Pathogenesis

Established celiac disease is characterized by an inflammatory response in the proximal small intestine. This inflammation consists of increased numbers of lymphocytes, plasma cells, and macrophages in the lamina propria and increased lymphocytes in the surface layer of the epithelium, called intra-epithelial lymphocytes. The surface enterocytes are shorter and wider than normal and have poorly ordered nuclei. The normally tall thin villi are shortened and flattened. The cryptal layer is increased in depth. These changes may be patchy and affect variable lengths of the proximal small intestine ( Figure 1).

The lamina propria is packed with T cells, many of which are CD4+ cells that respond to gliadin molecules in a manner that is DQ2 or DQ8 restricted. These cells are thought to be crucial in

Figure 1 Inflammatory response in proximal small intestine. Proximal small intestinal tissue from a normal control (A) and from a celiac patient (B) was stained with hematoxylin and eosin. Shortened and flattened villi, shorter and wider enterocytes, increased numbers of intraepithelial lymphocytes, and a cryptal layer with increased depth are all present in (B) but not in (A).

Figure 1 Inflammatory response in proximal small intestine. Proximal small intestinal tissue from a normal control (A) and from a celiac patient (B) was stained with hematoxylin and eosin. Shortened and flattened villi, shorter and wider enterocytes, increased numbers of intraepithelial lymphocytes, and a cryptal layer with increased depth are all present in (B) but not in (A).

the actual pathology of the lesion, and clones derived from such cells have been used to characterize the response to gliadin. Lymphocytes in the intraepithelial layer are also increased in number in untreated celiac disease, many of which bear the 7S TCR. These cells slowly decrease when gluten is removed. An early event in the pathology is an increased expression of class II HLA molecules by enterocytes and antigen-presenting cells such as the macrophages within the lamina propria. These molecules are involved in the presentation of the exogenous and possibly the endogenous antigens that are released in the setting of inflammation.

In addition to the pathological changes in the small bowel mucosa, a potent humoral response occurs in untreated celiac disease. In the intestinal mucosa there are increased numbers of plasma cells secreting IgA, IgG, and IgM directed against gluten peptides and other plasma cells secreting antibodies directed against connective tissue autoantigens, particularly tissue transglutaminase. Those antibodies are found in the intestinal juice and the serum. The dynamics of the humoral response seems to parallel the dynamics of cellular injury, although antibodies may rise prior to mucosal relapse and disappear prior to healing.

There is also increased permeability of the small intestine to macromolecules. It is not clear if this increased permeability precedes the development of gliadin sensitivity. It may persist after healing of the microscopic lesions has occurred. Family members without the disease may have increased permeability. Recently, it has been suggested that gluten itself may rapidly cause an increase in paracellular permeability due to the uncoupling of intercellular tight junctions via the release of zonulin.

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