Fig. 15.40 Amino acid changes in the sequence of an MHC class II protein correlate with susceptibility to and protection from diabetes. The HLA‑DQβ1 chain contains an aspartic acid (Asp) residue at position 57 in most people; in Caucasoid populations, patients with type 1 diabetes (T1DM) more often have valine, serine, or alanine at this position instead, as well as other differences. Asp 57, shown in red on the backbone structure of the DQβ chain in the top panel, forms a salt bridge (shown in green in the center panel) to an arginine residue (shown in pink) in the adjacent α chain (gray). The change to an uncharged residue (for example, alanine, shown in yellow in the bottom panel) disrupts this salt bridge, altering the stability of the DQ molecule. The non‑obese diabetic (NOD) strain of mice, which develops spontaneous diabetes, shows a similar substitution of serine for aspartic acid at position 57 of the homologous I‑Aβ chain, and NOD mice transgenic for β chains with Asp 57 have a marked reduction in diabetes incidence. Courtesy of C. Thorpe.
Fig. 15.41 Crohn’s disease results from a breakdown of the normal homeostatic mechanisms that limit inflammatory responses to the gut microbiota. The innate and adaptive immune systems normally cooperate to limit inflammatory responses to intestinal bacteria through a combination of mechanisms: a mucus layer produced by goblet cells; tight junctions between the intestinal epithelial cells; antimicrobial peptides released from epithelial cells and Paneth cells; and induction of Treg cells that inhibit effector CD4 T‑cell development and promote the production of IgA antibodies that are transported into the intestinal lumen, where they inhibit translocation of intestinal bacteria (not shown). In individuals with impaired homeostatic mechanisms, dysregulated TH1‑and TH17‑cell responses to the intestinal microbiota can result, generating disease‑causing chronic inflammation. Crohn’s disease susceptibility genes of innate immunity include NOD2 and the autophagy genes ATG16L1 and IRGM. A major susceptibility gene that affects adaptive immune cells is IL23R, which is expressed by TH17 cells (see also Fig. 15.34).
autoantigenic peptides might be expressed at too low a level or bind too poorly to MHC molecules to drive thymic negative selection, but might be present at a sufficient level or bind strongly enough to drive positive selection. This hypothesis is supported by observations that I-Ag7, the MHC class II molecule in NOD mice, binds many peptides very poorly and may therefore be less effective in driving thymic negative selection.
15-23 Genetic variants that impair innate immune responses can predispose to T-cell-mediated chronic inflammatory disease.