Graves' ophthalmopathy is a distressing autoimmune disease of unknown etiology. Analysis of the genes for antibodies secreted by orbital tissue-infiltrating plasma cells might provide insight into the pathogenesis of this disease. We, therefore, constructed an immunoglobulin heavy (H) chain and an immunoglobulin kappa light (L) chain cDNA library from the orbital tissue of a patient with active Graves' ophthalmopathy. Analysis of 15 H (IgG1) and 15 L (kappa) chains revealed a restricted spectrum of variable region genes. Fourteen of 15 variable kappa genes were about 94% homologous to the closest known germline gene, KL012. Thirteen of 15 H chain genes were 91% and 90% homologous to the closest germline genes, DP10 and hv1263, respectively. Remarkably, these germline genes also code for other autoantibodies to striated muscle (KL012) and thyroid peroxidase (KL012 and hv1263). These studies raise the possibility that particular germline genes may be associated with autoimmunity in humans. Further, the present study opens the way to identifying ocular autoantigens that may be the target of an humoral immune response.