Despite confirming much of our knowledge from experimental immunology, these studies have also revealed our ignorance of gene-regulatory mechanisms that predispose to human disease. For instance, the vast majority of risk alleles identified to date (>80%) are not contained within exons (the protein-coding regions of genes), and many variants reside kilobases away from immunologically relevant genes. Understanding how genetic variation at these noncoding sequences in the genome can contribute to disease is a very active area of research. Recent evidence using computational algorithms, coupled to transcriptional and epigenetic profiling of human immune-cell populations,
TH1 cell TH17 cell IL-12 production IL-23 production IFN-˜production IFN-˜IL-17 and IL-22 production IL-17, IL-22 IL-12R°2IL-12R°1 IL-12 IL-12p40IL-12p35 IL-23R CCR6 IL-12R°1 IL-23 IL-12p19IL-12p40 Ankylosing spondylitis Infammatory bowel disease Psoriasis Multiple sclerosis Type 1 diabetes Rheumatoid arthritis JAK2TYK2 STAT4 JAK2TYK2 STAT3 1 2 3 4 5 Systemic lupus erythematosus Ulcerative colitis 7 8 6 Dendritic cell NF˛B Dectin-1 CARD9 PTGER4 °-glucan 1, 2 3 2 22 1, 2, 3 1, 2, 3, 4 1, 2, 3, 44, 7, 8 1, 2, 3, 4, 5, 6, 7 2, 6, 7, 8 2, 3, 4 1, 2, 3, 4, 5, 6, 7 4, 7, 8 1, 2, 4
Fig. 15.35 Associations of components of the IL-12R and IL-23R response pathways with autoimmune diseases.
Multiple components of the interleukin‑12 (IL‑12R) and ‑23 (IL‑23R) receptor response pathways show significant genome‑wide associations with a broad range of immune‑mediated diseases; that is, these components map within genomic intervals that are associated with the respective disease in genome‑wide association studies. Although this figure shows these components in the conventional context of T helper 1 (TH1) and TH17 lymphocytes, it is now recognized that they are widely expressed in innate lymphoid cells and the specific cell type may vary from phenotype to phenotype. Adapted from Parkes M. et al.: Nat. Rev. Genetics 2013, 14:661. With permission from Macmillan Publishers Ltd.
suggests that many of the causal variants are located within critical gene-regulatory elements that control gene expression in immune cells (for example enhancers). Many of these gene-regulatory elements are utilized by effector or regulatory T cells following their activation, further confirming T-cell activation as a key event in the etiology of autoimmune disorders. Ultimately, a deeper understanding of how these variants contribute to disease will require new techniques to experimentally mimic and manipulate risk alleles, either singly or in combination, in order to fully elucidate how they affect the biology of immune-cell populations relevant to disease.
Despite our current ignorance of how most common genetic variants predispose to (or protect from) autoimmune disorders, several other approaches have begun to shed light on the genetic mechanisms of disease. These include the study of mutations that cause overt alterations in molecules regulating tolerance or the innate immune system; the study of patients with rare, monogenic defects of immune tolerance; and investigations into how certain HLA alleles predispose to disease by their ability to present certain self antigens. We will briefly explore each of these in the following sections.
15-20 Many genes that predispose to autoimmunity fall into categories that affect one or more tolerance mechanisms.