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* Department of Molecular Sciences,
Department of Surgery, and
Mid-South Center for Biodefense and Security, University of Tennessee Health Science Center, Memphis, TN 38163;
Research Center, Veterans Affairs Medical Center, Memphis, TN 38104; and
¶ Department of Immunology, Mayo Clinic, Rochester, MN 55905
Our epidemiologic studies on invasive Group A Streptococci (GAS) infections identified specific HLA class II haplotypes/alleles conferring high-risk or protection from streptococcal toxic shock syndrome with a strong protection conferred by the DRB1*15/DQB1*06 haplotype. We used HLA-transgenic mice to provide an in vitro and in vivo validation for the direct role of HLA class II allelic variation in streptococcal toxic shock syndrome. When splenocytes from mice expressing the protective HLA-DQB1*06 (DQ6) allele were stimulated with a mixture of streptococcal superantigens (SAgs), secreted by the prevalent M1T1 strain, both proliferative and cytokine responses were significantly lower than those of splenocytes from mice expressing the neutral DRB1*0402/DQB1*0302 (DR4/DQ8) alleles (p < 0.001). In crisscross experiments, the presentation of SAgs to pure T cells from either the DQ6 or the DR4/DQ8 mice resulted in significantly different levels of response depending on the HLA type expressed on the APCs. Presentation by HLA-DQ6 APCs elicited significantly lower responses than the presentation by HLA-DR4/DQ8 APCs. Our in vitro data were supported by in vivo findings, as the DQ6 mice showed significantly longer survival post-i.v. infection with live M1T1 GAS (p < 0.001) and lower inflammatory cytokine responses as compared with the DR4/DQ8 mice (p < 0.01). The data presented here provide evidence for a direct role of HLA class II molecules in modulating responses to GAS SAgs and underscore the dominant role of HLA class II allelic variation in potentiating the severity of GAS systemic infections.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant AI40198-06 (to M.K.), U.S. Army Medical Research Acquisition Activity Grant W81XWH-05-1-0227 (to M.K.), and Research and Development Office, Medical Research Service, Department of Veterans Affairs (Merit Award) (to M.K.).
2 Address correspondence and reprint requests to Dr. Malak Kotb, University of Tennessee Health Science Center, 956 Court Avenue, Suite A-202, Memphis, TN 38163. E-mail address: mkotb{at}utmem.edu
3 Abbreviations used in this paper: GAS, Group A streptococci; NF, necrotizing fasciitis; SAg, superantigen; Spe, streptococcal pyrogenic exotoxin; SSD, severe systemic disease; STSS, streptococcal toxic shock syndrome; tg, transgenic.
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