Functional relevance of activated beta 1 integrins in mercury-induced nephritis

Cell adhesion through different adhesion molecules is a crucial event in th e inflammatory response. Integrins can only bind and mediate cellular adhes ion after their activation by different specific stimuli. The state of beta 1 integrin activation can be assessed by a group of monoclonal antibodies (HUTS) that selectively recognize beta 1 integrins in their active form. A similar activated epitope in the rat was defined using the anti-human monoc lonal antibody HUTS-21, which recognizes an activation-dependent epitope on the beta 1 chain. It was found that the divalent cations Mn2+ and Hg2+ wer e able to induce in vitro the activation of beta 1 integrins on rat lymphoc ytes. The Hg2+ cation induces an autoimmune disease in the Brown Norway rat characterized by synthesis and glomerular deposits of anti-glomerular base ment membrane antibodies, proteinuria, and interstitial nephritis. Using th e mercury model of nephritis, it was found that the expression of HUTS-21 e pitope is induced in vivo in rat lymphocytes, and its appearance is correla ted with the other parameters at the onset of the disease. In addition, the administration of HUTS-21 monoclonal antibody to HgCl2-treated rats offere d evidence of its protective effects (1) against infiltration of renal inte rstitium by leukocytes, and (2) in the reduction of anti-glomerular basemen t membrane synthesis and glomerular deposition. Nevertheless, urinary prote in values remained unaffected. These results demonstrate a key role of beta 1-activated integrins in both leukocyte cell-cell interactions and leukocy te infiltration pathway mechanism, and also indicate that leukocyte migrati on may have less importance in the development of this disease than previou sly thought.