Immune Response to Connective Tissue Components of the Basement Membrane

Abstract

The immune response to connective tissue components of basement membrane (type IV collagen and laminin) and to interstitial collagen (type I) has been examined in human and murine systems. We also examined the role that immunologic sensitization to autologous connective tissue components might play in inducing an inflammatory response resulting in pathologic sequelae. Mice receiving a single subcutaneous injection of 5 μg type IV or type I murine collagens, or murine laminin in complete Freund's adjuvant mount a delayed-type hyper-sensitivity response characterized by a mononuclear cell infiltrate when challenged in the footpad with the sensitizing antigen. Cell-mediated immunity to these connective tissue antigens can be transferred to normal syngeneic mice with sensitized T-lymphocytes. In addition, repeated immunizations with these homologous connective tissue components elicit antibody responses in mice. Our data demonstrate the immunogenic nature of types IV and I collagen, and of laminin in a syngeneic murine model. We have demonstrated autoantibodies to the basement membrane and interstitial collagens in the sera of patients with scleroderma (systemic sclerosis); ELISA ratios correlate directly with the extent of pulmonary fibrosis in these patients. Anti-type IV collagen autoantibodies were found to be primarily IgM and anti-type I collagen antibodies, primarily IgG. An antibody response to autologous connective tissue antigens could lead to complement activation, immune complex formation, and deposition of the complexes along vascular endothelium with recruitment of blood monocytes in situ, mirroring the early scleroderma lesion (perivascular mononuclear cell infiltrates). In vitro we examined the role of human peripheral blood mononuclear cells in the activation of fibroblasts. Adherent human blood monocytes release mediators which stimulate fibroblast proliferation and collagen deposition. A model is presented for the induction of immunity to autologous connective tissue components, leading to mononuclear cell inflammation, fibroblast activation and fibrosis. Selective immunity to basement membrane collagens may influence the clinical expression of diffuse connective tissue syndromes such as scleroderma (systemic sclerosis).