A Comprehensive Overview on Myositis-Specific Antibodies: New and Old Biomarkers in Idiopathic Inflammatory Myopathy

Abstract

Autoantibodies specific for idiopathic inflammatory myopathy (myositis-specific autoantibodies (MSAs)) are clinically useful biomarkers to help the diagnosis of polymyositis/dermatomyositis (PM/DM). Many of these are also associated with a unique clinical subset of PM/DM, making them useful in predicting and monitoring certain clinical manifestations. Classic MSAs known for over 30 years include antibodies to Jo-1 (histidyl transfer RNA (tRNA) synthetase) and other aminoacyl tRNA synthetases (ARS), anti-Mi-2, and anti-signal recognition particle (SRP). Anti-Jo-1 is the first autoantibodies to ARS detected in 15-25 % of patients. In addition to anti-Jo-1, antibodies to seven other aminoacyl tRNA synthetases (ARS) have been reported with prevalence, usually 1-5 % or lower. Patients with any anti-ARS antibodies are associated with anti-synthetase syndrome characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon, and others. Several recent studies suggested heterogeneity in clinical features among different anti-ARS antibody-positive patients and anti-ARS may also be found in idiopathic ILD without myositis. Anti-Mi-2 is a classic marker for DM and associated with good response to steroid treatment and good prognosis. Anti-SRP is specific for PM and associated with treatment-resistant myopathy histologically characterized as necrotizing myopathy. In addition to classic MSAs, several new autoantibodies with strong clinical significance have been described in DM. Antibodies to transcription intermediary factor 1γ/α (TIF1γ/α, p155/140) are frequently found in DM associated with malignancy while anti-melanoma differentiation-associated gene 5 (MDA5; CADM140) are associated with clinically amyopathic DM (CADM) complicated by rapidly progressive ILD. Also, anti-MJ/nuclear matrix protein 2 (NXP-2) and anti-small ubiquitin-like modifier-1 (SUMO-1) activating enzyme (SAE) are recognized as new DM-specific autoantibodies. Addition of these new antibodies to clinical practice in the future will help in making earlier and more accurate diagnoses and better management for patients.

Keywords: Anti-nuclear antibodies; Autoantibodies; Dermatomyositis; Inflammatory myopathy; Polymyositis.

Fig. 1

A summary of the association of myositis-specific autoantibodies with the spectrum of muscle and skin involvements in different subsets of PM/DM

Fig. 2

Immunoprecipitation analysis of protein components of autoantigens recognized by autoantibodies in PM/DM. ³⁵S-methionine-labeled K562 cell extract was immunoprecipitated by sera from patients with PM/DM. Main components of each autoantigen are indicated by arrowheads. Jo-1 histidyl tRNA synthetase, EJ glycyl tRNA synthetase, PL-7 threonyl tRNA synthetase, PL-12 alanyl tRNA synthetase, OJ isoleucyl tRNA synthetase, multienzyme complex, KS asparaginyl tRNA synthetase, SMN survival of motor neuron, SRP signal recognition particle, PM-Scl polymyositis-scleroderma, Mi-2, Mi-2+, TIF1α, TIF1γ/α transcription intermediary factor 1α, TIF1β transcription intermediary factor 1β, MJ/NXP-2 nuclear matrix protein 2, MDA5 melanoma differentiation-associated gene 5, SAE small ubiquitin-like modifier 1 (SUMO-1) activating enzyme, Ku, NHS normal human serum

Fig. 3

Immunofluorescence antinuclear antibodies using sera from patients with PM/DM. HEp-2 ANA slides were stained using sera from patients with PM/DM. a Anti-U1RNP, b anti-Mi-2, c anti-TIF1γ/α, d anti-TIF1β, e anti-SAE, f, g anti-MJ/NXP-2, h anti-SMN, i, j anti-PM-Scl, k anti-U3RNP, l anti-Jo-1, m anti-PL-7, n anti-PL-12, m anti-SRP, p anti-MDA5

Fig. 4

Summary of HEp-2 cell immunofluorescence patterns corresponding to different autoantibody specificities in PM/DM

Fig. 5

Formation of cryptic epitopes via a somatic mutation. A somatic mutation that causes amino acid replacement may create cryptic epitopes, which can be recognized as non-self and trigger autoimmune response. Top, normal protein digested by trypsin makes normal peptides that are supposed to have immunological tolerance. Bottom, if arginine is replaced by other amino acid, trypsin digestion may create cryptic epitopes that have no or incomplete immunological tolerance and trigger autoimmune response

Fig. 6

Hypothesis on the production of anti-TIF1γ/α antibodies based on mutation of TIF1γ or interaction of viral proteins with TIF1. In old adult DM patients with malignancy, TIF1γ mutation may allow development of malignancy while the mutated protein may also trigger autoimmune response to TIF1γ. In JDM or young adult DM patients, interaction of viral proteins with TIF1 proteins may create cryptic epitopes, leading to the autoimmune response