In addition to NOD2, other deficiencies in innate immunity have been identified in patients with CD, including defective CXCL8 production and neutrophil accumulation, which can synergize with NOD2 defects to promote intestinal inflammation. Thus, compound defects in innate immunity and the regulation of inflammation may act synergistically to promote immunopathology in CD. GWASs have identified other susceptibility genes for CD that may be linked to impaired innate immune functions (see Fig. 15.34). Defects in two genes (ATG16L1 and IRGM) that contribute to autophagy have been linked to CD, suggesting that other mechanisms that impair clearance of commensal bacteria might predispose to chronic intestinal inflammation. Autophagy, or the digestion of a cell’s cytoplasm by its own lysosomes, is important in the turnover of damaged cellular organelles and proteins; autophagy also has a role in antigen processing and presentation (see Section 6-9), and contributes to the clearance of some phagocytosed bacteria.
While defects in important pathways of the innate immune system contribute to CD, genes that regulate the adaptive immune response have also been associated with susceptibility. Most notably, there are variants of the gene for the IL-23 receptor (IL23R) that predispose to disease, consistent with heightened TH17 responses in diseased tissues. Collectively, the growing number of susceptibility genes that confer increased risk for CD point to abnormal regulation of homeostatic innate and adaptive immune responses to the intestinal microbiota as a common factor.
15-24 External events can initiate autoimmunity.
The geographic distribution of autoimmune diseases reveals a heterogeneous distribution among different continents, countries, and ethnic groups. For example, the incidence of disease in the Northern Hemisphere seems to decrease from north to south. This gradient is particularly prominent for diseases such as multiple sclerosis and type 1 diabetes in Europe, where the incidence is greater in the northern countries than in Mediterranean regions. Numerous epidemiologic and genetic associations suggest that this may be partly related to levels of vitamin D. The active form of vitamin D is formed in the skin in response to sunlight—which is less intense and less available in northern latitudes—and has numerous immunoregulatory functions that affect cells of the innate and adaptive immune systems, including suppression of TH17 cell development. Studies have also shown an increased incidence of autoimmunity in more developed countries, the basis of which is unknown.
Besides vitamin D levels, there are numerous other nongenetic factors contributing to these geographic variations, including socioeconomic status and diet. The contribution of nongenetic factors to disease is exemplified in genetically identical mice, which develop autoimmunity at different rates and severity. There is an emerging appreciation for the diversity of the commensal microbiota having a role in contributing to autoimmune disease—including extraintestinal disease—reflecting the importance of the interplay of the microbiome with the innate and adaptive immune systems in shaping the
Fig. 15.42 Infectious agents could break self-tolerance in several different ways. Left panels: because some antigens are sequestered from the circulation, either behind a tissue barrier or within the cell, an infection that breaks cell and tissue barriers might expose hidden antigens. Right panels: molecular mimicry might result in infectious agents inducing either T‑ or B‑cell responses that can cross‑react with self antigens.
systemic immune response. Finally, exposure to infections and environmental toxins may be factors that help trigger autoimmunity. However, it should be noted that epidemiological and clinical studies over the past century have also shown a negative correlation between exposure to some types of infections in early life and the development of allergy and autoimmune diseases. This ‘hygiene hypothesis’ proposes that a lack of infection during childhood may affect the regulation of the immune system in later life, leading to a greater likelihood of allergic and autoimmune responses (see Section 14-4).