title: Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases.
abstract: Autoimmune diseases occur when immune cells fail to develop or lose their tolerance toward self and destroy body's own tissues. Both insufficient negative selection of self-reactive T cells and impaired development of regulatory T cells preventing effector cell activation are believed to contribute to autoimmunity. Genetic predispositions center around the major histocompatibility complex (MHC) class II loci involved in antigen presentation, the key determinant of CD4+ T cell activation. Recent studies suggested that variants in the MHC region also exhibit significant non-additive interaction effects. However, collective interactions involving large numbers of single nucleotide polymorphisms (SNPs) contributing to such effects are yet to be characterized. In addition, relatively little is known about the cell-type-specificity of such interactions in the context of cellular pathways. Here, we analyzed type 1 diabetes (T1D) and rheumatoid arthritis (RA) genome-wide association data sets via large-scale, high-performance computations and inferred collective interaction effects involving MHC SNPs using the discrete discriminant analysis. Despite considerable differences in the details of SNP interactions in T1D and RA data, the enrichment pattern of interacting pairs in reference epigenomes was remarkably similar: statistically significant interactions were epigenetically active in cell-type combinations connecting B cells to T cells and intestinal epithelial cells, with both helper and regulatory T cells showing strong disease-associated interactions with B cells. Our results provide direct genetic evidence pointing to the important roles B cells play as antigen-presenting cells toward CD4+ T cells in the context of central and peripheral tolerance. In addition, they are consistent with recent experimental studies suggesting that the repertoire of B cell-specific self-antigens in the thymus are critical to the effective control of corresponding autoimmune activation in peripheral tissues.
authors.affiliation: Biotechnology High-Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Maryland, United States of America.
authors.forename: Hyung Jun
authors.initials: HJ
authors.lastname: Woo
authors.affiliation: Biotechnology High-Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Maryland, United States of America.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Yu
authors.affiliation: Biotechnology High-Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Maryland, United States of America.
authors.forename: Jaques
authors.initials: J
authors.lastname: Reifman
mesh_terms: D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000473:pathology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology; D057890:Epigenomics; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II