RESUMO
In multiple sclerosis (MS) lymphoid follicle-like aggregates have been reported in the meninges of patients. Here we investigated the functional relevance of B cell infiltration into the central nervous system (CNS) in MP4-induced experimental autoimmune encephalomyelitis (EAE), a B cell-dependent mouse model of MS. In chronic EAE, B cell aggregates were characterized by the presence of CXCL13(+) and germinal center CD10(+) B cells. Germline transcripts were expressed in the CNS and particularly related to TH17-associated isotypes. We also observed B cells with restricted VH gene usage that differed from clones found in the spleen. Finally, we detected CNS-restricted spreading of the antigen-specific B cell response towards a myelin and a neuronal autoantigen. These data imply the development of autonomous B cell-mediated autoimmunity in the CNS in EAE - a concept that might also apply to MS itself.
Assuntos
Autoantígenos/imunologia , Linfócitos B/imunologia , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Bainha de Mielina/imunologia , RNA Mensageiro/metabolismo , Animais , Cerebelo/imunologia , Cerebelo/metabolismo , Quimiocina CXCL13/imunologia , Modelos Animais de Doenças , Camundongos , Proteína Básica da Mielina/imunologia , Proteína Proteolipídica de Mielina/imunologia , Neprilisina/imunologia , Baço/imunologia , Baço/metabolismoRESUMO
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) and characterized by the infiltration of immune cells, demyelination and axonal loss. Loss of axons and nerve fiber pathology are widely accepted as correlates of neurological disability. Hence, it is surprising that the development of neuroprotective therapies has been neglected for a long time. A reason for this could be the diversity of the underlying mechanisms, complex changes in nerve fiber pathology and the absence of biomarkers and tools to quantify neuroregenerative processes. Present therapeutic strategies are aimed at modulating or suppressing the immune response, but do not primarily attenuate axonal pathology. Yet, target-oriented neuroprotective strategies are essential for the treatment of MS, especially as severe damage of nerve fibers mostly occurs in the course of disease progression and cannot be impeded by immune modulatory drugs. This review shall depict the need for neuroprotective strategies and elucidate difficulties and opportunities.
Assuntos
Esclerose Múltipla/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Animais , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologiaRESUMO
The role of fibroblast growth factor-2 (FGF-2) in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis is discussed. This study is the first to use FGF-2(-/-) mice to further address the involvement of FGF-2 in the disease process. We demonstrate that immunization with myelin oligodendrocyte glycoprotein peptide 35-55 induces more severe experimental autoimmune encephalomyelitis in FGF-2(-/-) mice compared with FGF-2(+/+) mice. The antigen-specific cytokine response to myelin oligodendrocyte glycoprotein peptide and the degree of central nervous system inflammation was similar in both groups. However, FGF-2(-/-) mice displayed increased infiltration of CD8(+) T cells and macrophages/microglia. In addition, nerve fibre degeneration and axonal loss were augmented, whereas the extent of remyelination in central nervous system lesions was reduced. FGF-2 has been associated with the induction of demyelination and the inhibition of myelin production by oligodendrocytes. Our study supports the opposing notion that FGF-2 can also assert a neuroprotective function. This may be particularly appealing when it comes to targeting the neurodegenerative aspect of multiple sclerosis.
Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fármacos Neuroprotetores/metabolismo , Animais , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Camundongos , Camundongos KnockoutRESUMO
Experimental autoimmune encephalomyelitis (EAE) is frequently used for studies of multiple sclerosis (MS). Because in most EAE models T cells mediate the pathology in the absence of B cells/autoantibodies, the notion has evolved that also MS may be a primarily T cell-mediated disease. We have previously introduced MBP-PLP fusion protein (MP4)-induced EAE in C57BL/6 mice. Here we show that the disease in this model is antibody-dependent. Immunization of B cell-deficient mice did not induce EAE. When such B cell-deficient mice were, however, injected with MBP/PLP-specific antibodies in addition to the immunization with MP4, they developed disease of a severity and course that was similar to the wild-type mice. The deposition of antibodies in demyelinated lesions provided further evidence for the contribution of MBP/PLP-specific antibodies to CNS lesion formation. Based upon these data we suggest a two-stage model for the involvement of MBP/PLP-specific antibodies in autoimmune CNS pathology.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Proteína Básica da Mielina/imunologia , Proteína Proteolipídica de Mielina/imunologia , Proteínas Recombinantes de Fusão/imunologia , Animais , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologiaRESUMO
Due to the limited numbers of PBMCs that can be obtained from the blood of individual mice, the key question whether central disease parameters such as onset, progression and severity correlate with the magnitude and cytokine quality of the T cell response in experimental autoimmune encephalomyelitis (EAE) has remained unanswered. Here we introduce an ELISPOT-based PBMC test system in which as little as 150 µl of murine blood are sufficient, allowing to bleed mice repeatedly while continuing to observe the clinical course of EAE. Using this technique, we demonstrate that longitudinal measurements of antigen-specific IFN-γ and IL-17 production in the blood are a highly suitable approach to predict the disease outcome in remitting-relapsing PLP:139-151- and chronic MOG:35-55-induced EAE of SJL/J and C57BL/6 mice, respectively. Our data propound cytokine monitoring as promising tool in the quest for more efficient diagnostic and prognostic options in human multiple sclerosis and other autoimmune diseases.