In some patients with polyneuropathy there are IgM monoclonal antibodies (m-proteins) that bind to peripheral nerve myelin and that may cause the neuropathy. These M-proteins bind to carbohydrate determinants that are shared by a number of peripheral nerve glycoproteins, including the myelin-associated glycoprotein (MAG), and two glycolipids in peripheral nerve. We have characterized these two glycolipids from human cauda equina and found that they belong to a new class of glycolipids termed sulfated glucuronyl-glycolipids (SGGLs). Subcellular localization studies of bovine peripheral nerve have demonstrated that they are enriched in the axolemma-enriched fraction, while present in myelin and other glial-related membranes in lower concentrations. In addition, these glycolipids are present in bovine dura master and transformed rat Schwann cells. In this project, we plan to further characterize the antigenic determinant(s) that bind to M-proteins in patients with neuropathy and to develop synthetic analogues of the antigenic epitopes. These analogues could then be used therapeutically to block or remove circulating M-proteins in patients and improve the neuropathy. To better understand the role of these glycolipids in the pathogenesis of this disorder, we plan to immunize animals with SGGLs to induce experimental allergic neuritis (EAN) and to obtain polyclonal antibodies against these peripheral nerve glycolipids. Establishing the EAN model with structurally well-defined glycolipid antigens should be extremely important in affording a direct proof that these antigens can actually cause the neuropathy. The polyclonal antisera will be useful in studying their demyelinating and myelination-inhibiting activities in vitro and in vivo, in developing sensitive assays for quantitating these antigens, and for the immunocytochemical localization of these antigens in the nerve. Once this animal model is established, the pathogenetic mechanisms underlying this disorder can be studied in terms of humoral and cellular immune mechanisms, and T- and B-cell interactions regulating the secretion of M-proteins. The results of this project would therefore be important not only for understanding the pathogenesis and pathophysiology of the demyelinating neuropathy associated with IgM M-proteins and plasma cell dyscrasia, but also for providing vital information on the mechanisms of other autoimmune diseases such as multiple sclerosis, Guillain-Barre syndrome, etc.
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