Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care

J Immunol. 2011 Mar 1;186(5):3156-63. doi: 10.4049/jimmunol.1002057. Epub 2011 Jan 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Transformed
  • Cell Polarity / genetics
  • Cell Polarity / immunology*
  • Cytokines / biosynthesis
  • Cytokines / genetics*
  • Gene Expression Regulation, Bacterial / immunology
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / immunology*
  • HLA-DQ Antigens / genetics
  • HLA-DR Antigens / genetics
  • HLA-DR Serological Subtypes
  • HLA-DR7 Antigen / genetics
  • Humans
  • Receptors, Antigen, T-Cell / biosynthesis
  • Shock, Septic / genetics
  • Shock, Septic / immunology*
  • Shock, Septic / therapy
  • Streptococcal Infections / genetics
  • Streptococcal Infections / immunology*
  • Streptococcal Infections / therapy
  • Streptococcus pyogenes / immunology*
  • Streptococcus pyogenes / isolation & purification
  • Superantigens / physiology*


  • Cytokines
  • HLA-DQ Antigens
  • HLA-DQ5 antigen
  • HLA-DQ6 antigen
  • HLA-DR Antigens
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • HLA-DR7 Antigen
  • Receptors, Antigen, T-Cell
  • Superantigens