Chronic T-cell responses against food proteins are normally prevented by the development of oral tolerance (see Section 12-18). Why this breaks down in patients with celiac disease is unknown. The properties of the HLA-DQ2 molecule provide a partial explanation, but there must be additional factors because most HLA-DQ2-positive individuals do not develop celiac disease, and the high concordance rates in monozygotic twins indicate a role for additional genetic factors. The incidence of celiac disease is especially high in individuals with trisomy 21 (Down syndrome), approximately sixfold higher than in the normal population, underscoring the impact of genetic factors on disease prevalence. Polymorphisms in the gene for CTLA-4 or in other immunoregulatory genes have been suggested to be associated with susceptibility. There could also be differences in how individuals digest gliadin in the intestine, so that differing amounts survive for deamidation and presentation to T cells.
The gluten protein also seems to have several properties that contribute to pathogenesis. As well as its relative resistance to digestion, there is mounting evidence that some gliadin-derived peptides stimulate the innate immune system by inducing the release of IL-15 by intestinal epithelial cells. This process is antigen-nonspecific and involves peptides that cannot be bound by HLA-DQ2 molecules or recognized by CD4 T cells. IL-15 release leads to the activation of dendritic cells in the lamina propria, as well as the upregulation of MIC-A expression by epithelial cells. CD8 T cells in the mucosal epithelium can be activated via their NKG2D receptors, which recognize MIC-A, and they can kill MIC-A-expressing epithelial cells via these same NKG2D receptors (Fig. 14.27). Triggering of these innate immune responses by α-gliadin may create some intestinal damage on its own and also induce some of the co-stimulatory events necessary for initiating an antigen-specific CD4 T-cell response to other parts of the α-gliadin molecule. The ability of gluten to stimulate both innate and adaptive immune responses may thus explain its unique ability to induce celiac disease.
Summary.
Non-IgE-mediated immunological hypersensitivity reflects normal immune mechanisms that are inappropriately directed against innocuous antigens or inflammatory stimuli. It comprises both immediate-type and delayed-type reactions. Immediate-type reactions are due to the binding of specific IgG antibodies to allergen-modified cell surfaces, as in drug-induced hemolytic anemia, or to the formation of immune complexes of antibodies bound to poorly catabolized antigens, as occurs in serum sickness. Cellular hypersensitivity reactions mediated by TH1 cells and cytotoxic T cells develop more slowly than immediate-type reactions. The TH1-mediated hypersensitivity reaction in the skin provoked by mycobacterial tuberculin is used to diagnose previous exposure to Mycobacterium tuberculosis. The allergic reaction to poison ivy is due to the recognition and destruction by cytotoxic T cells of skin cells modified by a plant molecule, and to cytotoxic T-cell cytokines. These T-cell-mediated responses require the induced synthesis of effector molecules and develop over 1–10 days.
Summary to Chapter 14.