Antisynthetase syndrome

Background

Anti-synthetase syndrome (ASS) is an autoimmune disease named after the aminoacyl-tRNA synthetases (aaRSs). The clinical symptoms include inflammatory myopathies, polymyositis, dermatomyositis, interstitial lung diseases (ILD), polyarthritis, and Raynaud's phenomenon. The hallmark of the disease is the serum titers of the autoantibodies against one of the aaRSs. To date, eight aaRSs have been described as the target of ASS autoantibodies. Histidyl-tRNA synthetase (HisRS or HARS1), eliciting anti-Jo-1 antibodies (Abs), is the most common, followed by anti-PL-7 and anti-PL-12 targeting threonyl- and alanyl-tRNA synthetases (ThrRS or TARS1 and AlaRS or AARS1), respectively.

Fig. 1 Clinical manifestations and cellular/molecular pathogenesis of ASS.

Autoantibody Targets and Mechanistic Pathways

The most common autoantibody found in ASS is anti-Jo-1, which is present in 66% of cases. Other autoantibodies found in ASS include anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-KS, Anti-EJ, and Anti-Zo. Anti-PL7 and anti-PL12 may be associated with more ILD, while anti-Jo-1 tends to be associated with more arthritis.

Mechanisms

• Disruption of Protein Synthesis
  Aminoacyl-tRNA synthetases facilitate the attachment of amino acids to their corresponding tRNA molecules, which is essential for protein translation. Autoantibodies against these enzymes inhibit their function, impairing protein synthesis and subsequent cellular dysfunction, and causing muscle weakness, inflammation, and other clinical features.
• Formation of Immune Complexes
  Autoantibodies against tRNA synthetases can form immune complexes with the enzymes. These complexes can deposit in tissues, triggering inflammatory responses through the activation of the complement system and recruitment of inflammatory cells. This immune complex-mediated inflammation contributes to the pathogenesis of muscle damage in myositis and lung damage in ILD.
• Endoplasmic Reticulum (ER) Stress
  The accumulation of misfolded or improperly synthesized proteins due to inhibited tRNA synthetase activity can lead to ER stress, which may further contribute to inflammation and apoptosis. Persistent ER stress and UPR activation can exacerbate muscle inflammation and fibrosis, as well as contribute to lung injury.

Fig. 2 Involvement of endoplasmic reticulum stress in the musculoskeletal system in idiopathic inflammatory myopathies.

Antibody drugs used in immunotherapy

1. Rituximab
   Rituximab depletes B cells, which are involved in the autoimmune process, and is used in cases where patients do not respond to conventional treatments or have severe disease.
2. Abatacept
   Abatacept inhibits T cell activation by blocking the co-stimulatory signals required for T cell activation, which helps modulate the autoimmune response.
3. Tocilizumab
   Tocilizumab blocks the IL-6 receptor, which is involved in inflammation and autoimmune processes. It's particularly used when there is significant inflammatory activity.
4. Belimumab
   Belimumab inhibits BLyS, a factor that promotes B cell survival, which can help reduce the number of autoantibody-producing B cells.
5. Infliximab
   Infliximab is an anti-TNF-alpha monoclonal antibody that helps reduce inflammation by targeting and neutralizing TNF-alpha, a key cytokine in the inflammatory process.