DERMATITIS HERPETIFORMIS & THE MUCOSAL IMMUNE RESPONSE

点击翻译按钮获取中文摘要

Dermatitis herpetiformis (DH) is a blistering skin disease characterized by the presence of cutaneous deposits of IgA, an associated gluten sensitive enteropathy, and a high incidence of the HLA B8/DR3 haplotype. The purpose of this project is to investigate the role of the mucosal immune response (MIR), the cutaneous IgA deposits and the HLA association in the pathophysiology of DH. The specific aims are: 1. Determine the relationship between serum and secretory antibodies directed against dietary antigens and the factors important in their origin and antigenic specificity. 2. Elute and characterize the IgA in DH skin. 3. Characterize the IgA binding sites in DH skin. 4. Investigate the nature of the HLA class II region gene structure to determine if unique differences are present in patients with DH. The relationship between serum and secretory antibodies to dietary antigens will be determined by comparing isoelectric focusing (IEF) spectrotypes and analysis of idiotypic (Id) specificity. Affinity purified IgA antibodies against dietary antigens will be used to raise anti-Id antibodies. These anti-Id antibodies will be used to determine if cross-reactive idiotypes (CRI) are present in patients with DH, if secretory and serum antibodies express CRI and if the cutaneous IgA deposits express CRI. Serum and secretory IgA antibodies against dietary antigens will be examined for cross-reactivity against other dietary antigens and against peptides from human adenovirus. IgA binding structures in DH skin will be determined using gold labeled antibodies and immunoelectron microscopy. In addition, immunoprecipitation experiments using DH and normal fibroblasts will be done to evaluate the nature of dermal micro-fibrillar proteins and IgA binding proteins. IgA eluted from DH skin and affinity purified from serum will be analyzed by IEF and tested for binding to normal and DH skin. Finally, genomic DNA from patients with DH and normal subjects will be examined using cDNA for HLA DP, DQ and DR genes to determine if HLA class II region gene express distinctive polymorphisms. These studies will provide insights into the pathophysiology of DH, the relationship of the serum and secretory IgA responses to mucosal antigen exposure and the role of HLA associations in autoimmune disease.