Arthritis Rheum. 1984 Aug;14(1):24–35. doi: 10.1016/0049-0172(84)90006-4. [DOI] [PubMed] [Google Scholar]
  3. Bell D. A., Rigby R., Stiller C. R., Clark W. F., Harth M., Ebers G. HLA antigens in systemic lupus erythematosus: relationship to disease severity, age at onset, and sex. J Rheumatol. 1984 Aug;11(4):475–479. [PubMed] [Google Scholar]
  4. Benacerraf B., Germain R. N. A single major pathway of T-lymphocyte interactions in antigen-specific immune suppression. Scand J Immunol. 1981;13(1):1–10. doi: 10.1111/j.1365-3083.1981.tb00104.x. [DOI] [PubMed] [Google Scholar]
  5. Berzofsky R. N., Dorsch C. A., Stevens M. B. Limited anti-DNA antibody specificity in systemic lupus erythematosus. Arthritis Rheum. 1977 Sep-Oct;20(7):1320–1325. doi: 10.1002/art.1780200704. [DOI] [PubMed] [Google Scholar]
  6. Bias W. B., Hsu S. H., Pollard M. K., Harvey J., Lotze M. T., Arnett F. C., Stevens M. B. HLA-DR characterization of a Chippewa Indian subpopulation with high prevalence of rheumatoid arthritis. Hum Immunol. 1981 Mar;2(2):155–163. doi: 10.1016/0198-8859(81)90062-8. [DOI] [PubMed] [Google Scholar]
  7. Block S. R., Winfield J. B., Lockshin M. D., D'Angelo W. A., Christian C. L. Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets. Am J Med. 1975 Oct;59(4):533–552. doi: 10.1016/0002-9343(75)90261-2. [DOI] [PubMed] [Google Scholar]
  8. Burek C. L., Hoffman W. H., Rose N. R. The presence of thyroid autoantibodies in children and adolescents with autoimmune thyroid disease and in their siblings and parents. Clin Immunol Immunopathol. 1982 Dec;25(3):395–404. doi: 10.1016/0090-1229(82)90204-5. [DOI] [PubMed] [Google Scholar]
  9. Datta S. K., Manny N., Andrzejewski C., André-Schwartz J., Schwartz R. S. Genetic studies of autoimmunity and retrovirus expression in crosses of New Zealand black mice I. Xenotropic virus. J Exp Med. 1978 Mar 1;147(3):854–871. doi: 10.1084/jem.147.3.854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. DeHoratius R. J., Pillarisetty R., Messner R. P., Talal N. Anti-nucleic acid antibodies in systemic lupus erythematosus patients and their families. Incidence and correlation with lymphocytotoxic antibodies. J Clin Invest. 1975 Nov;56(5):1149–1154. doi: 10.1172/JCI108190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. FIALKOW P. J., FUDENBERG H., EPSTEIN W. V. "ACQUIRED" ANTIBODY HEMOLYTIC ANEMIA AND FAMILIAL ABERRATIONS IN GAMMA GLOBULINS. Am J Med. 1964 Feb;36:188–199. doi: 10.1016/0002-9343(64)90082-8. [DOI] [PubMed] [Google Scholar]
  12. Grossman C. J. Interactions between the gonadal steroids and the immune system. Science. 1985 Jan 18;227(4684):257–261. doi: 10.1126/science.3871252. [DOI] [PubMed] [Google Scholar]
  13. HOLBOROW E. J., WEIR D. M., JOHNSON G. D. A serum factor in lupus erythematosus with affinity for tissue nuclei. Br Med J. 1957 Sep 28;2(5047):732–734. doi: 10.1136/bmj.2.5047.732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harley J. B., Alexander E. L., Bias W. B., Fox O. F., Provost T. T., Reichlin M., Yamagata H., Arnett F. C. Anti-Ro (SS-A) and anti-La (SS-B) in patients with Sjögren's syndrome. Arthritis Rheum. 1986 Feb;29(2):196–206. doi: 10.1002/art.1780290207. [DOI] [PubMed] [Google Scholar]
  15. Harley J. B., Reichlin M., Arnett F. C., Alexander E. L., Bias W. B., Provost T. T. Gene interaction at HLA-DQ enhances autoantibody production in primary Sjögren's syndrome. Science. 1986 May 30;232(4754):1145–1147. doi: 10.1126/science.3458307. [DOI] [PubMed] [Google Scholar]
  16. Hochberg M. C., Boyd R. E., Ahearn J. M., Arnett F. C., Bias W. B., Provost T. T., Stevens M. B. Systemic lupus erythematosus: a review of clinico-laboratory features and immunogenetic markers in 150 patients with emphasis on demographic subsets. Medicine (Baltimore) 1985 Sep;64(5):285–295. [PubMed] [Google Scholar]
  17. Howie J. B., Helyer B. J. The immunology and pathology of NZB mice. Adv Immunol. 1968;9:215–266. doi: 10.1016/s0065-2776(08)60444-7. [DOI] [PubMed] [Google Scholar]
  18. Jungers P., Nahoul K., Pelissier C., Dougados M., Tron F., Bach J. F. Low plasma androgens in women with active or quiescent systemic lupus erythematosus. Arthritis Rheum. 1982 Apr;25(4):454–457. doi: 10.1002/art.1780250415. [DOI] [PubMed] [Google Scholar]
  19. Knight J. G., Adams D. D. Genes determining autoimmune disease in New Zealand mice. J Clin Lab Immunol. 1981 May;5(3):165–170. [PubMed] [Google Scholar]
  20. Knight J. G., Adams D. D. The genetic basis of autoimmune disease. Ciba Found Symp. 1982;(90):35–56. doi: 10.1002/9780470720721.ch4. [DOI] [PubMed] [Google Scholar]
  21. Lahita R. G., Bradlow H. L., Kunkel H. G., Fishman J. Increased 16 alpha-hydroxylation of estradiol in systemic lupus erythematosus. J Clin Endocrinol Metab. 1981 Jul;53(1):174–178. doi: 10.1210/jcem-53-1-174. [DOI] [PubMed] [Google Scholar]
  22. Lahita R. G., Bradlow L., Fishman J., Kunkel H. G. Estrogen metabolism in systemic lupus erythematosus: patients and family members. Arthritis Rheum. 1982 Jul;25(7):843–846. doi: 10.1002/art.1780250726. [DOI] [PubMed] [Google Scholar]
  23. Lahita R. G., Chiorazzi N., Gibofsky A., Winchester R. J., Kunkel H. G. Familial systemic lupus erythematosus in males. Arthritis Rheum. 1983 Jan;26(1):39–44. doi: 10.1002/art.1780260107. [DOI] [PubMed] [Google Scholar]
  24. Laster A. J., Conley C. L., Kickler T. S., Dorsch C. A., Bias W. B. Chronic immune thrombocytopenic purpura in monozygotic twins: genetic factors predisposing to ITP. N Engl J Med. 1982 Dec 9;307(24):1495–1498. doi: 10.1056/NEJM198212093072406. [DOI] [PubMed] [Google Scholar]
  25. Lawley T. J., Hall R. P., Fauci A. S., Katz S. I., Hamburger M. I., Frank M. M. Defective Fc-receptor functions associated with the HLA-B8/DRw3 haplotype: studies in patients with dermatitis herpetiformis and normal subjects. N Engl J Med. 1981 Jan 22;304(4):185–192. doi: 10.1056/NEJM198101223040401. [DOI] [PubMed] [Google Scholar]
  26. Lerner R. A., Wilson C. B., Villano B. C., McConahey P. J., Dixon F. J. Endogenous oncornaviral gene expression in adult and fetal mice: quantitative, histologic, and physiologic studies of the major viral glycorprotein, gp70. J Exp Med. 1976 Jan 1;143(1):151–166. doi: 10.1084/jem.143.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Levy J. A. Xenotropic C-type viruses and autoimmune disease. J Rheumatol. 1975 Jun;2(2):135–148. [PubMed] [Google Scholar]
  28. Lippman S. M., Arnett F. C., Conley C. L., Ness P. M., Meyers D. A., Bias W. B. Genetic factors predisposing to autoimmune diseases. Autoimmune hemolytic anemia, chronic thrombocytopenic purpura, and systemic lupus erythematosus. Am J Med. 1982 Dec;73(6):827–840. doi: 10.1016/0002-9343(82)90773-2. [DOI] [PubMed] [Google Scholar]
  29. MORTEO O. G., FRANKLIN E. C., MCEWEN C., PHYTHYON J., TANNER M. Studies of relatives of patients with systemic lupus erythematosus. Arthritis Rheum. 1961 Aug;4:356–363. doi: 10.1002/art.1780040404. [DOI] [PubMed] [Google Scholar]
  30. Ott J. Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet. 1974 Sep;26(5):588–597. [PMC free article] [PubMed] [Google Scholar]
  31. Reveille J. D., Arnett F. C., Wilson R. W., Bias W. B., McLean R. H. Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus. Immunogenetics. 1985;21(4):299–311. doi: 10.1007/BF00430796. [DOI] [PubMed] [Google Scholar]
  32. Reveille J. D., Wilson R. W., Provost T. T., Bias W. B., Arnett F. C. Primary Sjögren's syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med. 1984 Dec;101(6):748–756. doi: 10.7326/0003-4819-101-6-748. [DOI] [PubMed] [Google Scholar]
  33. Roubinian J. R., Papoian R., Talal N. Androgenic hormones modulate autoantibody responses and improve survival in murine lupus. J Clin Invest. 1977 Jun;59(6):1066–1070. doi: 10.1172/JCI108729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stimson W. H., Hunter I. C. Oestrogen-induced immunoregulation mediated through the thymus. J Clin Lab Immunol. 1980 Jul;4(1):27–33. [PubMed] [Google Scholar]
  35. Yoshiki T., Mellors R. C., Strand M., August J. T. The viral envelope glycoprotein of murine leukemia virus and the pathogenesis of immune complex glomerulonephritis of New Zealand mice. J Exp Med. 1974 Oct 1;140(4):1011–1027. doi: 10.1084/jem.140.4.1011. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES