Neuronal molecular mimicry in immune‐mediated neurologic disease

Levin, Michael C.; Krichavsky, Marc Z.; Berk, Jeffrey; Foley, Shanon; Rosenfeld, Myrna R.; Dalmau, Josep; Chang, Greg; Posner, Jerome B.; Jacobson, Steven

doi:10.1002/ana.410440115

Cited by 68 publications

(48 citation statements)

References 38 publications

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“…In addition to its deleterious effects on neural cells, sCD100 could participate in the autoimmune response within the brain of patients suffering with neuroinflammatory demyelination (21,51). In fact, the two murine immune semaphorins, CD100 and SEMA-4A, are expressed constitutively in T cells and function as soluble ligands to CD72 and Tim2, respectively, to regulate the humoral and cellular immune response (7)(8)(9).…”

Section: Discussionmentioning

confidence: 99%

Semaphorin CD100 from Activated T Lymphocytes Induces Process Extension Collapse in Oligodendrocytes and Death of Immature Neural Cells

Giraudon¹,

Vincent²,

Vuaillat³

et al. 2004

The Journal of Immunology

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An inappropriate cross talk between activated T lymphocytes infiltrating the CNS and neural cells can sustain the onset and progression of demyelination and axonal degeneration in neuroinflammatory diseases. To mimic this deleterious cross talk, we designed an experimental paradigm consisting of transient cocultures of T lymphocytes chronically activated by retrovirus infection (not virus productive) with human multipotent neural precursors or primary oligodendrocytes from rat brain. We showed that activated T lymphocytes induced apoptotic death of multipotent neural progenitors and immature oligodendrocytes after a progressive collapse of their process extensions. These effects were reminiscent of those induced by brain semaphorin on neural cells. Blockade by specific Abs of soluble CD100 (sCD100)/semaphorin 4D released by activated T cells, or treatment with rsCD100, demonstrated that this immune semaphorin has the ability to collapse oligodendrocyte process extensions and to trigger neural cell apoptosis, most likely through receptors of the plexin family. The specific presence of sCD100 in the cerebrospinal fluid and of CD100-expressing T lymphocytes in the spinal cord of patients suffering with neuroinflammatory demyelination pointed to the potential pathological effect of sCD100 in the CNS. Thus, our results show that CD100 is a new important element in the deleterious T cell-neural cell cross talk during neuroinflammation and suggest its role in demyelination or absence of remyelination in neuroinflammatory diseases including multiple sclerosis and human T lymphotropic virus type 1-associated myelopathy.

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Section: Discussionmentioning

confidence: 99%

Semaphorin CD100 from Activated T Lymphocytes Induces Process Extension Collapse in Oligodendrocytes and Death of Immature Neural Cells

Giraudon¹,

Vincent²,

Vuaillat³

et al. 2004

The Journal of Immunology

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“…CTLs and activated macrophages into the CNS has been postulated to play a critical role in the pathogenesis of HAM/ TSP (Levin et al, 1997a(Levin et al, , 1998. With respect to bone marrow (BM) from individuals with HAM/TSP and likely a subset of asymptomatic carriers, previous studies utilizing PCR-in situ hybridization analyses have demonstrated that a vast majority of cells within the BM are positive for HTLV-I proviral DNA, but negative for viral RNA expression, suggesting the presence of an extensive latent infection (Levin et al, 1997b).…”

Section: Overview Of the Pathogenic Processmentioning

confidence: 99%

“…Additional damage may also be caused by the recognition and disruption of uninfected neurons by crossreactive anti-HTLV-I antibodies (Levin et al, 1998). CNS dysfunction may also be caused directly or indirectly by HTLV-I-induced dysregulation of astrocytic, macrophage, microglial, or neuronal function mediated by the multifunctional Tax protein.…”

Section: Transition From Normal Immune Surveillance To Neuroinflammationmentioning

confidence: 99%

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

Grant

Barmak

Alefantis

et al. 2002

Journal Cellular Physiology

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101

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Human T cell lymphotropic/leukemia virus type I (HTLV‐I) has been identified as the causative agent of both adult T cell leukemia (ATL) and HTLV‐I‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the exact sequence of events that occur during the early stages of infection are not known in detail, the initial route of infection may predetermine, along with host, environmental, and viral factors, the subset of target cells and/or the primary immune response encountered by HTLV‐I, and whether an HTLV‐I‐infected individual will remain asymptomatic, develop ATL, or progress to the neuroinflammatory disease, HAM/TSP. Although a large number of studies have indicated that CD4+ T cells represent an important target for HTLV‐I infection in the peripheral blood (PB), additional evidence has accumulated over the past several years demonstrating that HTLV‐I can infect several additional cellular compartments in vivo, including CD8+ T lymphocytes, PB monocytes, dendritic cells, B lymphocytes, and resident central nervous system (CNS) astrocytes. More importantly, extensive latent viral infection of the bone marrow, including cells likely to be hematopoietic progenitor cells, has been observed in individuals with HAM/TSP as well as some asymptomatic carriers, but to a much lesser extent in individuals with ATL. Furthermore, HTLV‐I+ CD34+ hematopoietic progenitor cells can maintain the intact proviral genome and initiate viral gene expression during the differentiation process. Introduction of HTLV‐I‐infected bone marrow progenitor cells into the PB, followed by genomic activation and low level viral gene expression may lead to an increase in proviral DNA load in the PB, resulting in a progressive state of immune dysregulation including the generation of a detrimental cytotoxic Tax‐specific CD8+ T cell population, anti‐HTLV‐I antibodies, and neurotoxic cytokines involved in disruption of myelin‐producing cells and neuronal degradation characteristic of HAM/TSP. J. Cell. Physiol. 190: 133–159, 2002. © 2002 Wiley‐Liss, Inc.

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“…Data indicate that IgG has a significant role in the pathogenesis of these diseases 7,8,21 . In HAM/TSP, patients are infected with HTLV-1, which is tropic for CD4 + T-lymphocytes 7 .…”

mentioning

confidence: 99%

Autoimmunity due to molecular mimicry as a cause of neurological disease

Levin

Lee

Kalume

et al. 2002

Nat Med

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237

223

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One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease 1,2 . This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS) 1-4 . There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/ tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5 -7 ). HAM/TSP patients develop antibodies to neurons 8 . We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5 ,9 ). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged 7 . Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS. To test for molecular mimicry between an environmental agent and the central nervous system (CNS), we isolated immunoglobulin G (IgG) from the serum of patients with human Tlymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and tested it for reactivity with human tissues (Fig. 1a). There was intense staining of neurons in brain and no staining of glia, dorsal root ganglion (peripheral nervous system) or systemic organs. A monoclonal antibody to HTLV-1-tax (tax mAb) mimicked IgG staining of neurons. To identify the protein, cortical neurons were isolated, proteins extracted and subjected to SDS-PAGE and western-blot analysis. The IgG recognized a band of approximately 33 kD (Fig. 1b), whereas IgG isolated from controls did not. Importantly, the tax mAb that stained CNS neurons reacted with the antigen. All patients with HAM/TSP (13/13) developed antibodies recognizing the neuronal antigen 8 . Nine of ten HTLV-1-seropositive patients without neurological symptoms and 12 HTLV-1-seronegative controls showed no reactivity (P < 0.0001 versus HAM/TSP) 8 . Clinically, the HAM/TSP patients presented with progressive neurological disease in which corticospinal tract damage (weakness, spasticity and pathological reflexes) predominated 6 . Many of our patients were originally diagnosed with MS. In fact, one of our patients was diagnosed with MS for 20 years before HTLV-1 testing 10 .To establish a direct link between the immune response to HTLV-1 and the neurological...

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Neuronal molecular mimicry in immune‐mediated neurologic disease

Cited by 68 publications

References 38 publications

Semaphorin CD100 from Activated T Lymphocytes Induces Process Extension Collapse in Oligodendrocytes and Death of Immature Neural Cells

Semaphorin CD100 from Activated T Lymphocytes Induces Process Extension Collapse in Oligodendrocytes and Death of Immature Neural Cells

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

Autoimmunity due to molecular mimicry as a cause of neurological disease

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