RESUMO
We are reviewing the current state of knowledge on the virological and immunological correlates of long COVID, focusing on recent evidence for the possible association between the increasing number of SARS-CoV-2 reinfections and the parallel pandemic of long COVID. The severity of reinfections largely depends on the severity of the initial episode; in turn, this is determined both by a combination of genetic factors, particularly related to the innate immune response, and by the pathogenicity of the specific variant, especially its ability to infect and induce syncytia formation at the lower respiratory tract. The cumulative risk of long COVID as well as of various cardiac, pulmonary, or neurological complications increases proportionally to the number of SARS-CoV-2 infections, primarily in the elderly. Therefore, the number of long COVID cases is expected to remain high in the future. Reinfections apparently increase the likelihood of long COVID, but less so if they are mild or asymptomatic as in children and adolescents. Strategies to prevent SARS-CoV-2 reinfections are urgently needed, primarily among older adults who have a higher burden of comorbidities. Follow-up studies using an established case definition and precise diagnostic criteria of long COVID in people with or without reinfection may further elucidate the contribution of SARS-CoV-2 reinfections to the long COVID burden. Although accumulating evidence supports vaccination, both before and after the SARS-CoV-2 infection, as a preventive strategy to reduce the risk of long COVID, more robust comparative observational studies, including randomized trials, are needed to provide conclusive evidence of the effectiveness of vaccination in preventing or mitigating long COVID in all age groups. Thankfully, answers not only on the prevention, but also on treatment options and rates of recovery from long COVID are gradually starting to emerge.
Assuntos
COVID-19 , Síndrome de COVID-19 Pós-Aguda , Adolescente , Criança , Idoso , Humanos , SARS-CoV-2 , COVID-19/epidemiologia , Reinfecção , PandemiasRESUMO
Toll-like receptors (TLR) control the activation of dendritic cells that prime CD4+ T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4+ T cell expansion. Addressing the underpinning mechanisms revealed that CD4+ T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen-specific CD4+ T cell expansion in lymph nodes, and the counter-regulatory role of TLR signaling in this process.
Assuntos
Encefalomielite Autoimune Experimental , Camundongos , Animais , Neutrófilos/patologia , Receptor Toll-Like 9/metabolismo , Linfócitos T CD4-Positivos , Linfonodos , Receptores Toll-Like/metabolismo , Camundongos Endogâmicos C57BLAssuntos
COVID-19 , Hipersensibilidade , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Europa (Continente)/epidemiologia , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , SARS-CoV-2 , Estados Unidos/epidemiologiaRESUMO
Tweetable abstract An opinion on the coronaviruses' evolution paradoxes, the continuing adaptation of the SARS-CoV-2 in humans following the zoonotic transmission, and clues into escape routes from host immune responses.
Assuntos
Evolução Molecular , Evasão da Resposta Imune , SARS-CoV-2/genética , COVID-19/imunologia , COVID-19/virologia , Genoma Viral , HumanosRESUMO
BACKGROUND: Although several studies have been launched towards the prediction of risk factors for mortality and admission in the intensive care unit (ICU) in COVID-19, none of them focuses on the development of explainable AI models to define an ICU scoring index using dynamically associated biological markers. METHODS: We propose a multimodal approach which combines explainable AI models with dynamic modeling methods to shed light into the clinical features of COVID-19. Dynamic Bayesian networks were used to seek associations among cytokines across four time intervals after hospitalization. Explainable gradient boosting trees were trained to predict the risk for ICU admission and mortality towards the development of an ICU scoring index. RESULTS: Our results highlight LDH, IL-6, IL-8, Cr, number of monocytes, lymphocyte count, TNF as risk predictors for ICU admission and survival along with LDH, age, CRP, Cr, WBC, lymphocyte count for mortality in the ICU, with prediction accuracy 0.79 and 0.81, respectively. These risk factors were combined with dynamically associated biological markers to develop an ICU scoring index with accuracy 0.9. CONCLUSIONS: to our knowledge, this is the first multimodal and explainable AI model which quantifies the risk of intensive care with accuracy up to 0.9 across multiple timepoints.
RESUMO
A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.
Assuntos
COVID-19/imunologia , Imunidade/imunologia , Influenza Humana/imunologia , Interferon Tipo I/imunologia , Interferons/imunologia , SARS-CoV-2/imunologia , Antivirais/imunologia , Antivirais/metabolismo , COVID-19/genética , COVID-19/virologia , Citocinas/genética , Citocinas/imunologia , Progressão da Doença , Expressão Gênica/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Imunidade/genética , Inflamação/genética , Inflamação/imunologia , Influenza Humana/genética , Interferon Tipo I/genética , Interferons/genética , Tempo de Internação , Prognóstico , SARS-CoV-2/fisiologia , Carga Viral/genética , Carga Viral/imunologia , Interferon lambdaRESUMO
B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention.
Assuntos
Antígenos CD/genética , Expressão Gênica , Interleucina-10/biossíntese , Plasmócitos/imunologia , Animais , Antígenos CD/imunologia , Subpopulações de Linfócitos B/imunologia , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Interleucina-10/genética , Ativação Linfocitária , Masculino , Camundongos , Plasmócitos/fisiologia , Receptores de Antígenos de Linfócitos B/metabolismo , Salmonelose Animal/imunologia , Transdução de Sinais , Linfócitos T/imunologia , Receptores Toll-Like/metabolismo , Regulação para Cima/genética , Vacinas/imunologia , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.
Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Proteínas I-kappa B/metabolismo , Succinatos/metabolismo , Animais , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Psoríase/tratamento farmacológico , Psoríase/patologia , Estresse Fisiológico/efeitos dos fármacos , Succinatos/administração & dosagem , Succinatos/química , Succinatos/farmacologia , Succinatos/uso terapêutico , Receptores Toll-Like/imunologiaRESUMO
Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1-/- mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1-/-, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease.
Assuntos
Hidroliases/metabolismo , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Tuberculose/imunologia , Tuberculose/metabolismo , Animais , Citocinas/imunologia , Citocinas/metabolismo , Progressão da Doença , Feminino , Expressão Gênica/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/microbiologia , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pneumopatias/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Succinatos/metabolismo , Transcrição Gênica/imunologia , Tuberculose/microbiologiaRESUMO
Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1ß-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1(-/-) mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.
Assuntos
Inflamação/enzimologia , Inflamação/patologia , Macrófagos/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Succinatos/farmacologia , Animais , Respiração Celular/efeitos dos fármacos , Feminino , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Succinato Desidrogenase/metabolismo , Ácido Succínico/metabolismoRESUMO
Regulatory T (Treg) cells expressing Foxp3 transcripton factor are essential for immune homeostasis. They arise in the thymus as a separate lineage from conventional CD4(+)Foxp3(-) T (Tconv) cells. Here, we show that the thymic development of Treg cells depends on the expression of their endogenous cognate self-antigen. The formation of these cells was impaired in mice lacking this self-antigen, while Tconv cell development was not negatively affected. Thymus-derived Treg cells were selected by self-antigens in a specific manner, while autoreactive Tconv cells were produced through degenerate recognition of distinct antigens. These distinct modes of development were associated with the expression of T cell receptor of higher functional avidity for self-antigen by Treg cells than Tconv cells, a difference subsequently essential for the control of autoimmunity. Our study documents how self-antigens define the repertoire of thymus-derived Treg cells to subsequently endow this cell type with the capacity to undermine autoimmune attack.
Assuntos
Antígeno CTLA-4/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/metabolismo , Subpopulações de Linfócitos T/fisiologia , Linfócitos T Reguladores/fisiologia , Timo/imunologia , Animais , Autoantígenos/imunologia , Antígeno CTLA-4/genética , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/genética , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T/genéticaRESUMO
Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.
Assuntos
Redes Reguladoras de Genes/imunologia , Imunidade Inata , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Transcrição Gênica/imunologia , Animais , Ácido Argininossuccínico/imunologia , Ácido Argininossuccínico/metabolismo , Aspartato Aminotransferase Mitocondrial/genética , Aspartato Aminotransferase Mitocondrial/imunologia , Ácido Aspártico/imunologia , Ácido Aspártico/metabolismo , Quimiocina CCL22/genética , Quimiocina CCL22/imunologia , Ciclo do Ácido Cítrico , Regulação da Expressão Gênica , Glutamina/deficiência , Glicosilação , Interleucina-6/genética , Interleucina-6/imunologia , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/imunologia , Macrófagos/classificação , Macrófagos/citologia , Macrófagos/imunologia , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Camundongos , Mitocôndrias/genética , Mitocôndrias/imunologia , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Transdução de Sinais , Uridina Difosfato N-Acetilglicosamina/imunologia , Uridina Difosfato N-Acetilglicosamina/metabolismoRESUMO
B-cell depletion can improve disease in some patients with rheumatoid arthritis or multiple sclerosis, indicating the pathogenic contribution of B cells to autoimmunity. However, studies in mice have demonstrated that B cells have immunosuppressive functions as well, with IL-10 being a critical mediator of B-cell-mediated suppression. IL-10-secreting B cells have been shown to promote disease remission in some mouse models of autoimmune disorders. Human B cells also produce IL-10, and evidence is accumulating that human IL-10-producing B cells might inhibit immunity. There is considerable interest in identifying the phenotype of B cells providing IL-10 in a suppressive manner, which would facilitate the analysis of the molecular mechanisms controlling this B-cell property. Here, we review current knowledge on the B-cell subpopulations found to provide suppressive functions in mice, considering both the pathological context in which they were identified and the signals that control their induction. We discuss the phenotype of B cells that have IL-10-dependent regulatory activities in mice, which leads us to propose that antibody-secreting cells are, in some cases at least, the major source of B-cell-derived regulatory IL-10 in vivo. Anti-inflammatory cytokine production by antibody-secreting cells offers a novel mechanism for the coordination of innate and humoral immune responses.
Assuntos
Artrite Reumatoide/imunologia , Linfócitos B Reguladores/imunologia , Interleucina-10/metabolismo , Esclerose Múltipla/imunologia , Plasmócitos/imunologia , Animais , Artrite Reumatoide/patologia , Linfócitos B Reguladores/patologia , Humanos , Imunidade Humoral , Imunidade Inata , Camundongos , Esclerose Múltipla/patologia , Plasmócitos/patologiaRESUMO
B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Imunidade/imunologia , Interleucinas/metabolismo , Infecções por Salmonella/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD40/imunologia , Feminino , Humanos , Interleucina-10/metabolismo , Interleucinas/imunologia , Ativação Linfocitária , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Plasmócitos/imunologia , Plasmócitos/metabolismo , Infecções por Salmonella/microbiologia , Linfócitos T/imunologia , Receptor 4 Toll-Like/imunologiaRESUMO
B cells can contribute to immunity through production of antibodies, presentation of antigen to T cells, and secretion of cytokines. B cell activation can result in various outcomes for the host. In general B cell responses are beneficial during infections, and deleterious during autoimmune diseases. However, B cells can also limit host defence against pathogens, and protect from autoimmune pathologies. B cells can therefore act both as drivers and as regulators of immunity. Understanding how these opposite functions are mediated shall stimulate the elaboration of novel approaches for manipulating the immune system. B cells might acquire distinct functional properties depending on their mode of activation. Antigen-specific B cell responses require triggering of B cell receptor (BCR) by antigen, and provision of helper signals by T cells. B cells also express various innate immune receptors, and can directly respond to microbial products. Here, we discuss how intrinsic signalling via Toll-like receptors contributes to the suppressive functions of B cells during autoimmune and infectious diseases.
Assuntos
Linfócitos B/metabolismo , Doenças Transmissíveis/imunologia , Encefalomielite Autoimune Experimental/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo , Linfócitos B/imunologia , Humanos , Receptores Toll-Like/imunologiaRESUMO
B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6-secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell-specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6-sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6-producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell-driven pathogenesis in T cell-mediated autoimmune disease such as EAE and MS.
Assuntos
Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Interleucina-6/metabolismo , Depleção Linfocítica/métodos , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/terapia , Transferência Adotiva , Análise de Variância , Animais , Anticorpos Monoclonais Murinos/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Primers do DNA/genética , Encefalomielite Autoimune Experimental/fisiopatologia , Citometria de Fluxo , Humanos , Interleucina-6/deficiência , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rituximab , Organismos Livres de Patógenos Específicos , Estatísticas não ParamétricasRESUMO
B cells and regulatory T (Treg) cells can both facilitate remission from experimental auto immune encephalomyelitis (EAE), a disease of the central nervous system (CNS) used as a model for multiple sclerosis (MS). Considering that B-cell-depletion therapy (BCDT) is used to treat MS patients, we asked whether Treg-cell activation depended on B cells during EAE. Treg-cell proliferation, accumulation in CNS, and augmentation of suppressive activity in the CNS were normal in B-cell-deficient mice, indicating that B cells are not essential for activation of the protective Treg-cell response and thus provide an independent layer of regulation. This function of B cells involved early suppression of the encephalitogenic CD4(+) T-cell response, which was enhanced in B-cell-deficient mice. CD4(+) T-cell depletion was sufficient to intercept the transition from acute-to-chronic EAE when applied to B-cell-deficient animals that just reached the peak of disease severity. Intriguingly, this treatment did not improve disease when applied later, implying that chronic disability was ultimately maintained independently of pathogenic CD4(+) T cells. Collectively, our data indicate that BCDT is unlikely to impair Treg-cell function, yet it might produce undesirable effects on T-cell-mediated autoimmune pathogenesis.
Assuntos
Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Fatores de Transcrição Forkhead/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Transferência Adotiva , Animais , Doença Crônica , Ativação Linfocitária/imunologia , Depleção Linfocítica , Camundongos , Índice de Gravidade de DoençaRESUMO
The immune system is composed of multiple cell types, which together improve the resistance of the organism against infections. The unfolding of a successful host response ensuring effective protection against pathogens requires an appropriate coordination of the different players of the immune system. Innate cells and T cells extensively communicate during immune reactions, providing multiple opportunities for the mutual coordination of these two defense pathways. Little is known about the functional interactions between B and innate cells, and it is generally assumed that they influence each other indirectly through effects on T cells. However, recent studies highlighted important roles for innate cells in initial presentation of antigen to B cells after immunization, and in long-term maintenance of antibody-producing cells in bone marrow after resolution of immune responses. Furthermore, it was found that activated B cells could regulate the activity of innate cells through production of cytokines. Here, we review how direct interactions between innate and B cells can contribute to orchestration of humoral and cellular immunity.
Assuntos
Linfócitos B/imunologia , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Animais , Formação de Anticorpos/imunologia , Medula Óssea/imunologia , Comunicação Celular/imunologia , Citocinas/imunologia , Humanos , Ativação Linfocitária/imunologia , Linfócitos T/imunologiaRESUMO
TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS.
Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Células Mieloides/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Separação Celular , Quimiocinas/biossíntese , Quimiotaxia de Leucócito/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Baço/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Activated B cells can regulate immunity and have been envisaged as a potential cell-based therapy for treating autoimmune diseases. However, activated human B cells can also propagate immune responses, and the effects resulting from their infusion into patients cannot be predicted. This led us to consider resting B cells, which in contrast are poorly immunogenic, as an alternative cellular platform for the suppression of unwanted immunity. Here, we report that resting B cells can be directly engineered with lentiviral vectors to express antigens in a remarkably simple, rapid, and effective way. Notably, this neither required nor induced activation of the B cells. With this approach we were able to produce reprogrammed resting B cells that inhibited antigen-specific CD4(+) T cells, CD8(+) T cells, and B cells upon adoptive transfer in mice. Furthermore, resting B cells engineered to ectopically express myelin oligodendrocyte glycoprotein antigen protected recipient mice from severe disability and demyelination in EAE, and even induced complete remission from disease in mice lacking functional natural Tregs, which otherwise developed chronic paralysis. In conclusion, our study introduces reprogrammed quiescent B cells as a novel tool for suppressing undesirable immunity.