Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100β molecule, a calcium binding protein of astroglia

Abstract

The pathogenic potential of autoimmune T cell responses to nonmyelin autoantigens was investigated in the Lewis rat using the astrocyte-derived calcium binding protein S100β, as a model nonmyelin autoantigen. The Lewis rat mounts a vigorous RT1B1 (major histocompatibility complex class II) restricted autoimmune response to an immunodominant S100β epitope (amino acid residues 76-91). The adoptive transfer of S100β-specific T cell lines induced a severe inflammatory response in the nervous system, but only minimal neurological dysfunction in naive syngeneic recipients. The inability of S100β-specific T cell transfer to induce severe disease was associated with a decreased recruitment of ED1+ macrophages into the central nervous system (CNS) in comparison with that seen in severe experimental autoimmune encephalomyelitis (EAE) induced by the adoptive transfer of myelin basic protein (MBP)-specific T line cells. Moreover, unlike encephalitogenic MBP- specific T cell lines, S100β-specific T cell lines exhibited no cytotoxic activity in vitro. Histopathological analysis also revealed striking differences in the distribution of inflammatory lesions in MBP- and S100β- specific T cell-mediated disease. In contrast to the MBP paradigm, S100β- specific T cell transfer induces intense inflammation not only in the spinal cord, but throughout the entire CNS and also in the uvea and retina of the eye. In view of the distribution of lesions throughout the grey and white matter of the CNS we propose to term this new model experimental autoimmune panencephalomyelitis (EAP) to differentiate it from EAE. These experiments demonstrate for the first time that nonmyelin CNS autoantigens can initiate a pathogenic autoimmune T cell response, although the nature of the target autoantigen profoundly influences the clinical and histopathological characteristics of the resulting autoimmune disease. This is not simply a consequence of the distribution of the autoantigen, as both MBP and S100β are coexpressed in many areas of the CNS, but reflects differences in the capacity of different regions of the CNS to process and present specific autoantigens. This new model of T cell-mediated autoimmune CNS disease exhibits a number of similarities to multiple sclerosis (MS), such as its mild clinical course and the involvement of areas of the brain and eye, which are absent in myelin-mediated models of EAE. Nonmyelin autoantigens may therefore play an unexpectedly important role in the immunopathogenesis of inflammatory diseases of the CNS.