@article{97f99126fb7b4da8a3da8ebfaad2b3e6,
title = "HLA-class II genes modify outcome of Toxoplasma gondii infection",
abstract = "Associations between Human Leukocyte Antigen (HLA) (i.e. human major histocompatibility complex [MHC]) genes and susceptibility to infections and inflammatory processes have been described, but causal relationships have not been proven. We characterized effects of HLA-DQ alleles on outcome of congenital toxoplasma infection and found that among Caucasians, the DQ3 gene frequency was significantly higher in infected infants with hydrocephalus (0.783) than infected infants without hydrocephalus (0.444) or published normal controls (0.487). We then developed a novel animal model to definitively determine the effect of these HLA DQ molecules on the severity of toxoplasmosis. Human MHC-Class II transgenes reduced parasite burden and necrosis in brains of mice infected with Toxoplasma gondii. Consistent with the observed association between DQ3 and hydrocephalus in human infants, in the murine model the DQ3(DQ8; DQB1*0302) gene protected less than DQ1 (DQ6; DQB1*0601). Our findings definitively prove a cause and effect relationship between human MHC genes and resistance to infection, provide novel means to characterise human immune responses that are protective or pathogenic in infections, and are important for vaccine development.",
keywords = "Congenital Toxoplasma infection, Encephalitis, HLA genes, Hydrocephalus, Major histocompatibility genes, Parasite burden, Toxoplasma gondii, Toxoplasmosis",
author = "MacK, {Douglas G.} and Johnson, {Jennifer J.} and Fiona Roberts and Roberts, {Craig W.} and Estes, {Randee G.} and Chella David and {Carl Grumet}, F. and Rima McLeod",
note = "Funding Information: We thank Yasu Sazuki for helpful and interesting discussions, Paul Terasaki and the UCLA Tissue Typing Laboratory for tissue typing, and Vicki Aitchison, Esther Castro and Ellen Holfels for their assistance in preparation of this manuscript. This work was supported by a Research to Prevent Blindness Career Development Award (DM), the Royal Pathological Society of Great Britain and Northern Ireland (FR), the Fulbright Foundation and Michael Reese Physicians Research and Education Foundation and Michael Reese Hospital and Medical Center Postdoctoral Fellowship (CR), the Research to Prevent Blindness Foundation (RM, Jules and Doris Stein RPB Professor at the University of Chicago), the NIH NIAID TMP program (AI 16945, AI 27530), The Toxoplasmosis Research Institute, The United Airlines Foundation, and The Hyatt Hotels Corporation. The Chicago Collaborative Toxoplasmosis Study Group (which has included Rima McLeod, Kenneth Boyer, Vicki Aitchison, Harald Anonsen, Kristen Bingen–Marshall, Audrey Cameron, Randee Estes, Rebecca Gaither, Colleen Harper, Peter Heydemann, Ellen Holfels, Joyce Hopkins, Theodore Karrison, Douglas Mack, James McAuley, Paul Meier, Marilyn Mets, Dushyant Patel, Paula Pitterle, Peter Rabiah, Jack Remington, Nancy Roizen, Laszlo Stein, Mark Stein, Charles Swisher, and Shawn Withers), characterised the infants with toxoplasmosis. Production of HLA transgenic mice was supported by an NIH grant from the NIAID program (AI 14764) and CA-24473.",
year = "1999",
month = sep,
doi = "10.1016/S0020-7519(99)00152-6",
language = "English (US)",
volume = "29",
pages = "1351--1358",
journal = "International Journal for Parasitology",
issn = "0020-7519",
publisher = "Elsevier Limited",
number = "9",
}