Myositis
Abstract Number 1240 - A Novel Murine Model of the Anti-Synthetase Syndrome Induced by Immunization with Histidyl-tRNA Synthetase
Authors: Yasuhiro Katsumata1, William Ridgway1, Timothy Oriss1, Noreen Fertig1, Xinyan Gu1, David Chin1, Andrew Weinberg2, Dana Ascherman1. 1University of Pittsburgh, Pittsburgh, PA; 2Providence Portland Medical Center, Portland, OR
PURPOSE: This study sought to address the functional role of Histidyl-tRNA Synthetase (Jo-1)-directed B and T cell responses in a murine model of the antisynthetase syndrome.
BACKGROUND: There is a reproducible phenotype of muscle inflammation and interstitial lung disease in subjects with autoantibodies recognizing Jo-1. To date, data do not support a direct role for these antibodies in the immunopathogenesis of myositis; however, the documented affinity maturation of an increasingly complex, polyclonal antibody response targeted against Jo-1 suggests that these autoantibodies are markers of an underlying pathogenic anti-Jo-1 T cell response.
METHODS: Recombinant fragments of human and murine Jo-1 were generated. C57BL/6, NOD, and NOD Congenic mice prone to autoimmunity (C57BL/6, NOD, and NOD) were immunized with CFA emulsifications of these fragments or overlapping peptides comprising the amino terminal 120 amino acids of murine Jo-1. At 10-14 days or 8 -week time points, mice were sacrificed for harvesting of serum and tissue. Lung specimens were examined histologically using H&E staining. Immunoprecipitation and ELISA were performed to detect antibodies recognizing murine versus human Jo-1. The proliferative response of CFSE-labeled splenic T cells to various forms of Jo-1 provided a measure of T cell autoreactivity.
RESULTS: Mice immunized with murine, but not human, versions of Jo-1 develop a striking phenotype of muscle and lung inflammation very similar to the human anti-synthetase syndrome. Despite 95% amino acid sequence homology, there was remarkable species specificity with predominant recognition of unique rather than shared epitopes. Additionally, immunization with purified peptides derived from murine Jo-1 generates autoreactive B and T cells targeting species-specific epitopes contained within the amino terminal 58 amino acids of murine Jo-1. The eventual spreading of B cell epitopes that uniformly occurs by later time points (8 weeks post immunization) in mice inoculated with murine Jo-1 provides even more evidence of an ongoing immune response mediated by autoreactive T cells directed against native (in this case, murine) Jo-1.
CONCLUSIONS: Immunization with murine Jo-1 generates muscle and lung inflammation in different congenic strains of NOD and C57BL/6 mice, supporting a direct role for this antigen in the pathogenesis of the anti-synthetase syndrome. This mouse model underscores the significance of directing B and T cell responses against species-specific epitopes of native/self Jo-1.
COMMENT: This remarkable work in a mouse model which closely mimics the human antisynthetase phenotype is the first model to suggest that Jo-1 antibodies are pathogenic, rather than merely an epiphenomenon. This elegant study demonstrates the potential pathogenicity of Jo-1 antibodies.