Microbial and autoantibody immunogenic repertoires in TIF1? autoantibody positive dermatomyositis

Spyridon Megremis; Thomas Walker; Xiaotong He; James O'Sullivan; William E.R. Ollier; Hector Chinoy; Neil Pendleton; Antony Payton; Lynne Hampson; Ian Hampson; Janine Lamb

We propose a model whereby pathogenesis of DM is dependent on dynamic and personalised viral exposure patterns, which start very early in life. The main two gateways of physiological transmission of viruses to humans are the respiratory and gastrointestinal systems, while non-physiological presentation of viruses is through immunisation. The link between DM and viruses is complex but strikingly present in our data since there is systematic enrichment for human proteome modules that are directly exploited by, or respond to, most of the viruses that we identified. We propose that an initial viral infection or virus delivery system presents the main antigen that induces antigen-specific antibody production in a predisposed immune environment. Since TRIM proteins share epitope homology with multiple viral species, these antibodies can also bind to TRIMs and potentially other homologous proteins. The outcome of this process is influenced by factors including the antibody populations at the site of infection (local antibodies), the status of the innate immune system, the virusspecific antibody concentration in serum (which usually peaks several weeks post infection), and the history of previous exposure primarily to the same or related viral strains (and epitopes) (Rojas et al., 2018) . Since HLA Class II molecules are major regulators of the adaptive immune response to antigenic challenge through T cell repertoire selection, the level of antibody production to different . CC-BY-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . viral antigens also may be mediated by HLA type. We previously identified that adult-onset anti-TIF1 positive DM is associated with HLA-DQB1*02:02 (Rothwell et al., 2019) . For the samples with available data included in this study, we observed that 6/15 (40%) DM and 3/17 (18%) HC are heterozygous for HLA-DQB1*02:02. The finding that in myositis, autoantigen expression correlates with expression of muscle regeneration markers (Pinal-Fernandez et al., 2019) suggests that after initial viral presentation, the increased concentrations of muscle proteins may then be sufficient even in the absence of viral proteins to invoke periodic rises of autoantibodies. Moreover, the continuous activation of innate immunity observed in DM (Neely, 2019; Pinal-Fernandez et al., 2019; Walsh et al., 2007; Wong et al., 2012) can also potentiate autoimmunity through chronic immune-mediated tissue damage resulting in autoantigen release without the need for specific activation of auto-reactive T cells by a microbial mimic (Panoutsakopoulou et al., 2001) . Therefore, following the initial viral exposure there is a high chance that this effect will spread amongst related proteins within specific signalling pathways (since protein homology is related to function) of the initial hit. In this model, in specific autoantibody-positive myositis subgroups, accumulated autoantibodies against proteins that participate in specific biological processes and signalling pathways would be observed. The finding that in healthy controls the protein coverage of the GO processes significantly decreases suggests more random targeting of human proteins by autoantibodies, opposite to that observed in DM and in support of our hypothesis.