Species-specific immune responses generated by histidyl-tRNA synthetase immunization are associated with muscle and lung inflammation.
Evidence implicating histidyl-tRNA synthetase (Jo-1) in the pathogenesis of the anti-synthetase syndrome includes established genetic associations linking the reproducible phenotype of muscle inflammation and interstitial lung disease with autoantibodies recognizing Jo-1. To better address the role of Jo-1-directed B and T cell responses in the context of different genetic backgrounds, we employed Jo-1 protein immunization of C57BL/6 and NOD congenic mice. Detailed analysis of early antibody responses following inoculation with human or murine Jo-1 demonstrates remarkable species-specifity, with limited cross recognition of Jo-1 from the opposite species. Complementing these results, immunization with purified peptides derived from murine Jo-1 generates B and T cells targeting species-specific epitopes contained within the amino terminal 120 amino acids of murine Jo-1. The eventual spreading of B cell epitopes that uniformly occurs 8 weeks post immunization with murine Jo-1 provides additional evidence of an immune response mediated by autoreactive, Jo-1-specific T cells. Corresponding to this self-reactivity, mice immunized with murine Jo-1 develop a striking combination of muscle and lung inflammation that replicates features of the human anti-synthetase syndrome.
Katsumata
Yasuhiro
Y
Department of Medicine, Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Ridgway
William M
WM
Oriss
Timothy
T
Gu
Xinyan
X
Chin
David
D
Wu
Yuehong
Y
Fertig
Noreen
N
Oury
Tim
T
Vandersteen
Daniel
D
Clemens
Paula
P
Camacho
Carlos J
CJ
Weinberg
Andrew
A
Ascherman
Dana P
DP
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006643:Histidine-tRNA Ligase / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007114:Immunization; D017563:Lung Diseases, Interstitial / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D017285:Polymyositis / Q000276:immunology* / Q000378:metabolism; D016415:Sequence Alignment; D013045:Species Specificity; D013577:Syndrome