Background/Purpose:

Anti-Jo-1 autoantibodies (Jo-1 Abs), directed against histidine tRNA synthetase (HisRS1), are detected in a high proportion of patients with both autoimmune inflammatory myopathy (IM) and interstitial lung disease (ILD), progressive and debilitating conditions for which no drugs are specifically approved. These patients receive immunosuppressive therapy which can be needed on a chronic basis to control their symptoms. In some individuals continued respiratory deterioration may occur despite immunosuppressive treatment, and may lead to fatal outcomes.  Several lines of evidence indicate that Jo-1 Ab may have pathogenic roles in IM and ILD.  We and others have demonstrated that HisRS1 and HisRS1-derived proteins possess immune-regulatory activities in addition to their roles in protein synthesis. As a key element of our effort to develop novel therapies for IM and ILD, we performed a detailed characterization of the Jo-1 Abs present in diverse populations of patients.

Methods:

A large panel of sera from healthy volunteers, IM patients with and without Jo-1 Abs, and patients with Jo-1 Abs for which the formal clinical diagnoses were unknown was obtained from a commercial vendor.  Plate-based immunoassays were developed to determine: i) the Jo-1 Ab titers by ELISA; (ii) Jo-1 Ab isotypes; (iii) the absolute concentration of IgM and IgG Jo-1 Ab;  iv) epitopes recognized by Jo-1 Abs using a panel of recombinant human HisRS1 protein fragments and alternatively-spliced forms (including those expressed in muscle and lung);  v) Jo-1 Ab affinity (by surface plasmon resonance); and vi)  circulating levels of HisRS1.

Results:

A wide range of Jo-1 Ab titers were found and these values correlated with the absolute amount of Jo-1 Abs.  The Jo-1 Ab titers and concentrations exhibited a broad range, with higher concentrations found in patients diagnosed with IM compared to those without a formal clinical diagnosis. Jo-1 Ab IgM was detected in some patients. The specific epitopes recognized by Jo-1 Abs were distributed across the entire HisRS protein and were interpreted in reference to the recently determined 3-D structure of human HisRS. The epitopes recognized varied considerably among subjects. Jo-1 Ab affinities measured were in the range of 10 – 0.01 nM. Circulating levels of HisRS1 protein were detected in some individuals.

Conclusion:

This molecular characterization of Jo-1 Abs provides deeper insight into the human autoimmune response to HisRS1 that occurs in a population of human subjects with autoimmune diseases.  Ongoing serial analysis of individual patients will provide greater insight into the progression of Jo-1 Abs with respect to isotypes, affinities, recognized epitopes, and their relationship to disease status. These data provide a framework for developing strategies to address the impact of Jo-1 Abs in IM and ILD.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-jo-1-autoantibodies-in-patients-with-inflammatory-myopathy-and-interstitial-lung-disease/