OLIGODENDROCYTE-SPECIFIC EXPRESSION AND AUTOANTIGENICITY OF TRANSALDOLASE IN MULTIPLE-SCLEROSIS

Although the etiology of multiple sclerosis (MS) is unknown, there is compelling evidence that its pathogenesis is mediated through the immu ne system. Molecular mimicry, i.e., crossreactivity between self-antig ens and viral proteins, has been implicated in the initiation of autoi mmunity and MS. Based on homology to human T cell lymphotropic virus t ype I (HTLV-I) a novel human retrotransposon was cloned and found to c onstitute an integral part of the coding sequence of the human transal dolase gene (TAL-H). TAL-H is a key enzyme of the nonoxidative pentose phosphate pathway (PPP) providing ribose-5-phosphate for nucleic acid synthesis and NADPH for lipid biosynthesis. Another fundamental funct ion of the PPP is to maintain glutathione at a reduced state and, cons equently, to protect sulfhydryl groups and cellular integrity from oxy gen radicals. Immunohistochemical analyses of human brain sections and primary murine brain cell cultures demonstrated that TAL is expressed selectively in oligodendrocytes at high levels, possibly linked to pr oduction of large amounts of lipids as a major component of myelin, an d to the protection of the vast network of myelin sheaths from oxygen radicals. High-affinity autoantibodies to recombinant TAL-H were detec ted in serum (25/87) and cerebrospinal fluid (15/20) of patients with MS. By contrast, TAL-H antibodies were absent in 145 normal individual s and patients with other autoimmune and neurological diseases. In add ition, recombinant TAL-H stimulated proliferation and caused aggregate formation of peripheral blood lymphocytes from patients with MS. Rema rkable amino acid sequence homologies were noted between TAL-H and cor e proteins of human retroviruses. Presence of crossreactive antigenic epitopes between recombinant TAL-H and HTLV-I/human immunodeficiency v irus type 1 (HIV-1) gag proteins was demonstrated by Western blot anal ysis. The results suggest that molecular mimicry between viral core pr oteins and TAL-H may play a role in breaking immunological tolerance a nd leading to a selective destruction of oligodendrocytes in MS.