RESUMEN
Although T cell help for B cells was described several decades ago, it was the identification of CXCR5 expression by B follicular helper T (Tfh) cells and the subsequent discovery of their dependence on BCL6 that led to the recognition of Tfh cells as an independent helper subset and accelerated the pace of discovery. More than 20 transcription factors, together with RNA-binding proteins and microRNAs, control the expression of chemotactic receptors and molecules important for the function and homeostasis of Tfh cells. Tfh cells prime B cells to initiate extrafollicular and germinal center antibody responses and are crucial for affinity maturation and maintenance of humoral memory. In addition to the roles that Tfh cells have in antimicrobial defense, in cancer, and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity. The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible division of labor in germinal center B cell selection and elimination.
Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Inmunidad Humoral , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Diferenciación Celular , Regulación de la Expresión Génica , Humanos , Memoria Inmunológica , Activación de Linfocitos , MicroARNs/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptores CXCR5/metabolismoRESUMEN
Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-ß without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.
Asunto(s)
Enfermedades Autoinmunes , Proteínas de Unión al ADN , Inmunoglobulina G , Factor 88 de Diferenciación Mieloide , Receptor Toll-Like 7 , Animales , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Humanos , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/inmunología , Ratones , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Masculino , Transducción de Señal , Mitocondrias/metabolismo , Secuenciación del Exoma , Anticuerpos Antinucleares/inmunología , Linfocitos B/inmunología , Ratones Noqueados , Ratones Endogámicos C57BL , Centro Germinal/inmunología , Linaje , Glándulas Salivales/inmunología , Glándulas Salivales/metabolismo , Glándulas Salivales/patología , Glicoproteínas de MembranaRESUMEN
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.
Asunto(s)
Linfocitos B/inmunología , Proteínas del Tejido Nervioso/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Autoanticuerpos/inmunología , Autoinmunidad , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteínas Ligadas a GPI/metabolismo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Histonas/inmunología , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismoRESUMEN
Understanding which arms of the immune response are responsible for protection against SARS-CoV-2 infection is key to predicting long-term immunity and to inform vaccine design. Two studies in this issue of Cell collectively suggest that, although SARS-CoV-2 infection may blunt long-lived antibody responses, immune memory might still be achieved through virus-specific memory T cells.
Asunto(s)
Infecciones por Coronavirus , Pandemias , Neumonía Viral , Linfocitos T , Linfocitos B , Betacoronavirus , COVID-19 , SARS-CoV-2RESUMEN
Some bacteria and parasites, such as Salmonella, actively disrupt germinal centers and elicit only low affinity antibodies, but the mechanisms by which microbes alter these responses is poorly understood. In this issue of Immunity, Biram et al. (2022) uncover a mechanism by which Salmonella recruits Sca-1+ monocytes to germinal centers and impairs metabolic adaptation.
Asunto(s)
Infecciones Bacterianas , Monocitos , Centro Germinal/inmunología , Humanos , SalmonellaRESUMEN
Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.
Asunto(s)
Inflamación/metabolismo , Estabilidad del ARN , ARN Mensajero/metabolismo , Ribonucleasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Secuencia de Bases , Codón de Terminación , Células HeLa , Humanos , Inflamación/genética , Inflamación/inmunología , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , Conformación de Ácido Nucleico , Polirribosomas/metabolismo , Biosíntesis de Proteínas , ARN Mensajero/química , Proteínas Ribosómicas/metabolismo , Transactivadores/metabolismoRESUMEN
Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.
Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Cambio de Clase de Inmunoglobulina , Células Plasmáticas/inmunología , Linfoma Plasmablástico/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Ratones , Ratones Endogámicos C57BL , Filogenia , Receptores de Antígenos de Linfocitos B/metabolismoRESUMEN
The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFß1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.
Asunto(s)
Artritis Reumatoide/genética , Enfermedad de Crohn/genética , Factores de Transcripción Forkhead/genética , Malaria Falciparum/genética , Polimorfismo de Nucleótido Simple , Animales , Artritis Reumatoide/fisiopatología , Núcleo Celular/metabolismo , Enfermedad de Crohn/fisiopatología , Proteínas de la Matriz Extracelular/inmunología , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Variación Genética , Humanos , Inflamación/genética , Malaria Falciparum/fisiopatología , Ratones , Monocitos/inmunología , Transcripción Genética , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
Asunto(s)
Mutación con Ganancia de Función , Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Animales , Autoinmunidad/genética , Linfocitos B , GMP Cíclico/análogos & derivados , Guanosina , Humanos , Lupus Eritematoso Sistémico/genética , Ratones , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismoRESUMEN
Follicular helper T cells (TFH cells) compose a heterogeneous subset of CD4(+) T cells that induce the differentiation of B cells into plasma cells and memory cells. They are found within and in proximity to germinal centers in secondary lymphoid organs, and their memory compartment also circulates in the blood. Our knowledge on the biology of TFH cells has increased significantly during the past decade, largely as a result of mouse studies. However, recent studies on human TFH cells isolated from lymphoid organ and blood samples and recent observations on the developmental mechanism of human TFH cells have revealed both similarities and differences between human and mouse TFH cells. Here we present the similarities and differences between mouse and human lymphoid organ-resident TFH cells and discuss the role of TFH cells in response to vaccines and in disease pathogenesis.
Asunto(s)
Tonsila Palatina/fisiopatología , Subgrupos de Linfocitos T/patología , Linfocitos T Colaboradores-Inductores/patología , Animales , Células Presentadoras de Antígenos/inmunología , Humanos , Memoria Inmunológica , Tonsila Palatina/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
The role of antibody affinity in plasma cell (PC) differentiation from germinal centers (GCs) remains contested. Parallel studies by Sprumont et al. and Sutton and Gao et al. show that PCs emerging from GCs produce antibodies with a diverse range of affinities and lack signatures of affinity-based selection. Therefore, commitment to the PC lineage is affinity independent.
Asunto(s)
Linfocitos B , Centro Germinal , Humanos , Activación de Linfocitos , Linaje de la Célula , Diferenciación Celular , Células PlasmáticasRESUMEN
Generation of broadly neutralizing antibodies is a key aim of HIV vaccine design, but the precursor B cells are rare. Abbott et al. (2018) report that high affinity and avidity immunogens are required to promote maturation of low frequency B cells in germinal centers.
Asunto(s)
Anticuerpos Anti-VIH , VIH-1/inmunología , Vacunas contra el SIDA , Anticuerpos Neutralizantes , Infecciones por VIH , HumanosRESUMEN
Antibody responses are classified according to whether B cells receive help from T cells--that is, whether they are thymus-dependent (TD) responses or thymus-independent (TI) responses. The latter can be elicited by microbial ligands (TI type 1) or by extensive crosslinking of the B cell antigen receptor (BCR; TI type 2). The hallmark of a TD response is the induction of germinal centers in which follicular helper T cells (T(FH) cells) select B cells with somatically mutated high-affinity BCRs to become memory cells. Studies have shown that B cells can also receive innate TD help from natural killer T cells (NKT cells) and innate TI help from cells such as neutrophils but that the outcome of such help differs from conventional TD and TI responses. Here we update the classification of antibody responses to take into account these emerging types of B cell helpers.
Asunto(s)
Formación de Anticuerpos , Subgrupos de Linfocitos B/inmunología , Inmunidad Humoral , Linfocitos T Colaboradores-Inductores/inmunología , Timo/inmunología , Animales , Subgrupos de Linfocitos B/citología , Comunicación Celular/inmunología , Centro Germinal/citología , Centro Germinal/inmunología , Humanos , Memoria Inmunológica , Activación de Linfocitos , Células T Asesinas Naturales/citología , Células T Asesinas Naturales/inmunología , Neutrófilos/citología , Neutrófilos/inmunología , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Linfocitos T Colaboradores-Inductores/citologíaRESUMEN
PURPOSE OF REVIEW: This review aims to provide an overview of the genes and molecular pathways involved in monogenic lupus, the implications for genome diagnosis, and the potential therapies targeting these molecular mechanisms. RECENT FINDINGS: To date, more than 30 genes have been identified as contributors to monogenic lupus. These genes are primarily related to complement deficiency, activation of the type I interferon (IFN) pathway, disruption of B-cell and T-cell tolerance and metabolic pathways, which reveal the multifaceted nature of systemic lupus erythematosus (SLE) pathogenesis. SUMMARY: In-depth study of the causes of monogenic lupus can provide valuable insights into of pathogenic mechanisms of SLE, facilitate the identification of effective biomarkers, and aid in developing therapeutic strategies.
Asunto(s)
Interferón Tipo I , Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/terapia , Lupus Eritematoso Sistémico/tratamiento farmacológico , Proteínas del Sistema Complemento , Interferón Tipo I/metabolismo , BiomarcadoresRESUMEN
T follicular helper (Tfh) cells cognately guide differentiation of antigen-primed B cells in secondary lymphoid tissues. 'Tfh-like' populations not expressing the canonical Tfh cell transcription factor BCL6 have also been described, which can aid particular aspects of B cell differentiation. Tfh and Tfh-like cells are essential for protective and pathological humoral immunity. These CD4+ T cells that help B cells are polarized to produce diverse combinations of cytokines and chemokine receptors and can be grouped into distinct subsets that promote antibodies of different isotype, affinity, and duration, according to the nature of immune challenge. However, unified nomenclature to describe the distinct functional Tfh and Tfh-like cells does not exist. While explicitly acknowledging cellular plasticity, we propose categorizing these cell states into three groups based on phenotype and function, paired with their anatomical site of action.
Asunto(s)
Linfocitos B , Centro Germinal , Diferenciación Celular , Inmunidad Humoral , Activación de Linfocitos , Linfocitos T Colaboradores-InductoresRESUMEN
The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.
RESUMEN
Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government's Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government's objectives and its commitment "to leveraging the benefits of genomics in the health system for all Australians." They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged.
Asunto(s)
Metagenómica/métodos , Grupos de Población/genética , Australia , Variación Genética/genética , HumanosRESUMEN
The transcription factor BATF directly regulates key components of the formation and function of follicular helper T cells and antibody class switching in B cells.
Asunto(s)
Linfocitos B/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Linfocitos T/inmunología , Proteínas Adaptadoras Transductoras de Señales , Animales , Linfocitos B/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Ligando de CD40/genética , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Proteínas Portadoras/metabolismo , Células Cultivadas , Citometría de Flujo , Perfilación de la Expresión Génica , Centro Germinal/inmunología , Centro Germinal/metabolismo , Ratones , Ratones Noqueados , Modelos Inmunológicos , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Lipid antigens trigger help from natural killer T cells (NKT cells) for B cells, and direct conjugation of lipid agonists to antigen profoundly augments antibody responses. Here we show that in vivo, NKT cells engaged in stable and prolonged cognate interactions with B cells and induced the formation of early germinal centers. Mouse and human NKT cells formed CXCR5(+)PD-1(hi) follicular helper NKT cells (NKT(FH) cells), and this process required expression of the transcriptional repressor Bcl-6, signaling via the coreceptor CD28 and interaction with B cells. NKT(FH) cells provided direct cognate help to antigen-specific B cells that was dependent on interleukin 21 (IL-21). Unlike T cell-dependent germinal centers, those driven by NKT(FH) cells did not generate long-lived plasma cells. Our results demonstrate the existence of a Bcl-6-dependent subset of NKT cells specialized in providing help to B cells.
Asunto(s)
Linfocitos B/inmunología , Células T Asesinas Naturales/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Comunicación Celular/inmunología , Células Cultivadas , Centro Germinal/inmunología , Humanos , Inmunofenotipificación , Interleucinas/inmunología , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/metabolismo , FenotipoRESUMEN
Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (TFH) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human TFH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. TFH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human TFH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.