RESUMO
Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the most prevalent neuroinflammatory diseases of the central nervous system (CNS). The immunological cascade of these disorders is complex, and the exact spatial and temporal role of different immune cells is not fully understood. Although MS has been considered for many years to be primarily T cell driven, it is well established that B cells and the humoral immune response play an important role in its pathogenesis. This has long been evident from laboratory findings that include the presence of oligoclonal bands in the CSF. In NMO, the importance of the humoral immune system appears even more obvious as evidenced by pathogenic antibodies against aquaporin 4 (AQP4). Besides their capacity to mature into antibody-producing plasma cells, B cells are potent antigen-presenting cells to T lymphocytes and they can provide soluble factors for cell activation and differentiation to other immune-competent cells. In MS and NMO, there are substantial data from clinical trials that B cell depletion with CD20-directed agents is effective and relatively safe. Plasma cells, which produce antibodies against molecular targets expressed by the host, but which also provide humoral immune responses against pathogens, are not targeted by anti-CD20 therapies. Therefore, the depletion of CD19-expressing cells would offer potential advantages with regard to efficacy, but potentially higher risks with regard to infectious complications. This review will outline the rationale for CD19 as a molecular target in CNS autoimmunity. The current stage of drug development is illustrated. Potential safety concerns will be discussed.
Assuntos
Antígenos CD19/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/fisiologia , HumanosRESUMO
Dendritic cells (DCs) are critical for the differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells remains elusive. Here, we used DCs stimulated with specific pathogens to prime CD4 T cells in vitro and found that these T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. More specifically, the transcriptome of in vitro C. rodentium-primed Th17 cells resembled that of Th17 cells primed following infection in vivo but was remarkably distinct from cytokine-polarized Th17 cells. We identified caspase-1 as a unique gene up-regulated only in pathogen-primed Th17 cells and discovered a critical role for T cell-intrinsic caspase-1, independent of inflammasome, in optimal priming of Th17 responses. T cells lacking caspase-1 failed to induce colitis or confer protection against C. rodentium infection due to suboptimal Th17 cell differentiation in vivo. This study underlines the importance of DC-mediated priming in identifying novel regulators of T cell differentiation.
Assuntos
Caspase 1/genética , Diferenciação Celular/genética , Células Th17/metabolismo , Células Th17/microbiologia , Transcrição Gênica/genética , Animais , Linhagem Celular Tumoral , Polaridade Celular , Citrobacter rodentium , Colite/genética , Colite/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Feminino , Técnicas de Inativação de Genes , Inflamassomos/metabolismo , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , TranscriptomaRESUMO
The toll-like receptor (TLR) and interleukin (IL)-1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll-IL-1 receptor homology domain-containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R-induced phosphoinositide 3-kinase-Akt-mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1ß-induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Diferenciação Celular/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Células Th17/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Diferenciação Celular/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Interleucina-1/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Células Th1/imunologia , Células Th1/patologia , Células Th17/patologiaRESUMO
Immune surveillance of the CNS is critical for preventing infections; however, there is no accepted experimental model to assess the risk of infection when utilizing disease-modifying agents. We tested two approved agents for patients with multiple sclerosis (MS), glatiramer acetate and fingolimod, in an experimental model of CNS immune surveillance. C57BL/6 mice were infected with the ME49 strain of the neuroinvasive parasite Toxoplasma gondii (T. gondii) and then treated with GA and fingolimod. Neither treatment affected host survival; however, differences were observed in parasite load and in leukocyte numbers in the brains of infected animals. Here we demonstrate that this model could be a useful tool for analyzing immune surveillance.
Assuntos
Sistema Nervoso Central/imunologia , Vigilância Imunológica/efeitos dos fármacos , Imunossupressores/uso terapêutico , Peptídeos/uso terapêutico , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Toxoplasmose/tratamento farmacológico , Animais , Antígenos CD/metabolismo , Modelos Animais de Doenças , Cloridrato de Fingolimode , Acetato de Glatiramer , Camundongos , Camundongos Endogâmicos C57BL , Esfingosina/uso terapêutico , Toxoplasmose/mortalidadeRESUMO
Treatment of central nervous system (CNS) autoimmune disorders frequently involves the reduction, or depletion of immune-competent cells. Alternatively, immune cells are being sequestered away from the target organ by interfering with their movement from secondary lymphoid organs, or their migration into tissues. These therapeutic strategies have been successful in multiple sclerosis (MS), the most prevalent autoimmune inflammatory disorder of the CNS. However, many of the agents that are currently approved or in clinical development also have severe potential adverse effects that stem from the very mechanisms that mediate their beneficial effects by interfering with CNS immune surveillance. This review will outline the main cellular components of the innate and adaptive immune system that participate in host defense and maintain immune surveillance of the CNS. Their pathogenic role in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also discussed. Furthermore, an experimental model is introduced that may assist in evaluating the effect of therapeutic interventions on leukocyte homeostasis and function within the CNS. This model or similar models may become a useful tool in the repertoire of pre-clinical tests of pharmacological agents to better explore their potential for adverse events.