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.

Large-scale interaction effects reveal missing heritability in schizophrenia, bipolar disorder and posttraumatic stress disorder

“…Extensions of the independent loci (IL) analysis by pairwise testing may partially capture such effects, but in the largest SZ meta-analysis to date, it was reported that pairwise tests did not yield new associations. 4 In this work, we characterized non-additive interaction effects of common variants on SZ and BP risks using a recently developed algorithm (discrete discriminant analysis, DDA), 9 , 10 which greatly extends the scale of interacting partners simultaneously considered beyond SNP pairs by using the regularized inference of high-dimensional interactions within large SNP groups. Over-fitting is avoided by optimizing the risk prediction quantified by the area under the curve (AUC) of receiver operating characteristics, estimated from cross-validation.…”

Interaction of HLA Class II rs9272219 and TMPO rs17028450 (Arg690Cys) Variants Affects Neuromyelitis Optica Spectrum Disorder Susceptibility in an Admixed Mexican Population

“…Epistatic interactions between HLA and non-HLA genetic variants have been previously reported for other autoimmune diseases including SLE, MS, rheumatoid arthritis, ankylosing spondylitis and psoriasis (Matzaraki et al, 2017;Diaz-Gallo et al, 2018;Hanson et al, 2020). In addition, a significant interaction between r9273363 (HLA DQB1) and SNPs rs9272219 (HLA DQA1) was reported in RA and type 1 diabetes, and this HLA region was identified as epigenetically active in B cells (Woo et al, 2017). Since Lamin B1 and LAP2 are expressed in the thymus, the LAP2 690Cys variant may indirectly affect AIRE function in medullary TECs, perhaps altering the presentation of AQP4 or other antigens in the thymus, allowing autoreactive T cells that recognize these antigens to escape negative selection.…”

Transcriptional Changes in Regulatory T Cells From Patients With Autoimmune Polyendocrine Syndrome Type 1 Suggest Functional Impairment of Lipid Metabolism and Gut Homing

“…Furthermore, String gene ontology enrichment analysis was performed in order to investigate any links between gene ontology and biological processes for the differentially expressed genes (Supplementary Table 1). As antigen presenting cells and their HLA-proteins which present peptides to T cells have pivotal roles in immune reactivity and tolerance, it is to no surprise that String reported an association between FOXP3 and HLA-DQB1 as "being comentioned" in PubMed-abstracts in numerous articles, e.g (42). The gene ontology enrichment strengthened this association by pointing out the relevance of HLA-molecules for proper immune function.…”