Histidyl-tRNA synthetase (HisRS, Jo-1) is an aminoacyl-tRNA synthetase that charges transfer RNAs (tRNAs) with a cognate histidine residue to produce histidyl-tRNA. Histidyl-tRNA is essential for the incorporation of histidine into proteins. Systemic autoimmune diseases lead to aminoacyl-tRNA synthetase autoantibodies that are directed against self structures. HisRS is an antigen in systemic autoimmune diseases such as rheumatic arthritis or polymyositis with associated interstitial lung disease, thrombocytopenia and Raynaud’s phenomenon (vasospastic attacks that cause blood vessels to constrict). HisRS autoantibodies are unlike anti-synthetase antibodies because they bind the nonlinear, exposed epitopes on native HisRS when the enzyme is complexed to tRNA(His).