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

In DM, we identified autoantibodies against a very large number of human proteins (>2500), representing about 14% of the current human proteome (UniProtKB/Swiss-Prot database, last modified 29 July 2019). This was double the proportion compared to the HC-enriched proteome, with only 13% of autoantibodies being found in both DM and healthy controls, suggesting accumulation of autoantibodies in DM against a wider group of proteins. Interestingly three times the number of autoantibody targeted proteins were regulated by type I and II interferons in DM than in HC. This underscores the relevance of interferons in this disease (Neely, 2019; Somani et al., 2008) , and indicates the potential of interferon blockade as a therapy. The identification with high confidence of specific biological processes enriched in both DM and HC, suggests an organisational structure within the targets of these accumulated autoantibodies. Although deconvolution to individual samples is not possible with our data, this is consistent with an infection (exposure)-driven pathological autoantibodyproducing mechanism which progressively expands its repertoire (antigens) under the chronic burden of accumulated stimuli (Chan and Gack, 2016; Cusick et al., 2012; Munz et al., 2009; Panoutsakopoulou et al., 2001) . Biological processes enriched in DM are orientated around cytoskeletal organisation, microtubule movement, actin filaments and cell junctions. Eight of the identified protein targets participated in most of these processes indicating a key role in the regulation of multiple signalling pathways including the formation and disassembly of focal adhesions. The enrichment of antibodies against proteins with a role in the regulation of focal cell-cell adhesion in DM is particularly interesting, since disruption of these structures in epithelial cells is known to . 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 It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.25.007534 doi: bioRxiv preprint facilitate the spread of viruses, by allowing their release from the basal to the apical surface or the external environment (Spear, 2002; Torres-Flores and Arias, 2015) . Interestingly some of the DM associated viruses described here are known to manipulate junctional proteins namely Adenoviridae, Flaviridae, Herpesviridae, Retroviridae, Paramyxoviridae, and Picornaviridae which provides a functional link between DM and increased viral exposure (Mateo et al., 2015; Mothes et al., 2010; Zhong et al., 2013) .