Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat (original) (raw)
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Journal of Experimental Medicine, 2004
The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)-specific T cells in Lewis rats, whereas transfer of S100  -or myelin oligodendrocyte glycoprotein (MOG)-specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein ϩ T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.
Cell-Mediated Immune Responses in Paraneoplastic Neurological Syndromes
Clinical and Developmental Immunology, 2013
Paraneoplastic neurological syndromes (PNS) are disorders of the nervous system that are associated with remote effects of malignancy. PNS are considered to have an autoimmune pathology. It has been suggested that immune antitumor responses are the origin of improved outcome in PNS. We describe cell-mediated immune responses in PNS and their potential contributions to antitumor reactions. Experimental and neuropathological studies have revealed infiltrates in nervous tissue and disturbances in lymphocyte populations in both cerebrospinal fluid and peripheral blood. A predominance of cytotoxic T lymphocytes (CTLs) over T helper cells has been observed. CTLs can be specifically aggressive against antigens shared by tumors and nervous tissue. Based on genetic studies, a common clonal origin of lymphocytes from blood, tumor, and nervous tissue is suggested. Suppressive regulatory T (Treg) lymphocytes are dysfunctional. Simultaneously, in tumor tissue, more intense cell-mediated immune responses are observed, which often coincide with a less aggressive course of neoplastic disease. An increased titer of onconeural antibodies is also related to better prognoses in patients without PNS. The evaluation of onconeural and neuronal surface antibodies was recommended in current guidelines. The link between PNS emergence and antitumor responses may result from more active CTLs and less functional Treg lymphocytes.
Journal of Neuroimmunology, 2006
Recent work has shown neuro-protective effects of immunization with self-CNS antigens in animal models of Alzheimer's disease, prion diseases and CNS trauma. The major concern with such an approach is the inadvertent induction of autoimmune disease. The present work was initiated to study the incidence of autoimmune disease associated with the induction of T cell autoimmunity to a panel of 70 peptides derived from CNS proteins. Using a MHC class II motif developed in our laboratory to identify candidate peptides, we selected 70 peptides from 40 different CNS proteins. The proteins were selected randomly and represented various biological functions (surface receptors, structural proteins, synaptic proteins, neurodegeneration related proteins). Each peptide was emulsified in CFA and injected to autoimmuneprone Lewis rats. Immunogenicity was verified by peptide-specific LN cell proliferation. In addition, T cell lines were generated for many peptides and tested by adoptive transfer. Except for the previously reported pathogenicity of beta-synuclein, none of the 68 peptides from 39 proteins was found to induce CNS disease in recipient rats. These findings underscore the efficiency of immunological regulation in preventing CNS autoimmune disease, and confirm the uniqueness of the well-known pathogenic CNS auto-antigens. D
Frontiers in Immunology, 2017
There are common aspects and mechanisms between different types of autoimmune diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSDs), and autoimmune encephalitis (AE) as well as paraneoplastic inflammatory disorders of the central nervous system. To our present knowledge, depending on the disease, T and B cells as well as antibodies contribute to various aspects of the pathogenesis. Possibly the events leading to the breaking of tolerance between the different diseases are of great similarity and so far, only partially understood. Beside endogenous factors (genetics, genomics, epigenetics, malignancy) also exogenous factors (vitamin D, sun light exposure, smoking, gut microbiome, viral infections) contribute to susceptibility in such diseases. What differs between these disorders are the target molecules of the immune attack. For T cells, these target molecules are presented on major histocompatibility complex (MHC) molecules as MHC-bound ligands. B cells have an important role by amplifying the immune response of T cells by capturing antigen with their surface immunoglobulin and presenting it to T cells. Antibodies secreted by plasma cells that have differentiated from B cells are highly structure specific and can have important effector functions leading to functional impairment or/and lesion evolvement. In MS, the target molecules are mainly myelin-and neuron/axon-derived proteins; in NMOSD, mainly aquaporin-4 expressed on astrocytes; and in AE, various proteins that are expressed by neurons and axons.
European Journal of Immunology, 1993
Myelin oligodendrocyte glycoprotein (M0G)-specific T cells mediate an autoimmune inflammatory response in the central nervous system (CNS) that differs radically from conventional models of T cell-mediated experimental allergic encephalomyelitis (EAE). Using synthetic peptides an encephalitogenic T cell epitope of MOG for the Lewis rat was identified within the extracellular IgG V-like domain of the protein, amino acids 44-53 (FSRVVHLYRN).The adoptive transfer of CD4+ Tcells specific for this epitope induce an intense, dosedependent inflammatory response in the CNS of naive syngeneic recipients. However, unlike the inflammatory response induced by myelin basic protein (MBP)-specificT cell lines, inflammation mediated by the MOG peptide-specific T cells failed to induce a gross neurological deficit. This unexpected observation was not due to a reduction in the overall inflammatory response in the CNS, but was specifically associated with a decrease in the extent of parenchymal (as opposed to perivascular) inflammation, a selective decrease in the number of ED1+ macrophages infiltrating the CNS, and a total lack of peripheral nerve inflammation. The decreased recruitment of macrophages into the CNS could not be ascribed to deficiences in the synthesis of interferon-y, tumor necrosis factor-a, interleukin (1L)-6 or IL-2 by theT cell line. Moreover, this sub-clinical inflammatory response induced severe blood-brain barrier dysfunction as demonstrated by the induction of severe clinical disease following intravenous injection of a demyelinating MOG-specific monoclonal antibody. The neurological deficit in EAE thus exhibits an unexpected dependence on the identity of the target autoantigen, which determines the extent and nature of the local inflammatory response and ultimately the extent of the neurological deficit. Abbreviations: MS: Multiple sclerosis MOG: Myelin oligodendrocyte glycoprotein MBP: Myelin basic protein CNS: Central nervous system Key words: Experimental allergic encephalomyelitis I Multiple sclerosis I Myelin basic protein I Myelin oligodendrocyte glycoprotein I Autoimmunity pathological hallmarks of both CREAE and MS [3, 51 are absent in T cell-mediated, MBP-induced EAE [2,6].
Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs
The Journal of Immunology, 2002
Dendritic cells are thought to regulate tolerance induction vs immunization by transferring Ags and peripheral signals to draining lymph nodes (LN). However, whether myelin Ag transfer and presentation in LN occurs during demyelinating brain disease is unknown. In this study, we demonstrate redistribution of autoantigens from brain lesions to cervical LN in monkey experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Immunohistochemical analysis revealed significantly more cells containing myelin Ags in cervical LN of monkeys with EAE compared with those of healthy control monkeys. Myelin Ags were observed in cells expressing dendritic cell/macrophage-specific markers, MHC class II, and costimulatory molecules. Moreover, these cells were directly juxtaposed to T cells, suggesting that cognate interactions between myelin-containing APC and T cells are taking place in brain-draining LN. Indeed, myelin Ag-reactive T cells were observed in cervical LN from marmosets and rhesus monkeys. Importantly, these findings were paralleled by our findings in human tissue. We observed significantly more myelin Ag-containing cells in LN of individuals with MS compared with those of control individuals. These cells expressed APC markers, as observed in marmosets and rhesus monkeys. These findings suggest that during MS and EAE, modulation of T cell reactivity against brain-derived Ags also takes place in cervical LN and not necessarily inside the brain. A major implication is that novel therapeutic strategies may be targeted to peripheral events, thereby circumventing the blood-brain barrier.