Chronic Exposure to Staphylococcal Superantigen Elicits a Systemic Inflammatory Disease Mimicking Lupus

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.

Systemic Inflammatory Response Elicited by Superantigen Destabilizes T Regulatory Cells, Rendering Them Ineffective during Toxic Shock Syndrome

“…Subsequently, 76 µl of 1X PBS was added to this mix to make the volume to 100 µl, the entire content was then loaded into a 7-day release Alzet mini-osmotic pump as per manufacturer’s protocol (Durect Corporation, Cupertino, CA, USA). The pumps were then surgically implanted sub-cutaneously into the back of mice as per standard procedure as described previously (34). The surgical wounds were closed with surgical staples.…”

FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights

“…Pathological lesions in lungs of transgenic mice, temperature fluctuations, delayed lethal end point later at 96 hour are similar to those in nonhuman primates (NHPs) exposed to lethal doses of SEB 18,111. Low-dose continuous administration of SEB to HLA-DQ8 transgenic mice induces a lupus-like syndrome with multiple organ injury 23. An alternative murine model deploys a “double-hit” strategy with two low doses of SEB using C3H/HeJ mice, an LPS-resistant mouse strain 76.…”

“…The cytokines IL-1, TNFα, IFNγ, IL-2, interleukin 6 (IL-6), and chemokines, specifically macrophage chemoattractant protein 1 (MCP-1), are induced early by superantigens in human PBMC. There is also a good correlation of the induction of these cytokines with lethal superantigen-induced shock in murine models 19,21,23,49–52. IL-1 and TNFα also activate other cells, including fibroblasts, epithelial, and endothelial cells, to perpetuate inflammation by inducing cell adhesion molecules and additional mediators from these cells 53.…”

“…Activated cells produce cytokines, chemokines, tissue factors, lytic enzymes, and reactive oxygen species (ROS), activating both inflammation and coagulation 16–18. These cytokines include tumor necrosis factor α (TNFα), interferon gamma (IFNγ), and interleukin 1 (IL-1), proinflammatory mediators with potent immunoenhancing effects, known to be pathogenic at high levels in vivo 18–23…”

Mini-Osmotic Pump Infusion Model to Investigate the Systemic Effects of Chronic Continuous Exposure to Staphylococcal Superantigen in Mice

“…The ALZET ® Osmotic Pumps are small, infusion pumps commonly used to deliver drugs or agents to unrestrained laboratory animals. We have demonstrated that continuous delivery of small amounts of SSAg using such mini-osmotic pumps causes a distinct systemic inflammatory disease in our humanized mouse model (11). In this chapter, we describe the protocol to investigate the systemic effects of chronic exposure to SSAg delivered using miniosmotic pumps.…”