title: Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care.
abstract: Host immunogenetic variations strongly influence the severity of group A streptococcus sepsis by modulating responses to streptococcal superantigens (Strep-SAgs). Although HLA-II-DR15/DQ6 alleles strongly protect against severe sepsis, HLA-II-DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome. We found that, regardless of individual variations in TCR-Vβ repertoires, the presentation of Strep-SAgs by the protective HLA-II-DR15/DQ6 alleles significantly attenuated proliferative responses to Strep-SAgs, whereas their presentation by the high-risk alleles augmented it. Importantly, HLA-II variations differentially polarized cytokine responses to Strep-SAgs: the presentation of Strep-SAgs by HLA-II-DR15/DQ6 alleles elicited significantly higher ratios of anti-inflammatory cytokines (e.g., IL-10) to proinflammatory cytokines (e.g., IFN-γ) than did their presentation by the high-risk HLA-II alleles. Adding exogenous rIL-10 significantly attenuated responses to Strep-SAgs presented by the high-risk HLA-II alleles but did not completely block the response; instead, it reduced it to a level comparable to that seen when these superantigens were presented by the protective HLA-II alleles. Furthermore, adding neutralizing anti-IL-10 Abs augmented Strep-SAg responses in the presence of protective HLA-II alleles to the same level as (but no higher than) that seen when the superantigens were presented by the high-risk alleles. Our findings provide a molecular basis for the role of HLA-II allelic variations in modulating streptococcal sepsis outcomes and suggest the presence of an internal control mechanism that maintains superantigen responses within a defined range, which helps to eradicate the infection while attenuating pathological inflammatory responses that can inflict more harm than the infection itself.
authors.affiliation: Research Service, Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Nooh
authors.forename: Suba
authors.initials: S
authors.lastname: Nookala
authors.forename: Rita
authors.initials: R
authors.lastname: Kansal
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
mesh_terms: D002461:Cell Line, Transformed; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059810:HLA-DR Serological Subtypes; D015809:HLA-DR7 Antigen / Q000235:genetics; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D013290:Streptococcal Infections / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000302:isolation & purification; D018089:Superantigens / Q000502:physiology*
chemical_list: D016207:Cytokines; D006683:HLA-DQ Antigens; C410042:HLA-DQ5 antigen; C063831:HLA-DQ6 antigen; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D015809:HLA-DR7 Antigen; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens