Type I Collagen Is the Autoantigen in Experimental Autoimmune Anterior Uveitis

Abstract

This study was undertaken to identify and characterize the Ag responsible for the induction of experimental autoimmune anterior uveitis (EAAU). Melanin-associated Ag isolated from bovine iris and ciliary body was digested with the proteolytic enzyme V8 protease to solubilize the proteins and the pathogenic protein was purified to homogeneity. Lewis rats were sensitized to various fractions and investigated for the development of anterior uveitis and an immune response to the purified Ag. The uveitogenic Ag had a mass of 22 kDa (SDS-PAGE) and an isoelectric point of 6.75. The N-terminal amino acid sequence of this protein demonstrated 100% homology with the bovine type I collagen α-2 chain starting from amino acid 385 and will be referred to as CI-α2 (22 kDa). Animals immunized with bovine CI-α2 (22 kDa) developed both cellular and humoral immunity to the Ag. They developed anterior uveitis only if the CI-α2 chain underwent proteolysis and if the bound carbohydrates were intact. EAAU induced by CI-α2 (22 kDa) can be adoptively transferred to naive syngenic rats by primed CD4+ T cells. EAAU could not be induced by the adoptive transfer of sera obtained from animals immunized with CI-α2 (22 kDa). The α-1 and α-2 chains (intact or proteolytically cleaved) of type I collagen from calfskin were not pathogenic. Although human anterior uveitis has been historically characterized as a collagen disease, this is first time collagen has been directly identified as the target autoantigen in uveitis.

Inhibition of Complement Alternative Pathway Suppresses Experimental Autoimmune Anterior Uveitis by Modulating T Cell Responses

“…The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5-15). Antigen-specific CD4 ϩ T cells can adoptively transfer disease into naïve syngenic recipients (7,8,13) and are the predominant inflammatory cells within the uvea (5-15).Previous reports from our laboratory have established a critical role of complement in EAAU (9, 10). Complement has been recognized as a key innate immune defense system that plays an important role in fighting infections and modulating various immune and inflammatory responses by bridging the innate immunity with adaptive immune responses (16 -21).…”

“…The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5-15). Antigen-specific CD4 ϩ T cells can adoptively transfer disease into naïve syngenic recipients (7,8,13) and are the predominant inflammatory cells within the uvea (5-15).…”

“…Experimental autoimmune anterior uveitis (EAAU) is an organ-specific autoimmune disease of the eye that serves as an animal model of noninfectious autoimmune idiopathic AU (4 -15). The EAAU model has been extensively used in our laboratory to understand the underlying mechanisms involved in the pathogenesis of idiopathic AU (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In this experimental model, inbred Lewis rats are subcutaneously immunized in the footpad with melanin-associated antigen (MAA) isolated from the iris and the CB, and EAAU is induced in these animals by an antigen-specific CD4 ϩ T cell response to MAA (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…The EAAU model has been extensively used in our laboratory to understand the underlying mechanisms involved in the pathogenesis of idiopathic AU (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In this experimental model, inbred Lewis rats are subcutaneously immunized in the footpad with melanin-associated antigen (MAA) isolated from the iris and the CB, and EAAU is induced in these animals by an antigen-specific CD4 ϩ T cell response to MAA (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…In this experimental model, inbred Lewis rats are subcutaneously immunized in the footpad with melanin-associated antigen (MAA) isolated from the iris and the CB, and EAAU is induced in these animals by an antigen-specific CD4 ϩ T cell response to MAA (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Antigen-specific CD4 ϩ T cells can adoptively transfer disease into naïve syngenic recipients (7,8,13) and are the predominant inflammatory cells within the uvea (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”