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Structural and functional characterization of novel mimicry epitopes as potential triggers of multiple sclerosis and heart autoimmunity
Even though most humans carry autoreactive cells in their naïve peripheral repertoires, autoimmune responses do not ensue spontaneously. How this tolerance is maintained is a fundamental question. It has been suggested that environmental microbes that bear sequences similar to self-antigens can break self-tolerance by cross-reactivity. Using bioinformatics tools, we attempted to identify microbes that carry sequences identical to myelin proteolipid protein (PLP) 139-151 and cardiac myosin heavy chain (Myhc)-α 334-352, which induce experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myocarditis (EAM), respectively, in SJL (H-2 s) and A/J (H-2a) mice. These investigations led us to discover that Acanthamoeba castellanii, a pathogen of the human central nervous system (CNS), contains mimicry sequences for multiple myelin antigens, importantly PLP 139-151 and myelin basic protein (MBP) 89-101. Similar analysis for Myhc-α 334-352 revealed identification of four sequences, with one each from Bacillus spp., Cryptococcus neoformans, Magnetospirillum gryphiswaldense, and Zea mays. Expectedly, all the mimics induced the features of EAE or EAM reminiscent of the disease phenotypes produced by their corresponding cognate peptides, by generating T helper (Th) 1 and Th17 cytokine-producing cross-reactive CD4 T cells. Importantly, derivation of a homology model for the MBP mimic complexed with human leukocyte antigen-DR2 suggests that A. castellanii has the potential to predispose to CNS autoimmunity by generating MBP 85-99-reactive T cells in those exposed. Finally, by establishing an infection model, we demonstrated that SJL mice infected with A. castellanii show the generation of encephalitogenic CD4 T cells, thus providing a proof-of concept that autoreactive cells can contribute to the pathogenesis of Acanthamoeba infections. Future investigations may involve determination of Acanthamoeba exposure in multiple sclerosis patients by evaluating cross-reactive immune responses. In the long term, our data may provide a basis for considering autoimmunity in the therapy for patients affected with amoebic encephalitis. Likewise, the data obtained with the EAM model support the notion that environmental microbes, which are otherwise innocuous, can induce heart autoimmunity by generating pathogenic cross-reactive immune responses.
Massilamany, Chandirasegaran, "Structural and functional characterization of novel mimicry epitopes as potential triggers of multiple sclerosis and heart autoimmunity" (2013). ETD collection for University of Nebraska - Lincoln. AAI3557997.