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Delineating autoimmunity in infectious myocarditis and uveoretinitis

Arunakumar Basavarajappa Gangaplara, University of Nebraska - Lincoln

Abstract

Most healthy humans have a propensity to develop autoimmune diseases, as evidenced by the presence of autoreactive T cells/B cells, yet autoimmune responses do not occur spontaneously. How this tolerance is maintained is a fundamental question. It has been suggested that exposure to environmental microbes can break self-tolerance in the genetically susceptible individuals leading to clinical disease. We made attempts to delineate autoimmune mechanisms in two organ systems, with one each, representing non-immune- (heart), and immune-privileged (eye), microenvironments. Using coxsackievirus B3 (CVB3) as a bona fide pathogen of cardiovascular system (CVS), we demonstrated that mice infected with CVB3 show the generation of cardiac myosin heavy chain (Myhc)-α CD4 T cells that are capable of producing proinflammatory, T helper (Th)1 and Th17 cytokines. Furthermore, using major histocompatibility complex class II/IAk dextramers, we demonstrated that Myhc-α 334-352-specific CD4 T cells infiltrate into the hearts and the Myhc-α T cells were pathogenic in naïve recipients. In our efforts to identify novel microbial triggers of uveoretinitis, we used bioinformatics tools and searched for sequences identical to interphotoreceptor-binding protein (IRBP) 201-216. From a panel of 48 mimicry sequences, we noted that one epitope derived from Ehrlichia canis (EHC) designated, EHC 44-59 induced cross-reactive T cells for IRBP 201-216 with a skewed Th1 and Th17 cytokine responses. Unexpectedly however, EHC 44-59 failed to induce uveoretinitis, rather prevented the development of disease induced by IRBP 201-216, possibly by acting as altered peptide ligand. The implications of our observations are two-fold: (i) pathogens like CVB3 that primarily affect CVS can lead to secondary generation of autoimmune responses, likely reason for persistent chronic inflammation in the absence of detectable infectious particles. The data raise a question, whether autoimmunity should be targeted for therapy in the amelioration of viral myocarditis; and (ii) evolutionarily, coexistence of parasites with hosts may promote acquisition of host's genetic material as might have occurred in E. canis, and introduction of mutations under selection pressure may favor attenuation of host's immune response leading to their survival.^

Subject Area

Health Sciences, Immunology

Recommended Citation

Gangaplara, Arunakumar Basavarajappa, "Delineating autoimmunity in infectious myocarditis and uveoretinitis" (2013). ETD collection for University of Nebraska - Lincoln. AAI3602787.
http://digitalcommons.unl.edu/dissertations/AAI3602787

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