Generation of autonomously pathogenic neo‐autoreactive TH1 cells during the development of the determinant spreading cascade in murine autoimmune encephalomyelitis

Chronic progression of autoimmune disease is accompanied by the acquisition of autoreactivity to new self‐determinants. Recent evidence indicates that this process, commonly referred to as determinant spreading, may be pathogenic for chronicity. Our studies on experimental autoimmune encephalomyelitis (EAE), a murine model widely used in multiple sclerosis (MS) studies, have shown that determinant spreading develops as a predictable sequential cascade of neo‐autoimmunity during progression to chronic disease. By 7–8 weeks after immunization of (SWRxSJL)F 1 mice with the immunodominant myelin proteolipid protein determinant (PLP 139–151), splenocytes consistently respond to the immunodominant myelin basic protein determinant (MBP 87–99). In the present study, we directly address the pathogenicity of neo‐autoimmunity resulting from endogenous self‐priming during the course of disease. Our results indicate that T cells responding to the spreading MBP 87–99 determinant produce a proinflammatory cytokine profile consistent with type 1 helper T cells (Th1) cells. In addition, splenocytes activated to the spreading MBP 87–99 determinant consistently transfer acute EAE in naive recipients even when T cells reactive to the priming PLP 139–151 immunogen are eliminated by bromodeoxyuridine (BUdR)‐mediated photolysis. Our data indicate that endogenous neo‐autoantigen priming during chronic autoimmune disease generates type 1 helper T cells (Th1) cells that are autonomously pathogenic. These results provide further evidence supporting the view that determinant spreading is a pathogenic process that leads to chronic progression of autoimmune disease. © 1996 Wiley‐Liss, Inc.