Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond

Abstract

Anti-synthetase syndrome (ASSD) is an autoimmune disease characterized by the presence of autoantibodies targeting one of several aminoacyl t-RNA synthetases (aaRSs) along with clinical features including interstitial lung disease, myositis, Raynaud’s phenomenon, arthritis, mechanic’s hands, and fever. The family of aaRSs consists of highly conserved cytoplasmic and mitochondrial enzymes, one for each amino acid, which are essential for the RNA translation machinery and protein synthesis. Along with their main functions, aaRSs are involved in the development of immune responses, regulation of transcription, and gene-specific silencing of translation. During the last decade, these proteins have been associated with cancer, neurological disorders, infectious responses, and autoimmune diseases including ASSD. To date, several aaRSs have been described to be possible autoantigens in different diseases. The most commonly described are histidyl (HisRS), threonyl (ThrRS), alanyl (AlaRS), glycyl (GlyRS), isoleucyl (IleRS), asparaginyl (AsnRS), phenylalanyl (PheRS), tyrosyl (TyrRS), lysyl (LysRS), glutaminyl (GlnRS), tryptophanyl (TrpRS), and seryl (SerRS) tRNA synthetases. Autoantibodies against the first eight autoantigens listed above have been associated with ASSD while the rest have been associated with other diseases. This review will address what is known about the function of the aaRSs with a focus on their autoantigenic properties. We will also describe the anti-aaRSs autoantibodies and their association to specific clinical manifestations, and discuss their potential contribution to the pathogenesis of ASSD.

Prognosis of spontaneous pneumomediastinum occurring in dermatomyositis or polymyositis patients with interstitial lung disease according to antimelanoma differentiation-associated gene 5 antibody status: a retrospective cohort study

“…Therefore, we could not individually evaluate the characteristics of anti-ARS antibodies, although anti-PL-7 and anti-PL-12 antibody positivity has been reported to be associated with severe ILD. 22 In summary, SPNM occurred more frequently in anti-MDA5 antibody-positive DM/PM patients than in anti-MDA5 antibody-negative DM/PM patients, and twothirds of the SPNM group were anti-MDA5 antibody-positive. Overall, the SPNM group had a significantly higher mortality rate than the non-SPNM group.…”

“…Therefore, we could not individually evaluate the characteristics of anti-ARS antibodies, although anti-PL-7 and anti-PL-12 antibody positivity has been reported to be associated with severe ILD. 22 …”

High expression of TARS is associated with poor prognosis of endometrial cancer

“…The results suggested that activated CD4 + T cell, effector memory CD4 + T cell, memory B cell and type 2 T helper cell may participate in the high TARS expression related immune response in endometrial cancer. Autoantibodies directed against one or more ARSs are present in anti-synthetase syndrome (ASSD), an autoimmune illness that is also defined by clinical symptoms [ 35 ]. Zhou et al reported the tumor mutation burden and immune infiltrates in endometrial cancer [ 36 ].…”

Aminoacyl-tRNA synthetases in human health and disease

“…In addition to the genetic disorders of the aaRSs, there is also an acquired autoimmune condition affecting aaRSs, called Anti-Synthetase Syndrome (ASSD). ASSD is a rare condition that involves the production of autoantibodies that bind with, and mount a response against, aaRS proteins ( Kron and Härtlein, 2013 ; Galindo-Feria et al, 2022 ). ASSD is an idiopathic inflammatory myopathy with organ complications beyond the muscles, including interstitial lung disease ( Mahler et al, 2014 ).…”

“…The formal diagnostic criteria for ASSD are based on the presence of anti-aminoacyl tRNA synthetase antibodies along with major (interstitial lung disease and/or polymyositis or dermatomyositis) and minor (arthritis, Raynaud’s phenomenon, mechanic’s hands) criteria ( Solomon et al, 2011 ; Witt et al, 2016 ). The most commonly recognized autoantigen is HisRS (recognized by anti-Jo-1 autoantibodies), but to date, autoantibodies targeting eight aaRSs (HisRS, ThrRS, AlaRS, GlyRS, IleRS, AsnRS, PheRS, TyrRS) have been linked to ASSD ( Ascherman, 2015 ; Galindo-Feria et al, 2022 ). A combination of immunosuppressive agents is used to treat ASSD ( Witt et al, 2016 ).…”