Secreted Histidyl-tRNA Synthetase Splice Variants Elaborate Major Epitopes for Autoantibodies in Inflammatory Myositis

Zhou, Jie; Wang, Feng; Xu, Zhiwen; Lo, Woo-Kuen; Lau, Ching-Fun; Chiang, Kyle P.; Nangle, Leslie A.; Ashlock, Melissa A.; Mendlein, John; Yang, Xiang‐Lei; Zhang, Mingjie; Schimmel, Paul

doi:10.1074/jbc.c114.571026

Cited by 49 publications

(43 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because other tRNA synthetases not linked to the anti-synthetase syndrome do not manifest similar chemokine profiles [23], these studies also suggest that the capacity to activate innate immune signaling pathways is a key factor contributing to antigenicity and disease pathogenesis. More recent studies demonstrating upregulated mRNA expression of secretable splice variants of HRS (recognized by autoantibodies) in muscle tissue of dermatomyositis patients [24] support this hypothesis and suggest a mechanism by which altered forms of this protein elaborated in a tissue-specific Table 1 Role of Jo-1/HRS in adaptive vs. innate immunity Adaptive immunity Jo-1-specific T cells detected in peripheral blood of myositis patients Anti-Jo-1 antibodies undergo affinity maturation Anti-Jo-1 antibodies correlate with disease activity Jo-1/CFA immunization of mice generates species-specific immune responses, myositis, and ILD Innate immunity…”

Section: Jo-1-mediated Activation Of Innate Immune Signaling Pathwaysmentioning

confidence: 98%

Role of Jo-1 in the Immunopathogenesis of the Anti-synthetase Syndrome

Ascherman

2015

Curr Rheumatol Rep

View full text Add to dashboard Cite

Histidyl-tRNA synthetase (HRS = Jo-1) represents a key autoantibody target in the anti-synthetase syndrome that is marked by myositis as well as extra-muscular organ complications including interstitial lung disease (ILD). Over the last 25 years, a wealth of clinical, epidemiological, genetic, and experimental data have collectively supported a role for Jo-1 in mediating deleterious cell-mediated, adaptive immune responses contributing to the disease phenotype of the anti-synthetase syndrome. Complementing these studies, more recent work suggests that unique, non-enzymatic functional properties of Jo-1 also endow this antigen with the capacity to activate components of the innate immune system, particularly cell surface as well as endosomal Toll-like receptors and their downstream signaling pathways. Combining these facets of Jo-1-mediated immunity now supports a more integrated model of disease pathogenesis that should lead to improved therapeutic targeting in the anti-synthetase syndrome and related subsets of idiopathic inflammatory myopathy.

show abstract

Section: Jo-1-mediated Activation Of Innate Immune Signaling Pathwaysmentioning

confidence: 98%

Role of Jo-1 in the Immunopathogenesis of the Anti-synthetase Syndrome

Ascherman

2015

Curr Rheumatol Rep

View full text Add to dashboard Cite

show abstract

“…This study showed that a bacteria-derived virulence factor could use KRS as a cytokine to synergistically exacerbate inflammatory responses in the host. HRS secreted in its full-length form [97] induced lymphocyte migration and activated monocytes and immature dendritic cells through CCR5 binding [98].…”

Section: Secreted Arss Acting As Cytokines and Chemokinesmentioning

confidence: 99%

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Lee

Kim

2018

Biochemical Pharmacology

View full text Add to dashboard Cite

Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. It has taken scientists decades to appreciate that eukaryotic aminoacyl-tRNA synthetases (ARSs) play a role as global cell signaling mediators to regulate cell homeostasis, beyond their intrinsic function as protein synthesis enzymes. Recent discoveries revealed that ubiquitously expressed standby cytoplasmic ARSs sense and respond to danger signals and regulate immunity against infections, indicating their potential as therapeutic targets for infectious diseases. In this review, we discuss ARS-mediated anti-infectious signaling and the emerging role of ARSs in antimicrobial immunity. In contrast to their ability to defend against infection, host ARSs are inevitably co-opted by viruses for survival and propagation. We therefore provide a brief overview of the communication between viruses and the ARS system. Finally, we discuss encouraging new approaches to develop ARSs as therapeutics for infectious diseases.

show abstract

“…Resolaris (histidyl-tRNA synthetase, aTyr Pharma, Inc., San Diego, CA, USA) has been shown to reverse immune cell invasion of muscle tissue in an animal model of myopathy [30]. Furthermore, autoantibodies to cytoplasmic histidyl-tRNA synthetase have been associated with inflammatory myositis [31]. A multinational Phase Ib/II clinical trial of this agent in adult patients with FSHD is under way in Europe.…”

Section: Investigational Agents For Fshdmentioning

confidence: 98%