Cytokine, receptor, or intracellular signal ResultDefect Defects in cytokine production or signaling that can lead to autoimmunity TNF-˜TNF-˜In˜ammatory bowel disease, arthritis, vasculitis IL-2, IL-7, IL-2R In˜ammatory bowel disease STAT4 In˜ammatory bowel disease IL-23R In˜ammatory bowel disease, psoriasis IL-10, IL-10R, STAT3 In˜ammatory bowel disease TGF-°Ubiquitous underexpression leads to in˜ammatory bowel disease. Underexpression speciÿcally in T cells leads to SLE IL-3 Demyelinating syndrome IFN-˛Overexpression in skin leads to SLE SLE IL-1 receptor agonist Arthritis Overexpression Underexpression
Fig. 15.33 Categories of genetic defects that lead to autoimmune syndromes.
Many genes have been identified in which mutations predispose to autoimmunity in humans and animal models. These are best understood by the type of process affected by the genetic defect. A list of such genes (or the related protein product) is given here, organized by process (see the text for further discussion). In some cases, the same gene has been identified in mice and humans. In other cases, different genes affecting the same mechanism are implicated in mice and humans. The smaller number of human genes identified so far undoubtedly reflects the difficulty of identifying the genes responsible in outbred human populations.
In humans, genetic susceptibility to autoimmune disorders has been recently assessed by large-scale genome-wide association studies (GWASs), which look for a correlation between disease frequency and genetic variants (typically single-nucleotide polymorphisms, or SNPs). Such studies typically involve thousands of patients with a given autoimmune disease diagnosis and
Fig. 15.34 Manhattan plot depicting risk alleles from genome-wide association studies (GWASs) of Crohn’s disease. The plot highlights selected gene loci identified by analyses of single nuclear polymorphisms (SNPs) with highly significant disease associations in patients with Crohn’s disease compared with healthy controls (see also Section 15‑23). The height of the peaks reflects the statistical significance of the association. The dotted line indicates the threshold for significant associations (5 × 10–08). Figure courtesy of John Rioux and Ben Weaver.
healthy controls in order to identify highly significant associations. Example results from GWASs that identify candidate genes linked to Crohn's disease are shown in the ‘Manhattan’ plot in Fig. 15.34. These plots are so named because they resemble a profile view of skyscrapers in the Manhattan skyline. Here, genomic coordinates are located on the x-axis, with the negative logarithm of the P-value of the association being given on the y-axis, and each assayed SNP is represented by a dot. Thus, the variants with the greatest disease association are the ‘tallest skyscrapers’ on the plot. Using this approach, hundreds of significant variants have been identified for multiple autoimmune diseases, suggesting that genetic susceptibility to autoimmune disease in humans may be due to a combination of susceptibility alleles at multiple loci.
Analyses of GWASs from multiple autoimmune diseases indicate that certain immune pathways—most notably those involved in T-cell activation and function—are common to multiple different forms of autoimmunity. For example, type 1 diabetes, Graves’ disease, Hashimoto’s thyroiditis, rheumatoid arthritis, and multiple sclerosis all show genetic association with the CTLA4 locus on chromosome 2. The cell-surface protein CTLA-4 is produced by activated T cells and is an inhibitory receptor for B7 co-stimulatory molecules (see Section 9-17). Similarly, many of the most common autoimmune disorders have been linked to central factors involved in the development and function of the TH17 and TH1 immune pathways (Fig. 15.35).