Clark, Chad R.

ABSTRACT Superantigens (SAg), the potent activators of the immune system, are important determinants of Staphylococcus aureus virulence and pathogenicity. Superior response to SAg in human leukocyte antigen (HLA)-DR3 transgenic mice rendered them more susceptible than C57BL/6 mice to pneumonia caused by SAg-producing strains of S. aureus . Linezolid, a bacterial protein synthesis inhibitor, was superior to vancomycin in inhibiting SAg production by S. aureus in vitro and conferred greater protection from pneumonia caused by SAg-producing staphylococci.

Abstract 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.