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 micrograms type IV or type I murine collagens, or murine laminin in complete Freund's adjuvant mount a delayed-type hypersensitivity 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 filtrates). 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).

Immune Response to Laminin, a Noncollagenous Glycoprotein of Basement Membrane, in a Syngeneic Murine System

“…Cell-mediated and/or humoral immunity to basement membranes could be directed at either collagenous or noncollagenous components, or both. Data from our laboratory support the hypothesis that basement membrane damage could be initiated or perpetuated by immunity to basement membrane collagen (13,14). Significant titers of anti-type IV collagen antibodies were detected in the sera of some patients with scleroderma.…”

“…Antibodies to laminin were detected using the ELISA as we have de-scribed previously (13,14). Serial dilutions of rabbit antibodies (1 mg/ml) and immune mouse sera in PBS (pH 7.…”

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“…This damage may facilitate the movement of inflammatory cells across the basement membrane [11,35], ultimately leading to excessive fibrosis. In this context, type IV collagen autoimmunity, as mentioned in the Introduction, would play an additional role in fibroblast activation through the interaction between T lymphocytes and fibroblasts [9,10]. Such a hypothesis is supported by the findings in SSc patients that microvascular injury precedes fibrosis and that the degree of hypoxia is correlated with skin fibrosis [36,37].…”

“…For example, autoantibodies to type IV collagen have been observed in some SSc patients and may be involved in endothelial injury [7,8]. Immunization of mice with autologous type IV collagen leads to the activation of fibroblasts and to fibrosis [9]. Furthermore, type IV collagen activates T cells from patients with SSc [10], suggesting that the selective immunity to type IV collagen may influence the clinical expression of SSc.…”

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

“…Second, loss of endothelial cell-cell contact, even in heterozygous patients and animals, would likely predispose the vasculature to chronic, low-grade inflammation due to intermittent exposure of the vascular basement membrane, a potent inflammatory stimulus (Mackel et al, 1982). A related example of such a mechanism is observed in radiation-induced cavernous malformation (RICM) in which radiation-induced endothelial damage leads to the stimulation of pro-inflammatory signaling, the development of large, often multiple, vascular malformations that closely resemble CCMs, and hemorrhage (Cutsforth-Gregory et al, 2015, Nimjee et al, 2006, Park et al, 2011).…”