RESUMO
For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Memória Imunológica , Plasmócitos/imunologia , Plasmócitos/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Memória Imunológica/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Transcrição GênicaRESUMO
B cell subsets differ in development, tissue distribution, and mechanisms of activation. In response to infections, however, all can differentiate into extrafollicular plasmablasts that rapidly provide highly protective antibodies, indicating that these plasmablasts are the main humoral immune response effectors. Yet, the effectiveness of this response type depends on the presence of antigen-specific precursors in the circulating mature B cell pool, a pool that is generated initially through the stochastic processes of B cell receptor assembly. Importantly, germinal centers then mold the repertoire of this B cell pool to be increasingly responsive to pathogens by generating a broad array of antimicrobial memory B cells that act as highly effective precursors of extrafollicular plasmablasts. Such B cell repertoire molding occurs in two ways: continuously via the chronic germinal centers of mucosal lymphoid tissues, driven by the presence of the microbiome, and via de novo generated germinal centers following acute infections. For effectively evaluating humoral immunity as a correlate of immune protection, it might be critical to measure memory B cell pools in addition to antibody titers.
Assuntos
Subpopulações de Linfócitos B , Linfócitos B , Animais , Centro Germinativo , Humanos , Imunidade Humoral , Receptores de Antígenos de Linfócitos BRESUMO
Germinal centers (GCs) form in secondary lymphoid organs in response to infection and immunization and are the source of affinity-matured B cells. The duration of GC reactions spans a wide range, and long-lasting GCs (LLGCs) are potentially a source of highly mutated B cells. We show that rather than consisting of continuously evolving B cell clones, LLGCs elicited by influenza virus or SARS-CoV-2 infection in mice are sustained by progressive replacement of founder clones by naive-derived invader B cells that do not detectably bind viral antigens. Rare founder clones that resist replacement for long periods are enriched in clones with heavily mutated immunoglobulins, including some with very high affinity for antigen, that can be recalled by boosting. Our findings reveal underappreciated aspects of the biology of LLGCs generated by respiratory virus infection and identify clonal replacement as a potential constraint on the development of highly mutated antibodies within these structures.
Assuntos
Linfócitos B , Centro Germinativo , Infecções por Vírus de RNA , Animais , Camundongos , Linfócitos B/citologia , Linfócitos B/imunologia , Células Clonais , COVID-19 , Centro Germinativo/citologia , Centro Germinativo/imunologia , SARS-CoV-2 , Influenza Humana , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/patologia , Infecções por Vírus de RNA/virologiaRESUMO
Holistic understanding of physio-pathological processes requires noninvasive 3D imaging in deep tissue across multiple spatial and temporal scales to link diverse transient subcellular behaviors with long-term physiogenesis. Despite broad applications of two-photon microscopy (TPM), there remains an inevitable tradeoff among spatiotemporal resolution, imaging volumes, and durations due to the point-scanning scheme, accumulated phototoxicity, and optical aberrations. Here, we harnessed the concept of synthetic aperture radar in TPM to achieve aberration-corrected 3D imaging of subcellular dynamics at a millisecond scale for over 100,000 large volumes in deep tissue, with three orders of magnitude reduction in photobleaching. With its advantages, we identified direct intercellular communications through migrasome generation following traumatic brain injury, visualized the formation process of germinal center in the mouse lymph node, and characterized heterogeneous cellular states in the mouse visual cortex, opening up a horizon for intravital imaging to understand the organizations and functions of biological systems at a holistic level.
Assuntos
Imageamento Tridimensional , Animais , Camundongos , Imageamento Tridimensional/métodos , Microscopia Confocal/métodosRESUMO
Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. Herein, through a fine-needle aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant recipients (KTXs). We found that, unlike healthy subjects, KTXs presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cell, SARS-CoV-2 receptor binding domain-specific memory B cell, and neutralizing antibody responses. KTXs also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals and suggest a GC origin for certain humoral and memory B cell responses following mRNA vaccination.
RESUMO
Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
Assuntos
Infecções por Coronavirus/imunologia , Centro Germinativo/imunologia , Pneumonia Viral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , COVID-19 , Feminino , Centro Germinativo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Baço/imunologia , Baço/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection. Here, we investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs preferentially differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation temporally coincided with transient interferon (IFN)-γ production by Tfh cells. Depletion of IFN-γ in Tfh cells prevented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-γ was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted differentiation of a CXCR3+ GC B cell subset that were precursors of lung-BRMs and CXCR3+ memory B cells in the mediastinal lymph node. Absence of IFN-γ signaling or T-bet in GC B cells prevented CXCR3+ pre-memory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses. Thus, Tfh-cell-derived IFN-γ is critical for lung-BRM development and pulmonary immunity, with implications for vaccination strategies targeting BRMs.
Assuntos
Influenza Humana , Linfócitos T Auxiliares-Indutores , Humanos , Interferon gama/metabolismo , Células B de Memória , Células T Auxiliares Foliculares/metabolismo , Centro Germinativo , Diferenciação Celular , Receptores CXCR3/metabolismoRESUMO
Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4+ T cell expansion and differentiation in a dose-dependent manner and with paracrine activity. Within GC, IL-21 specifically promoted B cell centroblast identity and, when bioavailability was high, plasma cell differentiation. Critically, these actions may occur irrespective of cognate T-B interactions, making IL-21 a general promoter of growth as distinct to a mediator of affinity-driven selection via synaptic delivery. This promiscuous activity of IL-21 explains the consequences of IL-21 deficiency on antibody-based immunity.
Assuntos
Sinapses Imunológicas , Linfócitos T Auxiliares-Indutores , Diferenciação Celular , Centro Germinativo , InterleucinasRESUMO
T follicular helper (Tfh) cells are defined by a Bcl6+CXCR5hiPD-1hi phenotype, but only a minor fraction of these reside in germinal centers (GCs). Here, we examined whether GC-resident and -nonresident Tfh cells share a common physiology and function. Fluorescently labeled, GC-resident Tfh cells in different mouse models were distinguished by low expression of CD90. CD90neg/lo GCTfh cells required antigen-specific, MHCII+ B cells to develop and stopped proliferating soon after differentiation. In contrast, nonresident, CD90hi Tfh (GCTfh-like) cells developed normally in the absence of MHCII+ B cells and proliferated continuously during primary responses. The TCR repertoires of both Tfh subsets overlapped initially but later diverged in association with dendritic cell-dependent proliferation of CD90hi GCTfh-like cells, suggestive of TCR-dependency seen also in TCR-transgenic adoptive transfer experiments. Furthermore, the transcriptomes of CD90neg/lo and CD90hi GCTfh-like cells were enriched in different functional pathways. Thus, GC-resident and nonresident Tfh cells have distinct developmental requirements and activities, implying distinct functions.
Assuntos
Centro Germinativo/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Células T Auxiliares Foliculares/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular/imunologia , Diferenciação Celular , Proliferação de Células , Células Dendríticas/imunologia , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Células T Auxiliares Foliculares/imunologia , Subpopulações de Linfócitos T/imunologia , Antígenos Thy-1/metabolismoRESUMO
Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.
Assuntos
Linfócitos B/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Centro Germinativo/imunologia , SARS-CoV-2/fisiologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de mRNA/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adjuvantes Imunológicos , Animais , Células HEK293 , Humanos , Imunidade Humoral , Interleucina-6/genética , Interleucina-6/metabolismo , Lipossomos/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Subunidades Proteicas/genética , Vacinas de mRNA/genéticaRESUMO
Cell fate decisions during early B cell activation determine the outcome of responses to pathogens and vaccines. We examined the early B cell response to T-dependent antigen in mice by single-cell RNA sequencing. Early after immunization, a homogeneous population of activated precursors (APs) gave rise to a transient wave of plasmablasts (PBs), followed a day later by the emergence of germinal center B cells (GCBCs). Most APs rapidly exited the cell cycle, giving rise to non-GC-derived early memory B cells (eMBCs) that retained an AP-like transcriptional profile. Rapid decline of antigen availability controlled these events; provision of excess antigen precluded cell cycle exit and induced a new wave of PBs. Fate mapping revealed a prominent contribution of eMBCs to the MBC pool. Quiescent cells with an MBC phenotype dominated the early response to immunization in primates. A reservoir of APs/eMBCs may enable rapid readjustment of the immune response when failure to contain a threat is manifested by increased antigen availability.
Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunidade Humoral/imunologia , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Animais , Apresentação de Antígeno/imunologia , Diferenciação Celular/imunologia , Camundongos , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologiaRESUMO
The deployment of effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to eradicate the coronavirus disease 2019 (COVID-19) pandemic. Many licensed vaccines confer protection by inducing long-lived plasma cells (LLPCs) and memory B cells (MBCs), cell types canonically generated during germinal center (GC) reactions. Here, we directly compared two vaccine platforms-mRNA vaccines and a recombinant protein formulated with an MF59-like adjuvant-looking for their abilities to quantitatively and qualitatively shape SARS-CoV-2-specific primary GC responses over time. We demonstrated that a single immunization with SARS-CoV-2 mRNA, but not with the recombinant protein vaccine, elicited potent SARS-CoV-2-specific GC B and T follicular helper (Tfh) cell responses as well as LLPCs and MBCs. Importantly, GC responses strongly correlated with neutralizing antibody production. mRNA vaccines more efficiently induced key regulators of the Tfh cell program and influenced the functional properties of Tfh cells. Overall, this study identifies SARS-CoV-2 mRNA vaccines as strong candidates for promoting robust GC-derived immune responses.
Assuntos
Anticorpos Neutralizantes/metabolismo , Linfócitos B/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Centro Germinativo/imunologia , SARS-CoV-2/fisiologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas Sintéticas/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Células Cultivadas , Epitopos , Humanos , Ativação Linfocitária , Polissorbatos , RNA Viral/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Esqualeno , Vacinação , Vacinas de mRNARESUMO
The dynamic and complex community of microbes that colonizes the intestines is composed of bacteria, fungi, and viruses. At the mucosal surfaces, immunoglobulins play a key role in protection against bacterial and fungal pathogens, and their toxins. Secretory immunoglobulin A (sIgA) is the most abundantly produced antibody at the mucosal surfaces, while Immunoglobulin G (IgG) isotypes play a critical role in systemic protection. IgA and IgG antibodies with reactivity to commensal fungi play an important role in shaping the mycobiota and host antifungal immunity. In this article, we review the latest evidence that establishes a connection between commensal fungi and B cell-mediated antifungal immunity as an additional layer of protection against fungal infections and inflammation.
Assuntos
Antifúngicos , Imunoglobulina A Secretora , Humanos , Imunoglobulina G , Bactérias , Imunidade nas Mucosas , ImunoglobulinasRESUMO
The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV-1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native-like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world-wide are of the clade C subtype, we examined responses in non-human primates to well-ordered subtype C 16055 trimers administered in soluble or high-density liposomal formats. We detected superior germinal center formation and enhanced autologous neutralizing antibodies against the neutralization-resistant (tier 2) 16055 virus following inoculation of liposome-arrayed trimers. Epitope mapping of the neutralizing monoclonal antibodies (mAbs) indicated major contacts with the V2 apex, and 3D electron microscopy reconstructions of Fab-trimer complexes revealed a horizontal binding angle to the Env spike. These vaccine-elicited mAbs target the V2 cap, demonstrating a means to accomplish tier 2 virus neutralization by penetrating the dense N-glycan shield.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Fragmentos de Peptídeos/imunologia , Multimerização Proteica/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/metabolismo , Mapeamento de Epitopos , Epitopos/química , Epitopos/imunologia , Anticorpos Anti-HIV/química , Anticorpos Anti-HIV/metabolismo , HIV-1/classificação , HIV-1/genética , Humanos , Imunização , Modelos Moleculares , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Vírion/química , Vírion/imunologia , Vírion/ultraestrutura , Produtos do Gene env do Vírus da Imunodeficiência Humana/genéticaRESUMO
The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.
Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/uso terapêutico , Centro Germinativo/imunologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/terapia , HIV-1/imunologia , Animais , Células Cultivadas , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Centro Germinativo/virologia , Infecções por HIV/imunologia , Humanos , Imunização , Injeções Subcutâneas , Primatas , Multimerização Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologiaRESUMO
Utilizing an autoimmune bone marrow chimera model we determined that B cells depend critically on MHCII expression for participation in the germinal center, but cells displaying a 50% reduction in surface MHCII compete efficiently with their wild-type counterparts. This provides insights into the requirements for germinal center participation.
Assuntos
Linfócitos B , Centro GerminativoRESUMO
Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both positive and negative regulation of foreign antigen-specific B cell responses, control over autoreactive antibody responses and autoimmunity, and B cell class-switching to IgE and allergy development. Studies conducted on mice uncovered various subsets of CXCR5+FoxP3+CD4+ Tfr cells that could differently contribute to immune regulation. Moreover, recent studies of human Tfr cells revealed similar complexity with various subsets of follicular T cells of different origins and immunosuppressive and/or immunostimulatory characteristics. In this review we will overview and compare Tfr subsets currently identified in mice and humans and will discuss their origins and antigen specificity, as well as potential modes of action and contribution to the control of the autoimmune and allergic reactions.
Assuntos
Subpopulações de Linfócitos T , Linfócitos T Reguladores , Humanos , Animais , Camundongos , Linfócitos T CD4-Positivos , Linfócitos B , Autoimunidade , Centro Germinativo , Linfócitos T Auxiliares-IndutoresRESUMO
BACKGROUND AND PURPOSE: Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma-associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG. METHODS: We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC-positive and GC-negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed. RESULTS: Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC-positive, whereas 175 were GC-negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC-positive group than in the GC-negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358-105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029-0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742-67.000) were significantly associated with postthymectomy MG. CONCLUSIONS: Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.
Assuntos
Miastenia Gravis , Timoma , Neoplasias do Timo , Humanos , Timoma/complicações , Timoma/cirurgia , Estudos Retrospectivos , Timectomia/efeitos adversos , Neoplasias do Timo/complicações , Neoplasias do Timo/cirurgia , Miastenia Gravis/complicaçõesRESUMO
Acetylcholine receptor (AChR) myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness. The AChR+ autoantibodies are produced by B-cells located in thymic ectopic germinal centers (eGC). No therapeutic approach is curative. The inflammatory IL-23/Th17 pathway is activated in the thymus as well as in the blood and the muscle, contributing to the MG pathogenic events. We aimed to study a potential new therapeutic approach that targets IL-23p19 (IL-23) in the two complementary preclinical MG models: the classical experimental MG mouse model (EAMG) based on active immunization and the humanized mouse model featuring human MG thymuses engrafted in NSG mice (NSG-MG). In both preclinical models, the anti-IL-23 treatment ameliorated MG clinical symptoms. In the EAMG, the treatment reduced IL-17 related inflammation, anti-AChR IgG2b antibody production, activated transduction pathway involved in muscle regeneration and ameliorated the signal transduction at the neuromuscular junction. In the NSG-MG model, the treatment reduced pathogenic Th17 cell population and expression of genes involved in eGC stabilization and B-cell development in human MG thymus biopsies. Altogether, these data suggest that a therapy targeting IL-23p19 may promote significant clinical ameliorations in AChR+ MG disease due to concomitant beneficial effects on the thymus and skeletal muscle defects.
Assuntos
Interleucina-23 , Miastenia Gravis Autoimune Experimental , Camundongos , Humanos , Animais , Subunidade p19 da Interleucina-23 , Receptores Colinérgicos , Junção Neuromuscular/patologia , AutoanticorposRESUMO
Benign lymphadenopathy is common in the pediatric population and may be clinically striking. As in adults, lymph node evaluation in pediatric patients requires careful morphologic and immunohistochemical assessment and clinical contextualization of the findings. It is important for the pathologist to be familiar with benign and reactive conditions that may mimic malignancy. This review presents non-neoplastic or indolent processes or patterns of lymphoid hyperplasia that may be confused with or raise the differential of lymphoma, with a focus on those more commonly encountered in the pediatric/adolescent population.