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1.
Annu Rev Immunol ; 29: 215-33, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21219172

RESUMO

The clonal selection theory first proposed by Macfarlane Burnet is a cornerstone of immunology (1). At the time, it revolutionized the thinking of immunologists because it provided a simple explanation for lymphocyte specificity, immunological memory, and elimination of self-reactive clones (2). The experimental demonstration by Nossal & Lederberg (3) that B lymphocytes bear receptors for a single antigen raised the central question of where B lymphocytes encounter antigen. This question has remained mostly unanswered until recently. Advances in techniques such as multiphoton intravital microscopy (4, 5) have provided new insights into the trafficking of B cells and their antigen. In this review, we summarize these advances in the context of our current view of B cell circulation and activation.


Assuntos
Antígenos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Animais , Apresentação de Antígeno , Células Dendríticas/imunologia , Humanos
2.
Cell ; 170(5): 913-926.e19, 2017 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-28841417

RESUMO

Germinal centers (GCs) are the primary sites of clonal B cell expansion and affinity maturation, directing the production of high-affinity antibodies. This response is a central driver of pathogenesis in autoimmune diseases, such as systemic lupus erythematosus (SLE), but the natural history of autoreactive GCs remains unclear. Here, we present a novel mouse model where the presence of a single autoreactive B cell clone drives the TLR7-dependent activation, expansion, and differentiation of other autoreactive B cells in spontaneous GCs. Once tolerance was broken for one self-antigen, autoreactive GCs generated B cells targeting other self-antigens. GCs became independent of the initial clone and evolved toward dominance of individual clonal lineages, indicating affinity maturation. This process produced serum autoantibodies to a breadth of self-antigens, leading to antibody deposition in the kidneys. Our data provide insight into the maturation of the self-reactive B cell response, contextualizing the epitope spreading observed in autoimmune disease.


Assuntos
Linfócitos B/imunologia , Evolução Clonal , Centro Germinativo/citologia , Centro Germinativo/imunologia , Tolerância Imunológica , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Linfócitos B/citologia , Quimera/imunologia , Epitopos/imunologia , Rim/imunologia , Camundongos , Camundongos Endogâmicos C57BL
3.
Nat Immunol ; 20(11): 1506-1516, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611698

RESUMO

Fibroblastic reticular cells (FRCs) and their specialized collagen fibers termed 'conduits' form fundamental structural units supporting lymphoid tissues. In lymph nodes, conduits are known to transport interstitial fluid and small molecules from afferent lymphatics into the nodal parenchyma. However, the immunological contributions of conduit function have remained elusive. Here, we report that intestinal Peyer's patches (PPs) contain a specialized conduit system that directs the flow of water absorbed across the intestinal epithelium. Notably, PP FRCs responded to conduit fluid flow via the mechanosensitive ion channel Piezo1. Disruption of fluid flow or genetic deficiency of Piezo1 on CCL19-expressing stroma led to profound structural alterations in perivascular FRCs and associated high endothelial venules. This in turn impaired lymphocyte entry into PPs and initiation of mucosal antibody responses. These results identify a critical role for conduit-mediated fluid flow in the maintenance of PP homeostasis and mucosal immunity.


Assuntos
Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Mecanotransdução Celular/imunologia , Nódulos Linfáticos Agregados/imunologia , Animais , Anticorpos/imunologia , Anticorpos/metabolismo , Movimento Celular/imunologia , Quimiocina CCL19/metabolismo , Feminino , Mucosa Intestinal/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Canais Iônicos/genética , Canais Iônicos/metabolismo , Ativação Linfocitária , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Nódulos Linfáticos Agregados/metabolismo , Água/metabolismo
4.
Nat Immunol ; 16(1): 75-84, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25347465

RESUMO

In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.


Assuntos
Colágeno/metabolismo , Fibroblastos/citologia , Lectinas Tipo C/metabolismo , Linfonodos/citologia , Glicoproteínas de Membrana/metabolismo , Amidas/farmacologia , Animais , Sobrevivência Celular/imunologia , Colágeno/imunologia , Citoesqueleto/imunologia , Citoesqueleto/ultraestrutura , Inibidores Enzimáticos/farmacologia , Feminino , Fibroblastos/imunologia , Fibroblastos/ultraestrutura , Lectinas Tipo C/imunologia , Linfonodos/imunologia , Linfonodos/ultraestrutura , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Fosforilação , Piridinas/farmacologia , Organismos Livres de Patógenos Específicos
5.
Nat Immunol ; 15(10): 973-81, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25151489

RESUMO

Fibroblastic reticular cells (FRCs) are known to inhabit T cell-rich areas of lymphoid organs, where they function to facilitate interactions between T cells and dendritic cells. However, in vivo manipulation of FRCs has been limited by a dearth of genetic tools that target this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrated their indispensable role in antiviral T cell responses. Unexpectedly, loss of FRCs also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and identifies a subset of FRCs that control B cell homeostasis and follicle identity.


Assuntos
Linfócitos B/imunologia , Fibroblastos/imunologia , Homeostase/imunologia , Linfócitos T/imunologia , Animais , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Movimento Celular/imunologia , Sobrevivência Celular/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Imunidade Humoral/imunologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Linfócitos T/metabolismo
6.
Immunity ; 46(1): 106-119, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28099860

RESUMO

A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins, autoantibody, and complement. This uptake, mediated through CD21, triggered endosomal TLR7 and led to the secretion of interferon (IFN) α via an IRF5-dependent pathway. Blocking of FDC secretion of IFN-α restored B cell tolerance and reduced the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical source of the IFN-α driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in systemic lupus erythematosus.


Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Células Dendríticas Foliculares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Autoantígenos/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Interferon-alfa/biossíntese , Interferon-alfa/imunologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Reação em Cadeia da Polimerase , Receptor 7 Toll-Like/imunologia , Transcriptoma
7.
Nature ; 578(7793): 177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025017

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

9.
Nat Immunol ; 13(5): 499-510, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22466668

RESUMO

Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly elucidated. Here, comparative transcriptomic analyses of mouse LNSC subsets demonstrated the expression of important immune mediators, growth factors and previously unknown structural components. Pairwise analyses of ligands and cognate receptors across hematopoietic and stromal subsets suggested a complex web of crosstalk. Fibroblastic reticular cells (FRCs) showed enrichment for higher expression of genes relevant to cytokine signaling, relative to their expression in skin and thymic fibroblasts. LNSCs from inflamed lymph nodes upregulated expression of genes encoding chemokines and molecules involved in the acute-phase response and the antigen-processing and antigen-presentation machinery. Poorly studied podoplanin (gp38)-negative CD31(-) LNSCs showed similarities to FRCs but lacked expression of interleukin 7 (IL-7) and were identified as myofibroblastic pericytes that expressed integrin α(7). Together our data comprehensively describe the transcriptional characteristics of LNSC subsets.


Assuntos
Expressão Gênica/imunologia , Inflamação/imunologia , Linfonodos/imunologia , Células Estromais/imunologia , Células Estromais/metabolismo , Transcriptoma , Reação de Fase Aguda/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Fibroblastos/imunologia , Fibroblastos/metabolismo , Homeostase/imunologia , Inflamação/genética , Cadeias alfa de Integrinas/imunologia , Cadeias alfa de Integrinas/metabolismo , Interleucina-7/imunologia , Interleucina-7/metabolismo , Linfonodos/citologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pericitos/imunologia , Pericitos/metabolismo , Tolerância a Antígenos Próprios/imunologia , Análise Serial de Tecidos/métodos
10.
J Immunol ; 208(10): 2403-2424, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35477687

RESUMO

Lupus susceptibility results from the combined effects of numerous genetic loci, but the contribution of these loci to disease pathogenesis has been difficult to study due to the large cellular heterogeneity of the autoimmune immune response. We performed single-cell RNA, BCR, and TCR sequencing of splenocytes from mice with multiple polymorphic lupus susceptibility loci. We not only observed lymphocyte and myeloid expansion, but we also characterized changes in subset frequencies and gene expression, such as decreased CD8 and marginal zone B cells and increased Fcrl5- and Cd5l-expressing macrophages. Clonotypic analyses revealed expansion of B and CD4 clones, and TCR repertoires from lupus-prone mice were distinguishable by algorithmic specificity prediction and unsupervised machine learning classification. Myeloid differential gene expression, metabolism, and altered ligand-receptor interaction were associated with decreased Ag presentation. This dataset provides novel mechanistic insight into the pathophysiology of a spontaneous model of lupus, highlighting potential therapeutic targets for autoantibody-mediated disease.


Assuntos
Linfócitos B , Lúpus Eritematoso Sistêmico , Animais , Autoimunidade , Células Cultivadas , Loci Gênicos , Lúpus Eritematoso Sistêmico/genética , Camundongos , Receptores de Antígenos de Linfócitos T
11.
Brain Behav Immun ; 114: 511-522, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37369340

RESUMO

Among systemic lupus erythematosus (SLE) patients, neuropsychiatric symptoms are highly prevalent, being observed in up to 80% of adult and 95% of pediatric patients. Type 1 interferons, particularly interferon alpha (IFNα), have been implicated in the pathogenesis of SLE and its associated neuropsychiatric symptoms (NPSLE). However, it remains unclear how type 1 interferon signaling in the central nervous system (CNS) might result in neuropsychiatric sequelae. In this study, we validate an NPSLE mouse model and find an elevated peripheral type 1 interferon signature alongside clinically relevant NPSLE symptoms such as anxiety and fatigue. Unbiased single-nucleus sequencing of the hindbrain and hippocampus revealed that interferon-stimulated genes (ISGs) were among the most highly upregulated genes in both regions and that gene pathways involved in cellular interaction and neuronal development were generally repressed among astrocytes, oligodendrocytes, and neurons. Using image-based spatial transcriptomics, we found that the type 1 interferon signature is enriched as spatially distinct patches within the brain parenchyma of these mice. Our results suggest that type 1 interferon in the CNS may play an important mechanistic role in mediating NPSLE behavioral phenotypes by repressing general cellular communication pathways, and that type 1 interferon signaling modulators are a potential therapeutic option for NPSLE.


Assuntos
Lúpus Eritematoso Sistêmico , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Adulto , Humanos , Criança , Animais , Camundongos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/complicações , Encéfalo/metabolismo , Interferon-alfa/metabolismo
12.
Nature ; 546(7659): 539-543, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28614301

RESUMO

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.


Assuntos
Interferon Tipo I/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Microglia/imunologia , Microglia/patologia , Sinapses/patologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Comportamento Animal , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Interferon Tipo I/antagonistas & inibidores , Vasculite Associada ao Lúpus do Sistema Nervoso Central/psicologia , Masculino , Camundongos , Microglia/metabolismo , Fenótipo , Transdução de Sinais , Sinapses/imunologia , Transcriptoma
14.
Nat Immunol ; 11(5): 427-34, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20305659

RESUMO

A major pathway for B cell acquisition of lymph-borne particulate antigens relies on antigen capture by subcapsular sinus macrophages of the lymph node. Here we tested whether this mechanism is also important for humoral immunity to inactivated influenza virus. By multiple approaches, including multiphoton intravital imaging, we found that antigen capture by sinus-lining macrophages was important for limiting the systemic spread of virus but not for the generation of influenza-specific humoral immunity. Instead, we found that dendritic cells residing in the lymph node medulla use the lectin receptor SIGN-R1 to capture lymph-borne influenza virus and promote humoral immunity. Thus, our results have important implications for the generation of durable humoral immunity to viral pathogens through vaccination.


Assuntos
Moléculas de Adesão Celular/metabolismo , Células Dendríticas/metabolismo , Endocitose , Vírus da Influenza A/imunologia , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Anticorpos Antivirais/sangue , Apresentação de Antígeno , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Movimento Celular , Células Cultivadas , Ácido Clodrônico/administração & dosagem , Dendrímeros/administração & dosagem , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Endocitose/efeitos dos fármacos , Endocitose/genética , Imunidade Humoral/efeitos dos fármacos , Imunidade Humoral/genética , Cadeias Pesadas de Imunoglobulinas/genética , Imunoterapia Ativa , Vírus da Influenza A/patogenicidade , Vacinas contra Influenza/administração & dosagem , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Linfonodos/patologia , Linfonodos/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/virologia , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia
15.
Scand J Immunol ; 95(6): e13192, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35587582

RESUMO

The germinal center serves as a site of B cell selection and affinity maturation, critical processes for productive adaptive immunity. In autoimmune disease tolerance is broken in the germinal center reaction, leading to production of autoreactive B cells that may propagate disease. Follicular T cells are crucial regulators of this process, providing signals necessary for B cell survival in the germinal center. Here, we review the emerging roles of follicular T cells in the autoreactive germinal center. Recent advances in immunological techniques have allowed study of the gene expression profiles and repertoire of follicular T cells at unprecedented resolution. These studies provide insight into the potential role follicular T cells play in preventing or facilitating germinal center loss of tolerance. Improved understanding of the mechanisms of T cell help in autoreactive germinal centers provides novel therapeutic targets for diseases of germinal center dysfunction.


Assuntos
Doenças Autoimunes , Centro Germinativo , Linfócitos B , Humanos , Tolerância Imunológica , Linfócitos T Auxiliares-Indutores
16.
Immunity ; 38(6): 1164-75, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23770227

RESUMO

Stromal-derived follicular dendritic cells (FDCs) are a major reservoir for antigen that are essential for formation of germinal centers, the site where memory and effector B cells differentiate. A long-standing question is how FDCs retain antigen in its native form for extended periods and how they display it to specific B cells. Here we found that FDCs acquired complement-coated immune complexes (ICs) from noncognate B cells via complement receptors 1 and 2 (CD35 and CD21, respectively) and rapidly internalized them by an actin-dependent pathway. ICs were retained intact within a nondegradative cycling compartment and were displayed periodically on the cell surface where they were accessible to antigen-specific B cells. This would explain how antigens are protected from damage and retained over long periods of time, while remaining accessible for B cells.


Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Antígenos/metabolismo , Linfócitos B/imunologia , Células Dendríticas Foliculares/imunologia , Actinas/metabolismo , Animais , Apresentação de Antígeno , Complexo Antígeno-Anticorpo/imunologia , Antígenos/imunologia , Células Cultivadas , Endocitose/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptores de Complemento 3b/metabolismo , Receptores de Complemento 3d/metabolismo
17.
Immunity ; 38(5): 1063-72, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23684986

RESUMO

Cochlin, an extracellular matrix protein, shares homologies with the Factor C, a serine protease found in horseshoe crabs, which is critical for antibacterial responses. Mutations in the COCH gene are responsible for human DFNA9 syndrome, a disorder characterized by neurodegeneration of the inner ear that leads to hearing loss and vestibular impairments. The physiological function of cochlin, however, is unknown. Here, we report that cochlin is specifically expressed by follicular dendritic cells and selectively localized in the fine extracellular network of conduits in the spleen and lymph nodes. During inflammation, cochlin was cleaved by aggrecanases and secreted into blood circulation. In models of lung infection with Pseudomonas aeruginosa and Staphylococcus aureus, Coch(-/-) mice show reduced survival linked to defects in local cytokine production, recruitment of immune effector cells, and bacterial clearance. By producing cochlin, FDCs thus contribute to the innate immune response in defense against bacteria.


Assuntos
Células Dendríticas Foliculares/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Imunidade Inata , Infecções por Pseudomonas/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Endopeptidases/metabolismo , Proteínas da Matriz Extracelular/sangue , Proteínas da Matriz Extracelular/genética , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pseudomonas aeruginosa/imunologia , Baço/metabolismo
18.
J Immunol ; 205(6): 1678-1694, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32769120

RESUMO

The classical and lectin pathways of the complement system are important for the elimination of pathogens and apoptotic cells and stimulation of the adaptive immune system. Upon activation of these pathways, complement component C4 is proteolytically cleaved, and the major product C4b is deposited on the activator, enabling assembly of a C3 convertase and downstream alternative pathway amplification. Although excessive activation of the lectin and classical pathways contributes to multiple autoimmune and inflammatory diseases and overexpression of a C4 isoform has recently been linked to schizophrenia, a C4 inhibitor and structural characterization of the convertase formed by C4b is lacking. In this study, we present the nanobody hC4Nb8 that binds with picomolar affinity to human C4b and potently inhibits in vitro complement C3 deposition through the classical and lectin pathways in human serum and in mouse serum. The crystal structure of the C4b:hC4Nb8 complex and a three-dimensional reconstruction of the C4bC2 proconvertase obtained by electron microscopy together rationalize how hC4Nb8 prevents proconvertase assembly through recognition of a neoepitope exposed in C4b and reveals a unique C2 conformation compared with the alternative pathway proconvertase. On human induced pluripotent stem cell-derived neurons, the nanobody prevents C3 deposition through the classical pathway. Furthermore, hC4Nb8 inhibits the classical pathway-mediated immune complex delivery to follicular dendritic cells in vivo. The hC4Nb8 represents a novel ultrahigh-affinity inhibitor of the classical and lectin pathways of the complement cascade under both in vitro and in vivo conditions.


Assuntos
Convertases de Complemento C3-C5 da Via Clássica/metabolismo , Complemento C3/metabolismo , Complemento C4b/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurônios/fisiologia , Esquizofrenia/metabolismo , Anticorpos de Domínio Único/metabolismo , Animais , Afinidade de Anticorpos , Complexo Antígeno-Anticorpo/metabolismo , Diferenciação Celular , Células Cultivadas , Ativação do Complemento , Complemento C4b/genética , Complemento C4b/imunologia , Humanos , Camundongos , Camundongos Knockout , Multimerização Proteica , Regulação para Cima
19.
Nature ; 530(7589): 177-83, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26814963

RESUMO

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.


Assuntos
Complemento C4/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Esquizofrenia/genética , Alelos , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Complemento C4/química , Via Clássica do Complemento , Dendritos/metabolismo , Dosagem de Genes/genética , Regulação da Expressão Gênica/genética , Haplótipos/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Camundongos , Modelos Animais , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Fatores de Risco , Esquizofrenia/patologia , Sinapses/metabolismo
20.
Immunity ; 37(2): 199-207, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22921118

RESUMO

The complement system of innate immunity is important in regulating humoral immunity largely through the complement receptor CR2, which forms a coreceptor on B cells during antigen-induced activation. However, CR2 also retains antigens on follicular dendritic cells (FDCs). Display of antigen on FDCs is critical for clonal selection and affinity maturation of activated B cells. This review will discuss the role of complement in adaptive immunity in general with a focus on the interplay between CR2-associated antigen on B cells with CR2 expressed on FDCs. This latter interaction provides an opportunity for memory B cells to sample antigen over prolonged periods. The cocrystal structure of CR2 with its ligand C3d provides insight into how the complement system regulates access of antigen by B cells with implications for therapeutic manipulations to modulate aberrant B cell responses in the case of autoimmunity.


Assuntos
Linfócitos B/imunologia , Complemento C3d/imunologia , Células Dendríticas Foliculares/imunologia , Imunidade Humoral/imunologia , Receptores de Complemento 3d/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígenos/imunologia , Antígenos CD19/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Ativação do Complemento/imunologia , Complemento C3d/química , Complemento C3d/metabolismo , Células Dendríticas Foliculares/metabolismo , Humanos , Imunidade Inata , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Receptores de Complemento 3d/química , Receptores de Complemento 3d/metabolismo , Tetraspanina 28/imunologia
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