We assessed the clinicopathological features of 92 patients with primary Sjögren's syndrome-associated neuropathy (76 women, 16 men, 54.7 years, age at onset). The majority of patients (93%) were diagnosed with Sjögren's syndrome after neuropathic symptoms appeared. We classified these patients into seven forms of neuropathy: sensory ataxic neuropathy (n = 36), painful sensory neuropathy without sensory ataxia (n = 18), multiple mononeuropathy (n = 11), multiple cranial neuropathy (n = 5), trigeminal neuropathy (n = 15), autonomic neuropathy (n = 3) and radiculoneuropathy (n = 4), based on the predominant neuropathic symptoms. Acute or subacute onset was seen more frequently in multiple mononeuropathy and multiple cranial neuropathy, whereas chronic progression was predominant in other forms of neuropathy. Sensory symptoms without substantial motor involvement were seen predominantly in sensory ataxic, painful sensory, trigeminal and autonomic neuropathy, although the affected sensory modalities and distribution pattern varied. In contrast, motor weakness and muscle atrophy were observed in multiple mononeuropathy, multiple cranial neuropathy and radiculoneuropathy. Autonomic symptoms were often seen in all forms of neuropathy. Abnormal pupils and orthostatic hypotension were particularly frequent in sensory ataxic, painful, trigeminal and autonomic neuropathy. Unelicited somatosensory evoked potentials and spinal cord posterior column abnormalities in MRI were observed in sensory ataxic, painful and autonomic neuropathy. Sural nerve biopsy specimens (n = 55) revealed variable degrees of axon loss. Predominantly large fibre loss was observed in sensory ataxic neuropathy, whereas predominantly small fibre loss occurred in painful sensory neuropathy. Angiitis and perivascular cell invasion were seen most frequently in multiple mononeuropathy, followed by sensory ataxic neuropathy. The autopsy findings of one patient with sensory ataxic neuropathy showed severe large sensory neuron loss paralleling to dorsal root and posterior column involvement of the spinal cord, and severe sympathetic neuron loss. Degrees of neuron loss in the dorsal and sympathetic ganglion corresponded to segmental distribution of sensory and sweating impairment. Multifocal T-cell invasion was seen in the dorsal root and sympathetic ganglion, perineurial space and vessel walls in the nerve trunks. Differential therapeutic responses for corticosteroids and IVIg were seen among the neuropathic forms. These clinicopathological observations suggest that sensory ataxic, painful and perhaps trigeminal neuropathy are related to ganglioneuronopathic process, whereas multiple mononeuropathy and multiple cranial neuropathy would be more closely associated with vasculitic process.

Promoting remyelination, a major goal of an effective treatment for demyelinating diseases, has the potential to protect vulnerable axons, increase conduction velocity, and improve neurologic deficits. Strategies to promote remyelination have focused on transplanting oligodendrocytes (OLs) or recruiting endogenous myelinating cells with trophic factors. Ig-based therapies, routinely used to treat a variety of neurological and autoimmune diseases, underlie our approach to enhance remyelination. We isolated two human mAbs directed against OL surface antigens that promoted significant remyelination in a virusmediated model of multiple sclerosis. Four additional OL-binding human mAbs did not promote remyelination. Both human mAbs were as effective as human i.v. Ig, a treatment shown to have efficacy in multiple sclerosis, and bound to the surface of human OLs suggesting a direct effect of the mAbs on the cells responsible for myelination. Alternatively, targeting human mAbs to areas of central nervous system (CNS) pathology may facilitate the opsonization of myelin debris, allowing repair to proceed. Human mAbs were isolated from the sera of individuals with a form of monoclonal gammopathy. These individuals carry a high level of monoclonal protein in their blood without detriment, lending support to the belief that administration of these mAbs as a therapy would be safe. Our results are (i) consistent with the hypothesis that CNS-reactive mAbs, part of the normal Ig repertoire in humans, may help repair and protect the CNS from pathogenic immune injury, and (ii) further challenge the premise that Abs that bind OLs are necessarily pathogenic. E nhancement of remyelination and protection from axonal injury are important therapeutic goals in the treatment of inflammatory demyelinating central nervous system (CNS) disorders such as multiple sclerosis (MS). Remyelination in MS plaques can occur, but is limited (1, 2) even though oligodendrocyte (OL) progenitors are present in the adult (3, 4). A number of therapeutic strategies to promote remyelination have been tested in experimental animals. Transplantation of OLs (5) or their progenitors (6) into demyelinated tissue produces new myelin. Transplanted OL progenitors also can remyelinate demyelinated lesions in the adult CNS (7) and migrate toward an area of damage when placed in close proximity to the lesion (8). Unresolved issues remain concerning the survival of transplanted OL progenitors in the intact adult CNS and their ability to target to areas of myelin pathology (9). However, if CNS lesions are surgically approachable and axons are still intact, transplantation of glial cells may be a viable therapy for improving functional performance (10).The in vitro administration of growth or trophic factors induces the expansion of OL progenitors (11, 12) or promotes mature OLs to dedifferentiate and subsequently reinitiate a program of myelination (13,14). The in vivo administration of trophic factors via genetically engineered fibroblasts to the injured CNS promotes ax...

We previously identified the remyelinating activity of a natural IgMkappa oligodendrocyte-reactive autoantibody (SCH94.03), using a virus-induced murine model of multiple sclerosis. We now describe a second mouse IgMkappa monoclonal antibody (mAb) (SCH79.08) raised against normal mouse spinal cord homogenate, which reacts with myelin basic protein and also promotes remyelination. Because these two mAbs recognize different oligodendrocyte antigens, several previously identified oligodendrocyte-reactive IgMkappa mAbs (O1, O4, A2B5, and HNK-1), each with distinct antigen specificities, were evaluated and found to promote remyelination. In contrast, IgMkappa mAbs that did not bind to oligodendrocytes showed no remyelination. One of these, CH12 IgMkappa mAb, which shares variable region cDNA sequences with SCH94.03 except for amino acid differences in the complementarity-determining region 3 in both heavy and light chains, did not bind to oligodendrocytes and did not promote remyelination. The fact that multiple oligodendrocyte-reactive antibodies with distinct antigen reactivities induce remyelination argues against direct activation by a unique cell surface receptor. These findings are most consistent with the hypothesis that the binding of mAbs to oligodendrocytes in the lesions induces myelin repair via indirect immune effector mechanisms initiated by the mu-chain. Importantly, these studies indicate that oligodendrocyte-reactive natural autoantibodies may provide a powerful and novel therapeutic means to induce remyelination in multiple sclerosis patients.

A monoclonal antibody SCH94.03, made in syngeneic mice by injection of spinal cord homogenate, promotes central nervous system remyelination when injected into SJL/J mice chronically infected with Theiler's virus. To elucidate the mechanism of antibody‐mediated remyelination, SCH94.03 was investigated by immunocytochemistry, flow cytometry, immunoelectron microscopy, Western blotting, and immuno‐thin layer chromatography. All cell types investigated in vitro showed strong cytoplasmic staining with a pattern resembling a cytoskeletal protein. In contrast, among the primary cultured cells studied, only oligodendrocytes showed strong surface reactivity. Other cell types, including astrocytes, microglia, Schwann cells, myoblasts, and T and B lymphocytes, were negative. Mouse and rat oligodendrocytes which showed strong surface reactivity exhibited a well‐differentiated morphology, and ∼50% expressed myelin basic protein. Since oligodendrocyte progenitors were negative for surface staining, the expression of the antigens recognized by this monoclonal antibody appears to be developmentally regulated, i.e., transiently expressed on younger, terminally differentiating oligodendrocytes. Among the cell lines studied, only two rat oligodendrocyte lineage cell lines showed surface reactivity with SCH 94.03. Western blotting of secondary isolated oligodendrocytes lysates revealed reactivity with multiple protein bands of 27, 32, 50, 100, and 106 kDa, whereas there was no reactivity to lipid antigens by immuno‐thin layer chromatography. These results raise the possibility that SCH94.03 recognizes a novel oligodendrocyte‐specific surface antigen, and may act directly on oligodendrocytes to promote remyelination. © 1996 Wiley‐Liss, Inc.

Conditioned medium derived from a rat central nervous system neuronal cell line B104 (8104 CM) was shown previously to contain uncharacterized potent mitogen(s) for oligodendrocyte/type-2 astrocyte (O-2A) progenitor cells. In this study, we demonstrated that B104 cells produce and secrete platelet-derived growth factor (PDGF)-AA homodimer, but not PDGF-B chain. B104 cells did not express other known potent mitogens for O-2A progenitor cells, including fibroblast growth factor-2 and neurotrophin-3. Unexpectedly, B104 cells also expressed transcripts of transforming growth factor-ßl (TGF-ßl ) and -ß2 (TGF-ß2), which are known to regulate O-2A progenitor cell differentiation and proliferation, and secreted exclusively the 25-kDa active forms of TGF-131 and TGF-ß2. Neutralization of B104 CM with anti-PDGF-AA antibody decreased proliferation of O-2A progenitor cells, whereas neutralization with anti-TGF-ß antibodies had no effect. The combination of PDGF and TGF-ß on proliferation was not equivalent to the effect of 8104 CM, indicating the possibility of an unidentified growth factor. Bi 04 CM maintained a high expression of PDGF-a receptor in oligodendrocytes. The observation that both a stirnulatory factor (PDGF-AA) and a regulatory factor (TGFß) for O-2A progenitor cell proliferation and differentiation are produced from a single neuronal cell line emphasizes the potential critical interaction between neurons and O-2A progenitor cells in myelination and possibly in remyelination. Key Words: Oligodendrocyte/type-2 astrocyte progenitor-Platelet-derived growth factor-Plateletderived growth factor-a receptor-Transforming growth factor-/3-Myelination-Remyelination.

The accumulation of amyloid beta (Abeta) protein in the brain reflects the cognitive impairment noted in Alzheimer's disease. Recent studies have shown that brain Abeta disappeared and cognitive improvement occurred as a result of passive or active Abeta immunization. Peripheral administration of nonimmunization substances, such as GM1 ganglioside, also reduced brain Abeta. Therefore, we hypothesized that the rapid removal of Abeta from the blood by an extracorporeal system may act as a peripheral Abeta sink from the brain. In the present study, we investigated the Abeta removal activity of medical materials as a first step toward the design of an Abeta removal system. First, the removal activities of six materials were studied for Abeta(1-40) and Abeta(1-42) by batch analysis in albumin solution or in human plasma for 1-16 h. Two of the six materials reduced the Abeta concentrations by 90-99% within 1 h. Next, the two effective materials, hexadecyl-alkylated cellulose particles (HDC) and charcoal, were analyzed in a continuous single-pass system with minicolumns. Both materials showed around 81-90% removal activity for more than 2 h, which corresponded to over 4 l of plasma treatment in humans. In a human extracorporeal system, HDC also removed both Abeta(1-40) and Abeta(1-42) from whole blood circulation. In conclusion, biomedical materials were found that could remove Abeta(1-40) and Abeta(1-42) effectively in an extracorporeal system. It is now conceivable that further studies can be undertaken to reduce Abeta concentrations in the brain to improve cognitive function.

Infection of susceptible strains of mice with Daniel's (DA) strains of Theiler's murine encephalomyelitis virus (DAV) results in virus persistence in the central nervous system (CNS) white matter and chronic demyelination similar to that observed in multiple sclerosis. We investigated whether persistence is due to the immune system more efficiently clearing DAV from gray than from white matter of the CNS. Severe combined immunodeficient (SCID) and immunocompetent C.B-17 mice were infected with DAV to determine the kinetics, temporal distribution, and tropism of the virus in CNS. In early disease (6 h to 7 days postinfection), DAV replicated with similar kinetics in the brains and spinal cords of SCID and immunocompetent mice and in gray and white matter. DAV RNA was localized within 48 h in CNS cells of all phenotypes, including neurons, oligodendrocytes, astrocytes, and macrophages/microglia. In late disease (13 to 17 days postinfection), SCID mice became moribund and permitted higher DAV replication in both gray and white matter. In contrast, immunocompetent mice cleared virus from the gray matter but showed replication in the white matter of their brains and spinal cords. Reconstitution of SCID mice with nonimmune splenocytes or anti-DAV antibodies after establishment of infection demonstrated that both cellular and humoral immune responses decreased virus from the gray matter; however, the cellular responses were more effective. SCID mice reconstituted with splenocytes depleted of CD4 ؉ or CD8 ؉ T lymphocytes cleared virus from the gray matter but allowed replication in the white matter. These studies demonstrate that both neurons and glia are infected early following DAV infection but that virus persistence in the white matter is due to preferential clearance of virus from the gray matter by the immune system.

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