Oligodendrocyte-specific expression and autoantigenicity of transaldolase in multiple sclerosis.

Abstract

SummaryAlthough the etiology of multiple sclerosis (MS) is unknown, there is compelling evidence that its pathogenesis is mediated through the immune system. Molecular mimicry, i.e., crossreactivity between self-antigens and viral proteins, has been implicated in the initiation of autoimmunity and MS. Based on homology to human T cell lymphotropic virus type I (HTLV-I) a novel human retrotransposon was cloned and found to constitute an integral part of the coding sequence of the human transaldolase 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 function of the PPP is to maintain glutathione at a reduced state and, consequently, to protect sulfhydryl groups and cellular integrity from oxygen radicals. Immunohistochemical analyses of human brain sections and primary routine brain cell cultures demonstrated that TAL is expressed selectively in oligodendrocytes at high levels, possibly linked to production of large amounts of lipids as a major component of myelin, and to the protection of the vast network of myelin sheaths from oxygen radicals. High-affinity autoantibodies to recombinant TAL-H were detected in serum (25/87) and cerebrospinal fluid (15/20) of patients with MS. By contrast, TAL-H antibodies were absent in 145 normal individuals and patients with other autoimmune and neurological diseases. In addition, recombinant TAL-H stimulated proliferation and caused aggregate formation of peripheral blood lymphocytes from patients with MS. Remarkable amino acid sequence homologies were noted between TAL-H and core proteins of human retroviruses. Presence of crossreactive antigenic epitopes between recombinant TAL-H and HTLV-I/human immunodeficiency virus type 1 (HIV-1) gag proteins was demonstrated by Western blot analysis. The results suggest that molecular mimicry between viral core proteins and TAL-H may play a role in breaking immunological tolerance and leading to a selective destruction of oligodendrocytes in MS.

Inhibition of the catalytic activity of human transaldolase by antibodies and site‐directed mutagenesis

“…Catalytic activity of wild-type rTAL-H (50 ng) was also inhibited in the presence of 300/lg/ml purified immunoglobulins from MS patients ALV and LAK, by 37% and 26%, respectively (not shown). These data demonstrated that autoantibodies from patients with MS recognized not only the immunoblotted full-length TAL-H protein and its N-terminal fragment [13] but functionally relevant C-terminal epitopes as well. The pathological significance of inhibition of transaldolase activity by autoantibodies is unknown at this time, but capture of TAL-H by immunoglobulins on the surface of B lymphocytes may play an important role in presenting TAL-H to T cells.…”

“…In fact, activated B cells, by virtue of antigen capture on their surface immunoglobulins, are particularly efficient presenters of low abundance antigens [27]. Proliferation of T cells was stimulated by TAL-H in both patients (LAK, stimulation index, SI = 3.1 [13]; ALV, SI = 4.6, not shown). The identification of enzyme inhibitory autoantibodies capable of binding to native TAL-H may provide an example of how specific autoantibodies can influence autoimmune T cell responses in patients with MS.…”

“…No difference was noted between the wildtype or mutant TAL-H in reactivity with Ab 12484, suggesting that multiple epitopes outside the catalytic domain of the molecule are recognized by these antibodies. High-affinity antibodies to TAL-H are present in patients with MS [13]. Catalytic activity of wild-type rTAL-H (50 ng) was also inhibited in the presence of 300/lg/ml purified immunoglobulins from MS patients ALV and LAK, by 37% and 26%, respectively (not shown).…”

“…Importance of PPP has been documented in host defense mechanisms in all tissues against oxidative stress [1], in embryogenesis [2], neurulation [3], myelination [4], inflammation [5][6][7][8], lymphocyte activation [9,10], phagocytosis [6,8], cardiac arrhythmias [11], resistance to radiation of malignant tumors [12]. We recently demonstrated that transaldolase is expressed selectively in oligodendrocytes at high levels, possibly linked to production of large amounts of lipids as a major component of myelin and to the protection of myelin sheaths from oxygen radicals and that high-affinity autoantibodies to human transaldolase (TAL-H) are present in serum and cerebrospinal fluid of patients with multiple sclerosis (MS) [13].…”

Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

“…17 T cell responses and antibodies are also directed against all the major myelin proteins in MS including myelin basic protein (MBP), proteolipid protein (PLP)], myelin oligodendroglial glycoprotein (MOG), myelin associated glycoprotein (MAG), and MOBP. 17,19 Other protein components in the myelin sheath such as transaldolase and CNPase are targets of the immune response in MS. 19,20 Lipids and carbohydrates of the myelin sheath are also targeted in MS. 21 The immune response to one region of myelin basic protein has been studied the most intensively. The peptide between residues 82 and 99 on myelin basic protein is a major target of both T and B cell responses to MBP.…”