Enhanced susceptibility to superantigen-associated streptococcal sepsis in human leukocyte antigen-DQ transgenic mice.
Bacterial superantigens are believed to cause septic shock, although, because of the lack of superantigen-sensitive infection models, proof that superantigenicity underlies shock pathogenesis is lacking. This work demonstrates a clear superantigen effect in septic shock resulting from bacterial infection. Transgenic expression of human leukocyte antigen (HLA)-DQ, but not HLA-DR, specifically augments lymphocyte responses to streptococcal pyrogenic exotoxin A (SPEA). HLA-DQ transgenic mice had increased mortality after administration of SPEA or infection with Streptococcus pyogenes. Immune activation during infection was HLA-DQ transgene-dependent and was manifested by Vbeta-specific T cell repertoire changes and widespread lymphoblastic tissue infiltration. Unlike earlier models, which used toxin-induced shock, these T cell superantigen responses and lymphoblastoid changes were observed during invasive streptococcal sepsis. Lymphoid activation was undetectable in HLA-DQ mice infected with an isogenic SPEA(-) strain, which proves that a single superantigen can play a role in sepsis pathogenesis.
Sriskandan
S
S
Department of Infectious Diseases, Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom. s.sriskandan@ic.ac.uk
Unnikrishnan
M
M
Krausz
T
T
Dewchand
H
H
Van Noorden
S
S
Cohen
J
J
Altmann
D M
DM
D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D002455:Cell Division; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005098:Exotoxins / Q000276:immunology; D005786:Gene Expression Regulation; D006683:HLA-DQ Antigens / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology*; D013154:Spleen / Q000473:pathology; D013297:Streptococcus pyogenes / Q000472:pathogenicity*; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D001426:Bacterial Proteins; D005098:Exotoxins; D006683:HLA-DQ Antigens; D008565:Membrane Proteins; C117980:SpeA protein, Streptococcus pyogenes; D018089:Superantigens