Chronic nasal and skin colonization with superantigen (SAg)-producing Staphylococcus aureus is well documented in humans. Given that trans-mucosal and trans-cutaneous absorption of SAgs can occur, we determined whether chronic exposure to small amounts of SAg per se could activate autoreactive CD4+ and CD8+ T cells and precipitate any autoimmune disease without further external autoantigenic stimulation. Because HLA class II molecules present SAg more efficiently than do mouse MHC class II molecules, HLA-DQ8 transgenic mice were implanted s.c. with mini-osmotic pumps capable of continuously delivering the SAg, staphylococcal enterotoxin B (total of 10 μg/mouse), or PBS over 4 wk. Chronic exposure to staphylococcal enterotoxin B resulted in a multisystem autoimmune inflammatory disease with features similar to systemic lupus erythematosus. The disease was characterized by mononuclear cell infiltration of lungs, liver, and kidneys, accompanied by the production of anti-nuclear Abs and deposition of immune complexes in the renal glomeruli. The inflammatory infiltrates in various organs predominantly consisted of CD4+ T cells bearing TCR Vβ8. The extent of immunopathology was markedly reduced in mice lacking CD4+ T cells and CD28, indicating that the disease is CD4+ T cell mediated and CD28 dependent. The absence of disease in STAT4-deficient, as well as IFN-γ–deficient, HLA-DQ8 mice suggested the pathogenic role of Th1-type cytokines, IL-12 and IFN-γ. In conclusion, our study suggests that chronic exposure to extremely small amounts of bacterial SAg could be an etiological factor for systemic lupus erythematosus.
This work was supported by National Institutes of Health Grant 5K23AR057815-02, an American College of Rheumatology Research and Education Foundation Career Development Bridge Funding Award, and a Ronald F. Kinney Executive Dean for Research Career Development Award from the Mayo Foundation (all to V.R.C.), as well as a Mayo Clinic Research Early Career Development Award (to G.R.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- staphylococcal enterotoxin B
- systemic inflammatory response syndrome
- systemic lupus erythematosus
- Smith Ag
- staphylococcal superantigen
- regulatory T cell.
- Received April 13, 2012.
- Accepted June 7, 2012.
- Copyright © 2012 by The American Association of Immunologists, Inc.