Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Aug 1;172(2):537–545. doi: 10.1084/jem.172.2.537

Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease

PMCID: PMC2188326  PMID: 2373992

Abstract

BALB/c athymic nu/nu mice spontaneously developed organ-specific (gastritis, thyroiditis, oophoritis, or orchitis) and systemic (arteritis, glomerulonephritis, and polyarthritis) autoimmune diseases when transplanted with neonatal BALB/c thymuses. Transplantation of thymuses from adult BALB/c mice was far less effective in inducing histologically evident organ-specific autoimmune disease in nu/nu mice. Autoimmune disease developed, however, when adult thymuses were irradiated at a T cell-depleting dose before transplantation. Engrafting newborn thymuses into BALB/c mice T cell depleted by thymectomy, irradiation, and bone marrow transplantation produced similar organ-specific autoimmune disease as well, but thymus engrafting into T cell-nondepleted BALB/c mice (i.e., mice thymectomized as adults, but not irradiated) did not, despite the fact that transplanted thymuses grew well in both groups of mice. The mice with organ-specific autoimmune disease produced autoantibodies specific for the respective organ components, such as gastric parietal cells, thyroglobulins, oocytes, or sperm. The thymus-transplanted nu/nu mice also had hypergammaglobulinemia and developed anti-DNA autoantibodies, rheumatoid factors, and immune complexes in the circulation. These results indicate that: (a) the thymus of a murine strain that does not develop spontaneous autoimmune disease can produce pathogenic self- reactive T cells that mediate organ-specific and/or systemic autoimmune diseases; and (b) such self-reactive T cells, especially those mediating organ-specific autoimmune disease, spontaneously expand and cause autoimmune disease when released to the T cell-deficient or - eliminated periphery.

Full Text

The Full Text of this article is available as a PDF (951.3 KB).

Selected References

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

  1. Alexander E. L., Moyer C., Travlos G. S., Roths J. B., Murphy E. D. Two histopathologic types of inflammatory vascular disease in MRL/Mp autoimmune mice. Model for human vasculitis in connective tissue disease. Arthritis Rheum. 1985 Oct;28(10):1146–1155. doi: 10.1002/art.1780281011. [DOI] [PubMed] [Google Scholar]
  2. Andrews B. S., Eisenberg R. A., Theofilopoulos A. N., Izui S., Wilson C. B., McConahey P. J., Murphy E. D., Roths J. B., Dixon F. J. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978 Nov 1;148(5):1198–1215. doi: 10.1084/jem.148.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berden J. H., Hang L., McConahey P. J., Dixon F. J. Analysis of vascular lesions in murine SLE. I. Association with serologic abnormalities. J Immunol. 1983 Apr;130(4):1699–1705. [PubMed] [Google Scholar]
  4. Ceredig R., Dialynas D. P., Fitch F. W., MacDonald H. R. Precursors of T cell growth factor producing cells in the thymus: ontogeny, frequency, and quantitative recovery in a subpopulation of phenotypically mature thymocytes defined by monoclonal antibody GK-1.5. J Exp Med. 1983 Nov 1;158(5):1654–1671. doi: 10.1084/jem.158.5.1654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dobashi K., Ono S., Murakami S., Takahama Y., Katoh Y., Hamaoka T. Polyclonal B cell activation by a B cell differentiation factor, B151-TRF2. III. B151-TRF2 as a B cell differentiation factor closely associated with autoimmune disease. J Immunol. 1987 Feb 1;138(3):780–787. [PubMed] [Google Scholar]
  6. Dukor P., Miller J. F., House W., Allman V. Regeneration of thymus grafts. I. Histological and cytological aspects. Transplantation. 1965 Sep;3(5):639–668. doi: 10.1097/00007890-196509000-00006. [DOI] [PubMed] [Google Scholar]
  7. Elder M., Maclaren N., Riley W., McConnell T. Gastric parietal cell and other autoantibodies in the BB rat. Diabetes. 1982 Apr;31(4 Pt 1):313–318. doi: 10.2337/diab.31.4.313. [DOI] [PubMed] [Google Scholar]
  8. GOOD R. A., ROTSTEIN J., MAZZITELLO W. F. The simultaneous occurrence of rheumatoid arthritis and agammaglobulinemia. J Lab Clin Med. 1957 Mar;49(3):343–357. [PubMed] [Google Scholar]
  9. Gleichmann E., Van Elven E. H., Van der Veen J. P. A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE. Eur J Immunol. 1982 Feb;12(2):152–159. doi: 10.1002/eji.1830120210. [DOI] [PubMed] [Google Scholar]
  10. Glimcher L. H., Schwartz R. H., Longo D. L., Singer A. The specificity of the syngeneic mixed leukocyte response, a primary anti-I region T cell proliferative response, is determined intrathymically. J Immunol. 1982 Sep;129(3):987–991. [PubMed] [Google Scholar]
  11. Hang L., Theofilopoulos A. N., Dixon F. J. A spontaneous rheumatoid arthritis-like disease in MRL/l mice. J Exp Med. 1982 Jun 1;155(6):1690–1701. doi: 10.1084/jem.155.6.1690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Irvine W. J., Clarke B. F., Scarth L., Cullen D. R., Duncan L. J. Thyroid and gastric autoimmunity in patients with diabetes mellitus. Lancet. 1970 Jul 25;2(7665):163–168. doi: 10.1016/s0140-6736(70)92531-6. [DOI] [PubMed] [Google Scholar]
  13. Izui S., McConahey P. J., Dixon F. J. Increased spontaneous polyclonal activation of B lymphocytes in mice with spontaneous autoimmune disease. J Immunol. 1978 Dec;121(6):2213–2219. [PubMed] [Google Scholar]
  14. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  15. Khoury E. L., Bottazzo G. F., Pontes de Carvalho L. C., Wick G., Roitt I. M. Predisposition to organ-specific autoimmunity in Obese strain (OS) chickens: reactivity to thyroid, gastric, adrenal and pancreatic cytoplasmic antigens. Clin Exp Immunol. 1982 Aug;49(2):273–282. [PMC free article] [PubMed] [Google Scholar]
  16. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  17. Klinman D. M., Steinberg A. D. Systemic autoimmune disease arises from polyclonal B cell activation. J Exp Med. 1987 Jun 1;165(6):1755–1760. doi: 10.1084/jem.165.6.1755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Like A. A., Rossini A. A., Guberski D. L., Appel M. C., Williams R. M. Spontaneous diabetes mellitus: reversal and prevention in the BB/W rat with antiserum to rat lymphocytes. Science. 1979 Dec 21;206(4425):1421–1423. doi: 10.1126/science.388619. [DOI] [PubMed] [Google Scholar]
  19. Mihara M., Ohsugi Y., Saito K., Miyai T., Togashi M., Ono S., Murakami S., Dobashi K., Hirayama F., Hamaoka T. Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent occurrence of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals. J Immunol. 1988 Jul 1;141(1):85–90. [PubMed] [Google Scholar]
  20. Morse H. C., 3rd, Steinberg A. D., Schur P. H., Reed N. D. Spontaneous "autoimmune disease" in nude mice. J Immunol. 1974 Aug;113(2):688–697. [PubMed] [Google Scholar]
  21. Pals S. T., Radaszkiewicz T., Roozendaal L., Gleichmann E. Chronic progressive polyarthritis and other symptoms of collagen vascular disease induced by graft-vs-host reaction. J Immunol. 1985 Mar;134(3):1475–1482. [PubMed] [Google Scholar]
  22. Penhale W. J., Farmer A., McKenna R. P., Irvine W. J. Spontaneous thyroiditis in thymectomized and irradiated Wistar rats. Clin Exp Immunol. 1973 Oct;15(2):225–236. [PMC free article] [PubMed] [Google Scholar]
  23. Pereira A. B., Theofilopoulos A. N., Dixon F. J. Detection and partial characterization of circulating immune complexes with solid-phase anti-C3. J Immunol. 1980 Aug;125(2):763–770. [PubMed] [Google Scholar]
  24. Prud'Homme G. J., Park C. L., Fieser T. M., Kofler R., Dixon F. J., Theofilopoulos A. N. Identification of a B cell differentiation factor(s) spontaneously produced by proliferating T cells in murine lupus strains of the lpr/lpr genotype. J Exp Med. 1983 Feb 1;157(2):730–742. doi: 10.1084/jem.157.2.730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rolink A. G., Gleichmann H., Gleichmann E. Diseases caused by reactions of T lymphocytes to incompatible structures of the major histocompatibility complex. VII. Immune-complex glomerulonephritis. J Immunol. 1983 Jan;130(1):209–215. [PubMed] [Google Scholar]
  26. Rubin R. L., Joslin F. G., Tan E. M. An improved ELISA for anti-native DNA by elimination of interference by anti-histone antibodies. J Immunol Methods. 1983 Oct 28;63(3):359–366. doi: 10.1016/s0022-1759(83)80009-x. [DOI] [PubMed] [Google Scholar]
  27. Sakaguchi S., Fukuma K., Kuribayashi K., Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med. 1985 Jan 1;161(1):72–87. doi: 10.1084/jem.161.1.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sakaguchi S., Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol. 1989 Jan 15;142(2):471–480. [PubMed] [Google Scholar]
  29. Sakaguchi S., Sakaguchi N. Thymus and autoimmunity. Transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice. J Exp Med. 1988 Apr 1;167(4):1479–1485. doi: 10.1084/jem.167.4.1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sakaguchi S., Takahashi T., Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med. 1982 Dec 1;156(6):1577–1586. doi: 10.1084/jem.156.6.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schwartz R. S., Stollar B. D. Origins of anti-DNA autoantibodies. J Clin Invest. 1985 Feb;75(2):321–327. doi: 10.1172/JCI111704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shlomchik M., Mascelli M., Shan H., Radic M. Z., Pisetsky D., Marshak-Rothstein A., Weigert M. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med. 1990 Jan 1;171(1):265–292. doi: 10.1084/jem.171.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sternthal E., Like A. A., Sarantis K., Braverman L. E. Lymphocytic thyroiditis and diabetes in the BB/W rat. A new model of autoimmune endocrinopathy. Diabetes. 1981 Dec;30(12):1058–1061. doi: 10.2337/diab.30.12.1058. [DOI] [PubMed] [Google Scholar]
  34. Weigle W. O. Analysis of autoimmunity through experimental models of thyroiditis and allergic encephalomyelitis. Adv Immunol. 1980;30:159–273. doi: 10.1016/s0065-2776(08)60196-0. [DOI] [PubMed] [Google Scholar]
  35. Weston K. M., Yeh E. T., Sy M. S. Autoreactivity accelerates the development of autoimmunity and lymphoproliferation in MRL/Mp-lpr/lpr mice. J Immunol. 1987 Aug 1;139(3):734–742. [PubMed] [Google Scholar]
  36. Wofsy D., Seaman W. E. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med. 1985 Feb 1;161(2):378–391. doi: 10.1084/jem.161.2.378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yuuki H., Yoshikai Y., Kishihara K., Matsuzaki G., Ayukawa K., Nomoto K. The expression and sequences of T cell antigen receptor beta-chain genes in the thymus at an early stage after sublethal irradiation. J Immunol. 1989 May 15;142(10):3683–3691. [PubMed] [Google Scholar]
  38. de Carvalho L. C., Wick G., Roitt I. M. Requirement of T cells for the development of spontaneous autoimmune thyroiditis in obese strain (OS) chickens. J Immunol. 1981 Feb;126(2):750–753. [PubMed] [Google Scholar]
  39. van Rappard-van der Veen F. M., Rolink A. G., Gleichmann E. Diseases caused by reactions of T lymphocytes towards incompatible structures of the major histocompatibility complex. VI. Autoantibodies characteristic of systemic lupus erythematosus induced by abnormal T-B cell cooperation across I-E. J Exp Med. 1982 May 1;155(5):1555–1560. doi: 10.1084/jem.155.5.1555. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES