Recognition of Conserved Amino Acid Motifs of Common Viruses and Its Role in Autoimmunity

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Abstract
The triggers of autoimmune diseases such as multiple sclerosis (MS) remain elusive. Epidemiological studies suggest that common pathogens can exacerbate and also induce MS, but it has been difficult to pinpoint individual organisms. Here we demonstrate that in vivo clonally expanded CD4+ T cells isolated from the cerebrospinal fluid of a MS patient during disease exacerbation respond to a poly-arginine motif of the nonpathogenic and ubiquitous Torque Teno virus. These T cell clones also can be stimulated by arginine-enriched protein domains from other common viruses and recognize multiple autoantigens. Our data suggest that repeated infections with common pathogenic and even nonpathogenic viruses could expand T cells specific for conserved protein domains that are able to cross-react with tissue-derived and ubiquitous autoantigens. Infectious agents have been discussed as possible triggers for multiple sclerosis (MS). Molecular mimicry, meaning an antigenic similarity between pathogen proteins and self-proteins (also called autoantigens), is one mechanism that can activate autoreactive T cells. To identify potential triggers and autoantigens in MS, the authors of this study determined the specificity of T cell clones (TCCs) from cerebrospinal fluid (CSF) of an MS patient, which were clonally expanded during disease exacerbation. The CSF is in intimate contact with the central nervous system, which is damaged by autoreactive T cells in MS. The authors observed that these TCCs recognize amino acid motifs from functional protein domains that are evolutionarily conserved between viruses, prokaryotes, and eukaryotes. This phenomenon is reminiscent of pattern recognition by the innate immune system via Toll-like receptors, and represents an interesting bridge as to how immune responses against foreign agents may be misdirected against autoantigens. Three TCCs recognize arginine-rich motifs and respond to peptides from the ubiquitous, nonpathogenic Torque Teno virus (TTV), but also from other common viruses and autoantigens. TTV recognition by clonally expanded CSF TCCs, and the demonstration of viral infection in brains of people with MS, suggest that this virus may participate in triggering or sustaining autoimmune diseases such as MS.