Idiopathic acute anterior uveitis (AAU) is the most common form of intraocular inflammation in humans. The recurrent nature of the disease can lead to permanent visual loss from the secondary complications of cystoid macular edema, posterior subcapsular cataract and glaucoma. Experimental autoimmune anterior uveitis (EAAU) is an organ specific autoimmune disease of the eye and serves as a model of idiopathic human AAU. It is produced in Lewis rats by an antigen specific CD4+ T cell response to an antigen derived from bovine iris and ciliary body. We have purified the uveitogenic antigen to homogeneity and recent results from our laboratory suggest that the uveitogenic antigen is a 22 kDa fragment of bovine type I collagen alpha-2 chain and we refer it to as CI-alpha2 (22 kDa). Our results further suggest that the pathogenic antigen in EAAU is tissue specific, being localized solely to the eye. Although human AAU has been historically characterized as a collagen disease, this is the strongest evidence to date that collagen is the target autoantigen in uveitis.
The specific aims of this proposal are: 1. Expression and localization of CI-alpha2 (22 kDa) within the rat and human eye - expression within the ocular tissue. 2. Presence of CI-alpha2 (22 kDa) in intraocular fluid. 3. Induction of tolerance to CI-alpha2 (22 kDa) to inhibit EAAU. 4. Identification of CI-alpha2 (22 kDa) as the target antigen in idiopathic human AAU - i.e. correlation of idiopathic AAU with the immune response to bovine CI-alpha2 (22 kDa). We believe that these studies are essential to definitely prove that EAAU is an autoimmune response to ocular CI-alpha2 (22 kDa) and that it is the autoantigen responsible for idiopathic human AAU. These observations should also allow the development of effective therapy based on selective antigen specific modulation of the immune response in the treatment of this disease.
|Lyzogubov, Valeriy V; Tytarenko, Ruslana G; Bora, Nalini S et al. (2012) Inhibitory role of adiponectin peptide I on rat choroidal neovascularization. Biochim Biophys Acta 1823:1264-72|
|Matta, Bharati; Jha, Purushottam; Bora, Puran S et al. (2010) Antigen-specific tolerance inhibits autoimmune uveitis in pre-sensitized animals by deletion and CD4+CD25+ T-regulatory cells. Immunol Cell Biol 88:187-96|
|Lyzogubov, Valeriy V; Tytarenko, Ruslana G; Jha, Purushottam et al. (2010) Role of ocular complement factor H in a murine model of choroidal neovascularization. Am J Pathol 177:1870-80|
|Jha, Purushottam; Manickam, Balasubramanian; Matta, Bharati et al. (2009) Proteolytic cleavage of type I collagen generates an autoantigen in autoimmune uveitis. J Biol Chem 284:31401-11|
|Kaliappan, Sankaranarayanan; Jha, Purushottam; Lyzogubov, Valeriy V et al. (2008) Alcohol and nicotine consumption exacerbates choroidal neovascularization by modulating the regulation of complement system. FEBS Lett 582:3451-8|
|Bora, Nalini S; Jha, Purushottam; Bora, Puran S (2008) The role of complement in ocular pathology. Semin Immunopathol 30:85-95|
|Matta, Bharati; Jha, Purushottam; Bora, Puran S et al. (2008) Tolerance to melanin-associated antigen in autoimmune uveitis is mediated by CD4+CD25+ T-regulatory cells. Am J Pathol 173:1440-54|
|Jha, Purushottam; Bora, Puran S; Bora, Nalini S (2007) The role of complement system in ocular diseases including uveitis and macular degeneration. Mol Immunol 44:3901-8|
|Jha, Purushottam; Matta, Bharati; Lyzogubov, Valeriy et al. (2007) Crucial role of apoptosis in the resolution of experimental autoimmune anterior uveitis. Invest Ophthalmol Vis Sci 48:5091-100|