ABSTRACT
We report here identification of novel mimicry epitopes for interphotoreceptor retinoid-binding protein (IRBP) 201-216, a candidate ocular antigen that causes experimental autoimmune uveoretinitis (EAU) in A/J mice. One mimicry epitope from Ehrlichia canis (EHC), designated EHC 44-59, induced cross-reactive T cells for IRBP 201-216 capable of producing T helper (Th)1 and Th17 cytokines, but failed to induce EAU in A/J mice. In addition, animals first primed with suboptimal doses of IRBP 201-216 and subsequently immunized with EHC 44-59 did not develop EAU; rather, the mimicry epitope prevented the disease induced by IRBP 201-216. However, alteration in the composition of EHC 44-59 by substituting alanine with valine at position 49, similar to the composition of IRBP 201-216, enabled the mimicry epitope to acquire uveitogenicity. The data provide new insights as to how microbes containing mimicry sequences for retinal antigens can prevent ocular inflammation by acting as naturally occurring altered peptide ligands.
Subject(s)
Autoimmune Diseases of the Nervous System/prevention & control , Ehrlichia canis/immunology , Ehrlichiosis/prevention & control , Molecular Mimicry/immunology , Retinitis/prevention & control , Uveitis/prevention & control , Amino Acid Sequence , Animals , Autoimmune Diseases of the Nervous System/immunology , Autoimmune Diseases of the Nervous System/microbiology , Cattle , Ehrlichia canis/genetics , Ehrlichiosis/immunology , Ehrlichiosis/microbiology , Eye Proteins/administration & dosage , Eye Proteins/genetics , Eye Proteins/metabolism , Female , Ligands , Mice , Mice, Inbred A , Molecular Sequence Data , Retinitis/immunology , Retinitis/microbiology , Retinol-Binding Proteins/administration & dosage , Retinol-Binding Proteins/genetics , Retinol-Binding Proteins/metabolism , Uveitis/immunology , Uveitis/microbiologyABSTRACT
In this report, we have addressed the role of copper-zinc superoxide dismutase (SOD1) deficiency in the mediation of central nervous system autoimmunity. We demonstrate that SOD1-deficient C57Bl/6 mice develop more severe autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein (MOG) 35-55, compared with wild type mice. This alteration in the disease phenotype was not due to aberrant expansion of MOG-specific T cells nor their ability to produce inflammatory cytokines; rather lymphocytes generated in SOD1-deficient mice were more prone to spontaneous cell death when compared with their wild type littermate controls. The data point to a role for SOD1 in the maintenance of self-tolerance leading to the suppression of autoimmune responses.