Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis

Abstract

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.

Genetic Influences in Cancer‐Associated Myositis

“…The activity of more than one‐third of TRIM family genes has been linked to the development of malignancies. For example, TRIM47 and TRIM27 were reported by Megremis et al to be oncogenes involved in several types of malignant diseases including breast, ovarian, endometrial, lung, and colorectal cancers, as well as their progression and metastases ( 42 ) (Table 1 ). By contrast, tumor‐suppressor TRIM3 was located in a chromosomal hotspot whose loss of heterozygosity correlated with the metastatic spread of various cancers.…”

“…By contrast, tumor‐suppressor TRIM3 was located in a chromosomal hotspot whose loss of heterozygosity correlated with the metastatic spread of various cancers. Positivity for autoantibodies against the malignancy‐associated TRIM family appeared to be concurrent with a close temporal relationship between the onset of anti‐TIF1γ–positive DM and the diagnosis of cancer and explained a high proportion of CAM cases among anti‐TIF1γ–positive patients ( 42 ) (Table 1 ).…”

Inflammatory myopathies in childhood

“…Some of these TRIM proteins share epitope homology with specific viral species including poxviruses suggesting antibody accumulation in dermatomyositis against an expanded diversity of microbial proteins. Molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis [17] . The same group reported identification of three immunogenic linear epitopes with high sequence identity to SARS-CoV-2 proteins in patients with autoimmune dermatomyositis, including 'DDAVVC' in the RNA-dependant RNA polymerase protein previously predicted as a CD8 T cell epitope, in keeping with T cell antigen presentation derived from processing both structural and non-structural proteins [17] .…”

“…Molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis [17] . The same group reported identification of three immunogenic linear epitopes with high sequence identity to SARS-CoV-2 proteins in patients with autoimmune dermatomyositis, including 'DDAVVC' in the RNA-dependant RNA polymerase protein previously predicted as a CD8 T cell epitope, in keeping with T cell antigen presentation derived from processing both structural and non-structural proteins [17] . Further modern and indepth analyses of microbial and immunological interplay with respect to aetiopathogenesis seem to be very interesting and should yield relevant results in the near future.…”