Molecular mechanism and its regulation of heterophilic adhesion between α E 3 7 (CD103) and E-cadherin in autoimmune epithelial injury

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It is proposed that immuno-competent cells, which play an indispensable role in host defense in normal individuals, attack self tissues in autoimmune diseases. We have demonstrated that these immune cells are involving the tissue injuries as the effector cells not only in salivary gland destruction in Sjogren's syndrome, but also in interstitial alveolar damage in dermatomyositis, raising a hypothesis of autoimmune epithelitis. Given the observation that CD8+ T lymphocytes are infiltrated around the aciner epithelial cells and the CD8+ cells are expressing aEb7 (CD 103) adhesion molecules, it is suggested that these lymphocytes adhere to the epithelial cells through aEb7 and E-cadherin on the epithelial cells. However, the detailed molecular mechanism remains to be clarified. In this study, we focus on the aEb7 and E-cadherin adhesion and attempt to explore the immunological mechanism of autoimmune epithelial injuries. In addition, we investigate the efficient intervention of the adhesion for applying to the future clinical development. Monoclonal antibodies or peptide antagonist may be useful to inhibit the adhesion, but those may also interfere to homophilic adhesion between epithelial cells. To search the inhibitory modalities specifically block heterophilic adhesion between aEb7 and E-cadherin, but not homophilic adhesion, we generated a series of deletion mutant of wild type E-cadherins and established the L-cell transfectant expressing E-cadherin without each domains. Using these L-cells and transfectants with aE chain and b7 chasin of integrins, we identified that 5th domain is responsible for the heterophilic adhesion. On the basis of the findings, we examined expression of the aEb7 on the peripheral and tissue lymphocytes and E-cadherin in the inflamed tissues.