title: Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen-induced toxic shock syndrome.
abstract: Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon-γ (IFN-γ), followed by multiple organ dysfunction and often death. As IFN-γ possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-γ or targeted disruption of IFN-γ gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-γ(+/+) mice became sick and succumbed to TSS, HLA-DR3.IFN-γ(-/-) mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-γ(-/-) transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA-DR3.IFN-γ(-/-) transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vβ8(+) CD4(+) and CD8(+) T cells was even more pronounced in HLA-DR3.IFN-γ(-/-) transgenic mice when compared to HLA-DR3.IFN-γ(+/+) mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-γ(+/+) and HLA-DR3.IFN-γ(-/-) transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-γ(+/+) transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-γ(-/-) transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-γ(+/+) but not HLA-DR3.IFN-γ(-/-) mice during TSS. Overall, IFN-γ seemed to play a lethal role in the immunopathogenesis of TSS by inflicting fatal small bowel pathology. Our study thus identifies the important role for IFN-γ in TSS.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Ashenafi Y
authors.initials: AY
authors.lastname: Tilahun
authors.forename: Marah
authors.initials: M
authors.lastname: Holz
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004768:Enterotoxins / Q000633:toxicity; D015803:HLA-DR3 Antigen / Q000235:genetics; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007410:Intestinal Diseases / Q000150:complications* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012772:Shock, Septic / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D018089:Superantigens / Q000633:toxicity*
chemical_list: D057134:Antibodies, Neutralizing; D018925:Chemokines; D016207:Cytokines; D004768:Enterotoxins; D015803:HLA-DR3 Antigen; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma