RESUMO
Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.
Assuntos
Interferons , Lúpus Eritematoso Sistêmico , Humanos , Animais , Interferons/uso terapêutico , Linfócitos B , Linfócitos T Auxiliares-Indutores , AutoanticorposRESUMO
Maintenance of immunological self-tolerance requires lymphocytes carrying self-reactive antigen receptors to be selectively prevented from mounting destructive or inflammatory effector responses. Classically, self-tolerance is viewed in terms of the removal, editing, or silencing of B and T cells that have formed self-reactive antigen receptors during their early development. However, B cells activated by foreign antigen can enter germinal centers (GCs), where they further modify their antigen receptor by somatic hypermutation (SHM) of their immunoglobulin genes. The inevitable emergence of activated, self-reactive GC B cells presents a unique challenge to the maintenance of self-tolerance that must be rapidly countered to avoid autoantibody production. Here we discuss current knowledge of the mechanisms that enforce B cell self-tolerance, with particular focus on the control of self-reactive GC B cells. We also consider how self-reactive GC B cells can escape self-tolerance to initiate autoantibody production or instead be redeemed via SHM and used in productive antibody responses.
Assuntos
Autoimunidade , Linfócitos B/imunologia , Centro Germinativo/imunologia , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Linfócitos B/metabolismo , Centro Germinativo/metabolismo , Humanos , Tolerância Imunológica , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
Assuntos
Autoanticorpos , Doenças Autoimunes , RNA Longo não Codificante , Animais , Feminino , Humanos , Masculino , Camundongos , Autoanticorpos/genética , Doenças Autoimunes/genética , Autoimunidade/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Cromossomo X/genética , Cromossomo X/metabolismo , Inativação do Cromossomo X , Caracteres SexuaisRESUMO
The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.
Assuntos
Antígenos de Neoplasias , Neoplasias , Proteínas do Tecido Nervoso , Síndromes Paraneoplásicas do Sistema Nervoso , Animais , Humanos , Camundongos , Autoanticorpos , Capsídeo/metabolismo , Epitopos , Neoplasias/complicações , Síndromes Paraneoplásicas do Sistema Nervoso/metabolismo , Síndromes Paraneoplásicas do Sistema Nervoso/patologia , Antígenos de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases.
Assuntos
Autoanticorpos , Encefalite , Linfócitos T , Animais , Humanos , Camundongos , Autoanticorpos/metabolismo , Encefalite/metabolismo , Encefalite/terapia , Receptores de N-Metil-D-Aspartato , Doenças Autoimunes , Modelos Animais de DoençasRESUMO
The function and antigen-specificities of tumor-infiltrating B cells are mostly unknown. In a new study by Mazor et al., matrix metalloproteinase 14 (MMP14), a self-antigen that is overexpressed by ovarian cancers, is shown to drive B cell activation and autoantibody production in tertiary lymphoid structures (Mazor et al., 2022).
Assuntos
Autoanticorpos , Neoplasias Ovarianas , Autoantígenos , Linfócitos B , Feminino , HumanosRESUMO
The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.
Assuntos
Anticorpos Antineoplásicos , Neoplasias Ovarianas , Anticorpos Monoclonais , Autoanticorpos , Autoantígenos , Feminino , Humanos , Neoplasias Ovarianas/genética , Microambiente TumoralRESUMO
Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABAA) receptor. These antibodies induced severe encephalitis by directly inhibiting GABAA function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABAA inhibition and pathology. One antibody directly competes with a neurotransmitter and locks the receptor in a resting-like state. The second antibody targets the subunit interface involved in binding benzodiazepines and antagonizes diazepam potentiation. We identify key residues in these antibodies involved in specificity and affinity and confirm structure-based hypotheses for functional effects using electrophysiology. Together these studies define mechanisms of direct functional antagonism of neurotransmission underlying autoimmune encephalitis in a human patient.
Assuntos
Encefalite , Receptores de GABA-A , Autoanticorpos , Microscopia Crioeletrônica , Doença de Hashimoto , Humanos , Receptores de GABA-A/metabolismo , Ácido gama-AminobutíricoRESUMO
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
Assuntos
COVID-19/complicações , COVID-19/diagnóstico , Convalescença , Imunidade Adaptativa/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Progressão da Doença , Feminino , Humanos , Imunidade Inata/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Transcriptoma , Adulto Jovem , Síndrome de COVID-19 Pós-AgudaRESUMO
Human autoimmunity against elements conferring protective immunity can be symbolized by the 'ouroboros', a snake eating its own tail. Underlying infection is autoimmunity against three immunological targets: neutrophils, complement and cytokines. Autoantibodies against neutrophils can cause peripheral neutropenia underlying mild pyogenic bacterial infections. The pathogenic contribution of autoantibodies against molecules of the complement system is often unclear, but autoantibodies specific for C3 convertase can enhance its activity, lowering complement levels and underlying severe bacterial infections. Autoantibodies neutralizing granulocyte-macrophage colony-stimulating factor impair alveolar macrophages, thereby underlying pulmonary proteinosis and airborne infections, type I interferon viral diseases, type II interferon intra-macrophagic infections, interleukin-6 pyogenic bacterial diseases and interleukin-17A/F mucocutaneous candidiasis. Each of these five cytokine autoantibodies underlies a specific range of infectious diseases, phenocopying infections that occur in patients with the corresponding inborn errors. In this Review, we analyze this ouroboros of immunity against immunity and posit that it should be considered as a factor in patients with unexplained infection.
Assuntos
Autoanticorpos , Autoimunidade , Humanos , Autoanticorpos/imunologia , Animais , Citocinas/metabolismo , Citocinas/imunologia , Neutrófilos/imunologia , Proteínas do Sistema Complemento/imunologia , Doenças Autoimunes/imunologiaRESUMO
Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.
Assuntos
Autoanticorpos , Proteína HMGB1 , Animais , Camundongos , Complemento C1q , Proteína HMGB1/metabolismo , Doenças Neuroinflamatórias , Qualidade de Vida , Receptor para Produtos Finais de Glicação Avançada/metabolismoRESUMO
Anticytokine autoantibodies are an emerging mechanism of disease in previously healthy adults. Patients with these syndromes demonstrate a unique infectious phenotype associated with neutralizing autoantibodies that target a specific cytokine. Examples include anti-interferon (IFN)-γ autoantibodies and disseminated nontuberculous mycobacteria; anti-granulocyte macrophage colony-stimulating factor autoantibodies and cryptococcal meningitis; anti-interleukin (IL)-6 autoantibodies and staphylococcal skin infection; and anti-IL-17A, anti-IL-17F, or anti-IL-22 autoantibodies and mucocutaneous candidiasis in the setting of either APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome) or thymoma. Other anticytokine autoantibodies may contribute to an infectious phenotype such as anti-granulocyte colony stimulating factor and anti-IFN-α autoantibodies, although the strength of the association is less clear. Their identification not only affects disease management but also may uncover key mechanisms of host defense against specific organisms. Furthermore, it raises the possibility that currently idiopathic diseases will someday be explained by a yet unidentified anticytokine autoantibody. This review focuses on the current understanding, both clinical and mechanistic, of anticytokine autoantibody-associated immunodeficiency.
Assuntos
Autoanticorpos/imunologia , Citocinas/imunologia , Síndromes de Imunodeficiência/imunologia , Animais , Candidíase/diagnóstico , Candidíase/imunologia , Candidíase/terapia , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/terapia , Timoma/diagnóstico , Timoma/imunologia , Timoma/terapiaRESUMO
Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.
Assuntos
Linfócitos B/imunologia , Proteínas do Tecido Nervoso/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Autoanticorpos/imunologia , Autoimunidade , Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteínas Ligadas por GPI/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Histonas/imunologia , Switching de Imunoglobulina , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Plasmócitos/citologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismoRESUMO
Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Autoanticorpos , Síndrome de COVID-19 Pós-Aguda , QuimiocinasRESUMO
Autoimmune diseases currently affect 5-7% of the world's population; in most diseases there are circulating autoantibodies. Brain-reactive antibodies are present in approximately 2-3% of the general population but do not usually contribute to brain pathology. These antibodies penetrate brain tissue only early in development or under pathologic conditions. This restriction on their pathogenicity and the lack of correlation between serum titers and brain pathology have, no doubt, contributed to a delayed appreciation of the contribution of autoantibodies in diseases of the central nervous system. Nonetheless, it is increasingly clear that antibodies can cause damage in the brain and likely initiate or aggravate multiple neurologic conditions; brain-reactive antibodies contribute to symptomatology in autoimmune disease, infectious disease, and malignancy.
Assuntos
Autoanticorpos/metabolismo , Encéfalo/imunologia , Encéfalo/patologia , Hipóxia-Isquemia Encefálica/imunologia , Hipóxia-Isquemia Encefálica/patologia , Animais , Reações Antígeno-Anticorpo/imunologia , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipóxia-Isquemia Encefálica/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologiaRESUMO
Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.
Assuntos
Autoanticorpos/genética , Doenças Autoimunes/genética , Linfócitos B/imunologia , Linfoma/genética , Animais , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/patologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Transporte/genética , Evolução Clonal/genética , Evolução Clonal/imunologia , Ciclina D3/genética , Guanilato Ciclase/genética , Humanos , Proteínas Imediatamente Precoces/genética , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Proteínas Inibidoras de Diferenciação/genética , Linfoma/imunologia , Linfoma/patologia , Camundongos , Mutação/genética , Mutação/imunologia , Proteínas de Neoplasias/genética , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteínas Supressoras de Tumor/genética , Recombinação V(D)J/genéticaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.
Assuntos
Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Autoanticorpos/sangue , Betacoronavirus/isolamento & purificação , COVID-19 , Criança , Pré-Escolar , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Humanos , Imunidade Humoral , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/patologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Análise de Componente Principal , Proteoma/análise , SARS-CoV-2 , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.
Assuntos
Inflamação/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Adolescente , Anticorpos Antivirais/sangue , Autoanticorpos/sangue , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , COVID-19 , Quimiocina CCL3/metabolismo , Criança , Pré-Escolar , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunidade Humoral , Lactente , Recém-Nascido , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-18/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Adulto JovemRESUMO
The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.
Assuntos
Ferroptose/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Neutropenia/patologia , Neutrófilos/imunologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Autoanticorpos/imunologia , Autoimunidade/imunologia , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Humanos , Interferon-alfa/imunologia , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Regiões Promotoras Genéticas/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Many infections, including malaria, are associated with an increase in autoantibodies (AAbs). Prior studies have reported an association between genetic markers of susceptibility to autoimmune disease and resistance to malaria, but the underlying mechanisms are unclear. Here, we performed a longitudinal study of children and adults (n = 602) in Mali and found that high levels of plasma AAbs before the malaria season independently predicted a reduced risk of clinical malaria in children during the ensuing malaria season. Baseline AAb seroprevalence increased with age and asymptomatic Plasmodium falciparum infection. We found that AAbs purified from the plasma of protected individuals inhibit the growth of blood-stage parasites and bind P. falciparum proteins that mediate parasite invasion. Protected individuals had higher plasma immunoglobulin G (IgG) reactivity against 33 of the 123 antigens assessed in an autoantigen microarray. This study provides evidence in support of the hypothesis that a propensity toward autoimmunity offers a survival advantage against malaria.