DERMATITIS HERPETIFORMIS AND THE MUCOSAL IMMUNE RESPONSE

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DESCRIPTION: (Verbatim) Dermatitis herpetiformis (DH) is a blistering skin disease characterized by the presence of cutaneous IgA deposits and an associated, almost always asymptomatic, gluten sensitive enteropathy (GSE). The critical role of the mucosal immune response (MIR) in DH has been demonstrated by the observation that, despite the lack of clinical symptoms of GSE in the majority of DH patients, the cutaneous manifestations of DH can be controlled by a gluten free diet. The mechanisms that allow for the development of cutaneous IgA deposits and skin disease yet that prevent the development of symptoms of GSE are not known. The purpose of this project is to characterize the MIR in patients with DH in order to determine the factors that prevent the development of clinical signs of gastrointestinal disease yet result in cutaneous deposits of IgA and the development of the cutaneous manifestations of DH. In addition, this project will provide new information regarding factors that may modify and regulate the mucosal immune response to dietary proteins in man and how mucosal inflammation results in inflammatory disease in the skin, joints and other organs. The specific aims of this project are: 1. Determine the antigenic patients with DH and isolated GSE and control subjects using organ culture of specificity and dose response of the T cells in small bowel biopsies from isolated GSE. 2. Characterization of the circulating neutrophils in patient with small bowel biopsies and gliadin peptides, some of which induce disease in DH on gluten containing diets and of the level of cytokine(IL-1/TNFa)/chemokine(IL-8) expression in the skin. Skin biopsies from patients with DH from areas predisposed to develop skin lesions (extensor, surfaces) and those areas which normally do not develop skin lesions (upper inner arm) will be analyzed for IL-1a, TNF-a, IL-8, and other cyto/chemokine expression during periods of control of the skin disease and no skin lesions and during disease activity. Neutrophils will be analyzed during periods when skin lesions are present and not present to assess the level of activation and expression of cell surface molecules which play a role in neutrophil migration 3. Characterization of the CDR3 region of the T cell Vb families expressed in the small bowel biopsies of patients with DH and of patients with isolated symptomatic and asymptomatic GSE. cDNA from the small bowel of patients with DH, patients with isolated symptomatic GSE and patients with isolated, asymptomatic (treated) GSE and patients with non-gluten sensitive intestinal disease will be analyzed by RT-PCR for the evidence of clonality of the T cells in the gut using CDR3 spectrotype analysis and single strand conformational polymorphisms. These studies will provide insights into the pathogenesis of DH and isolated GSE, the relationship between the MIR and the skin and factors important in controlling the mucosal immune response in man.