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Autophagy is a regulated intracellular catabolic process by which invading pathogens, damaged organelles, aggregated proteins, and other macromolecules are degraded in lysosomes. It has been widely appreciated that autophagic activity plays an important role in regulating the development, fate determination, and function of cells in the immune system, including B lymphocytes. Autophagy encompasses several distinct pathways that have been linked to B cell homeostasis and function. While B cell presentation of major histocompatibility complex (MHC) class II-restricted cytosolic antigens to T cells involves both macroautophagy and chaperone-mediated autophagy (CMA), plasma cells and memory B cells mainly rely on macroautophagy for their survival. Emerging evidence indicates that core autophagy factors also participate in processes related to yet clearly distinct from classical autophagy. These autophagy-related pathways, referred to as noncanonical autophagy or conjugation of ATG8 to single membranes (CASM), contribute to B cell homeostasis and functions, including MHC class II-restricted antigen presentation to T cells, germinal center formation, plasma cell differentiation, and recall responses. Dysregulation of B cell autophagy has been identified in several autoimmune and autoinflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. In this review, we discuss recent advances in understanding the role of canonical and noncanonical autophagy in B cells, including B cell development and maturation, antigen processing and presentation, pathogen-specific antibody responses, cytokine secretion, and autoimmunity. Unraveling the molecular mechanisms of canonical and noncanonical autophagy in B cells will improve our understanding of B cell biology, with implications for the development of autophagy-based immunotherapies.
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Autofagia , Linfocitos B , Humanos , Autofagia/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Presentación de Antígeno/inmunología , Homeostasis/inmunología , Transducción de SeñalRESUMEN
Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.
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Leucemia de Células Pilosas , Animales , Humanos , Ratones , Linfocitos B/metabolismo , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/metabolismo , Leucemia de Células Pilosas/patología , Mutación , Proteínas Proto-Oncogénicas B-raf , Factores de Transcripción/genéticaRESUMEN
B cells play an important role in adaptive immunity and participate in the process of humoral immunity mainly by secreting antibodies. The entire development and differentiation process of B cells occurs in multiple microenvironments and is regulated by a variety of environmental factors and immune signals. Differentiation biases or disfunction of B cells participate in the process of many autoimmune diseases. Emerging studies report the impact of altered metabolism in B cell biology, including lipid metabolism. Here, we discuss how extracellular lipid environment and metabolites, membrane lipid-related components, and lipid synthesis and catabolism programs coordinate B cell biology and describe the crosstalk of lipid metabolic programs with signal transduction pathways and transcription factors. We conclude with a summary of therapeutic targets for B cell lipid metabolism and signaling in autoimmune diseases and discuss important future directions.
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There is a vital role of B cells in the pathogenesis of Systemic Lupus Erythematosus (SLE). Belimumab (Bel), an inhibitor of B cell activating factor (BAFF), and Rituximab (RTX), a monoclonal antibody targeting Cd20 antigen, have been used to manage systemic lupus. Several randomized controlled trials (RCTs) have evaluated these two agents' clinical efficacy and safety in different manifestations of SLE. This study aims to review the randomized control trials involving these two agents systematically and to explain if any disparity is noticed in the primary and secondary outcomes between these two agents. This study is done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After applying the inclusion criteria and quality assessment by independent reviewers and co-authors, relevant papers were identified, and data were extracted. The results have shown that RCTs involving Belimumab achieved primary endpoints; however, targeted endpoints were not achieved in studies involving Rituximab. It is concluded that despite the conflicting results obtained in clinical trials, both are effective in systemic lupus, as indicated in real-world clinical experience. However, better-designed multicenter studies evaluating these B-cell-targeting drugs are needed.
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Mouse kidney allografts are spontaneously accepted in select, fully mismatched donor-recipient strain combinations, like DBA/2J to C57BL/6 (B6), by natural tolerance. We previously showed accepted renal grafts form aggregates containing various immune cells within 2 weeks posttransplant, referred to as regulatory T cell-rich organized lymphoid structures, which are a novel regulatory tertiary lymphoid organ. To characterize the cells within T cell-rich organized lymphoid structures, we performed single-cell RNA sequencing on CD45+ sorted cells from accepted and rejected renal grafts from 1-week to 6-months posttransplant. Analysis of single-cell RNA sequencing data revealed a shifting from a T cell-dominant to a B cell-rich population by 6 months with an increased regulatory B cell signature. Furthermore, B cells were a greater proportion of the early infiltrating cells in accepted vs rejecting grafts. Flow cytometry of B cells at 20 weeks posttransplant revealed T cell, immunoglobulin domain and mucin domain-1+ B cells, potentially implicating a regulatory role in the maintenance of allograft tolerance. Lastly, B cell trajectory analysis revealed intragraft differentiation from precursor B cells to memory B cells in accepted allografts. In summary, we show a shifting T cell- to B cell-rich environment and a differential cellular pattern among accepted vs rejecting kidney allografts, possibly implicating B cells in the maintenance of kidney allograft acceptance.
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Linfocitos B Reguladores , Ratones , Animales , Transcriptoma , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Riñón , Aloinjertos , Diferenciación Celular , Rechazo de Injerto/etiología , Supervivencia de InjertoRESUMEN
Antibodies against foreign human leukocyte antigen (HLA) molecules are barriers to successful organ transplantation. B cell-depleting treatments are used to reduce anti-HLA antibodies but have limited efficacy. We hypothesized that the primary source for anti-HLA antibodies is long-lived plasma cells, which are ineffectively targeted by B cell depletion. To study this, we screened for anti-HLA antibodies in a prospectively enrolled cohort of 49 patients who received chimeric antigen receptor T-cell therapy (CARTx), targeting naïve and memory B cells (CD19-targeted, n = 21) or plasma cells (BCMA-targeted, n = 28) for hematologic malignancies. Longitudinal samples were collected before and up to 1 year after CARTx. All individuals were in sustained remission. We identified 4 participants with anti-HLA antibodies before CD19-CARTx. Despite B cell depletion, anti-HLA antibodies and calculated panel reactive antibody scores were stable for 1 year after CD19-CARTx. Only 1 BCMA-CARTx recipient had pre-CARTx low-level anti-HLA antibodies, with no follow-up samples available. These data implicate CD19neg long-lived plasma cells as an important source for anti-HLA antibodies, a model supported by infrequent HLA sensitization in BCMA-CARTx subjects receiving previous plasma cell-targeted therapies. Thus, plasma cell-targeted therapies may be more effective against HLA antibodies, thereby enabling improved access to organ transplantation and rejection management.
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Neoplasias Hematológicas , Inmunoterapia Adoptiva , Humanos , Antígeno de Maduración de Linfocitos B , Antígenos CD19 , Linfocitos BRESUMEN
The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies.
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Trasplante de Órganos , Trasplante de Órganos/efectos adversos , Factores de Riesgo , Histocompatibilidad , Prueba de Histocompatibilidad , Procesos de Grupo , Rechazo de Injerto/etiología , IsoanticuerposRESUMEN
Chronic active antibody-mediated rejection (caAMR) in kidney transplantation is a major cause of late graft loss and despite all efforts to date, there is no proven effective therapy. Indeed, the Transplant Society (TTS) consensus opinion called for a conservative approach optimizing baseline immunosuppression and supportive care focused on blood pressure, blood glucose, and lipid control. This review provides the rationale and early evidence in kidney transplant recipients with caAMR that supported the design of the IMAGINE study whose goal is to evaluate the potential impact of targeting the IL6/IL6R pathway.
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Trasplante de Riñón , Trasplantes , Humanos , Trasplante de Riñón/efectos adversos , Anticuerpos , Receptores de Trasplantes , Terapia de InmunosupresiónRESUMEN
During the development of humoral immunity, activated B lymphocytes undergo vigorous proliferative, transcriptional, metabolic, and DNA remodeling activities; hence, their genomes are constantly exposed to an onslaught of genotoxic agents and processes. Branched DNA intermediates generated during replication and recombinational repair pose genomic threats if left unresolved and so, they must be eliminated by structure-selective endonucleases to preserve the integrity of these DNA transactions for the faithful duplication and propagation of genetic information. To investigate the role of two such enzymes, GEN1 and MUS81, in B cell biology, we established B-cell conditional knockout mouse models and found that deletion of GEN1 and MUS81 in early B-cell precursors abrogates the development and maturation of B-lineage cells while the loss of these enzymes in mature B cells inhibit the generation of robust germinal centers. Upon activation, these double-null mature B lymphocytes fail to proliferate and survive while exhibiting transcriptional signatures of p53 signaling, apoptosis, and type I interferon response. Metaphase spreads of these endonuclease-deficient cells showed severe and diverse chromosomal abnormalities, including a preponderance of chromosome breaks, consistent with a defect in resolving recombination intermediates. These observations underscore the pivotal roles of GEN1 and MUS81 in safeguarding the genome to ensure the proper development and proliferation of B lymphocytes.
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Endonucleasas , Interferón Tipo I , Animales , Ratones , Linfocitos B/metabolismo , ADN , Endonucleasas/genética , Endonucleasas/metabolismo , Resolvasas de Unión Holliday/genética , Resolvasas de Unión Holliday/metabolismo , Interferón Tipo I/metabolismo , Proteína p53 Supresora de Tumor , GenomaRESUMEN
Hypoxia is a common hallmark of healthy tissues in physiological states or chronically inflamed tissues in pathological states. Mammalian cells sense and adapt to hypoxia mainly through hypoxia-inducible factor (HIF) signaling. Many studies have shown that hypoxia and HIF signaling play an important regulatory role in development and function of innate immune cells and T cells, but their role in B cell biology is still controversial. B cells experience a complex life cycle (including hematopoietic stem cells, pro-B cells, pre-B cells, immature B cells, mature naïve B cells, activated B cells, plasma cells, and memory B cells), and the partial pressure of oxygen (PO2) in the corresponding developmental niche of stage-specific B cells is highly dynamic, which suggests that hypoxia and HIF signaling may play an indispensable role in B cell biology. Based on the fact that hypoxia niches exist in the B cell life cycle, this review focuses on recent discoveries about how hypoxia and HIF signaling regulate the development, metabolism, and function of B cells, to facilitate a deep understanding of the role of hypoxia in B cell-mediated adaptive immunity and to provide novel strategies for vaccine adjuvant research and the treatment of immunity-related or infectious diseases.
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Linfocitos B , Hipoxia , Inmunidad Adaptativa , Animales , Linfocitos B/metabolismo , Hipoxia/metabolismo , Mamíferos/metabolismo , Oxígeno/metabolismo , Linfocitos TRESUMEN
Diminishing homeostatic proliferation of memory T cells is essential for improving the efficacy of lymphoablation in transplant recipients. Our previous studies in a mouse heart transplantation model established that B lymphocytes secreting proinflammatory cytokines are critical for T cell recovery after lymphoablation. The goal of the current study was to identify mediators of B cell activation following lymphoablation in allograft recipients. Transcriptome analysis revealed that macrophage-inducible C-type lectin (Mincle, Clec4e) expression is up-regulated in B cells from heart allograft recipients treated with murine anti-thymocyte globulin (mATG). Recipient Mincle deficiency diminishes B cell production of pro-inflammatory cytokines and impairs T lymphocyte reconstitution. Mixed bone marrow chimeras lacking Mincle only in B lymphocytes have similar defects in T cell recovery. Conversely, treatment with a synthetic Mincle ligand enhances T cell reconstitution after lymphoablation in non-transplanted mice. Treatment with agonistic CD40 mAb facilitates T cell reconstitution in CD4 T cell-depleted, but not in Mincle-deficient, recipients indicating that CD40 signaling induces T cell proliferation via a Mincle-dependent pathway. These findings are the first to identify an important function of B cell Mincle as a sensor of damage-associated molecular patterns released by the graft and demonstrate its role in clinically relevant settings of organ transplantation.
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Linfocitos B , Trasplante de Corazón , Aloinjertos , Animales , Linfocitos B/metabolismo , Citocinas/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos , Ratones , Ratones Endogámicos C57BLAsunto(s)
Linfocitos B/metabolismo , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/metabolismo , Antígenos/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Humanos , Memoria Inmunológica , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Vacunas/inmunologíaRESUMEN
Xenotransplantation is a potential solution for the severe shortage of human donor organs and tissues. The generation of humanized animal models attenuates strong innate immune responses, such as complement-mediated hyperacute rejection. However, acute vascular rejection and cell mediated rejection remain primary barriers to xenotransplantation, which limits its clinical application. In this study, we systematically investigated the immunosuppressive effect of LEF using a rat-to-mouse heart xenotransplantation model. SD rat xenogeneic hearts were transplanted into C57BL/6 mice, and survived 34.5 days after LEF treatment. In contrast, BALB/c allogeneic hearts were transplanted into C57BL/6 mice, and survived 31 days after LEF treatment. Compared to normal saline treatment, LEF treatment decreased xenoreactive T cells and CD19+ B cells in recipient splenocytes. Most importantly, LEF treatment protected myocardial cells by decreasing xenoreactive T and B cell infiltration, inflammatory gene expression, and IgM deposition in grafts. In vivo assays revealed that LEF treatment eliminated xenoreactive and alloreactive T and B lymphocytes by suppressing the activation of the NF-κB signaling pathway. Taken together, these observations complement the evidence supporting the potential use of LEF in xenotransplantation.
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Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Leflunamida/uso terapéutico , FN-kappa B/efectos de los fármacos , Trasplante Heterólogo/métodos , Animales , Rechazo de Injerto/patología , Humanos , Tolerancia Inmunológica , Inmunosupresores/farmacología , Leflunamida/farmacología , Masculino , Ratones , Ratas , Transducción de SeñalRESUMEN
Both acute and chronic antibody-mediated allograft rejection (AMR), which are directly mediated by B cells, remain difficult to treat. Long-lived plasma cells (LLPCs) in bone marrow (BM) play a crucial role in the production of the antibodies that induce AMR. However, LLPCs survive through a T cell-independent mechanism and resist conventional immunosuppressive therapy. Desensitization therapy is therefore performed, although it is accompanied by severe side effects and the pathological condition may be at an irreversible stage when these antibodies, which induce AMR development, are detected in the serum. In other words, AMR control requires the development of a diagnostic method that predicts its onset before LLPC differentiation and enables therapeutic intervention and the establishment of humoral immune monitoring methods providing more detailed information, including individual differences in the susceptibility to immunosuppressive agents and the pathological conditions. In this study, we reviewed recent studies related to the direct or indirect involvement of immunocompetent cells in the differentiation of naïve-B cells into LLPCs, the limitations of conventional methods, and the possible development of novel control methods in the context of AMR. This information will significantly contribute to the development of clinical applications for AMR and improve the prognosis of patients who undergo organ transplantation.
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Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Inmunosupresores/uso terapéutico , Aloinjertos/inmunología , Animales , Linfocitos B/metabolismo , Biomarcadores , Activación de Complemento/efectos de los fármacos , Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica , Centro Germinal/inmunología , Centro Germinal/metabolismo , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/metabolismo , Humanos , Memoria Inmunológica/efectos de los fármacos , Inmunosupresores/farmacología , Inmunoterapia , Técnicas de Diagnóstico Molecular/métodos , Terapia Molecular Dirigida/métodos , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Transducción de SeñalRESUMEN
Regulatory B cells (Bregs) have shown promise as anti-rejection therapy applied to organ transplantation. However, less is known about their effect on other B cell populations that are involved in chronic graft rejection. We recently uncovered that naïve B cells, stimulated by TLR ligand agonists, converted into B cells with regulatory properties (Bregs-TLR) that prevented allograft rejection. Here, we examine the granular phenotype and regulatory properties of Breg-TLR cells suppressing B cells. Cocultures of Bregs-TLR with LPS-activated B cells showed a dose-dependent suppression of targeted B cell proliferation. Adoptive transfers of Bregs-TLR induced a decline in antibody responses to antigenically disparate skin grafts. The role of Breg BCR specificity in regulation was assessed using B cell-deficient mice replenished with transgenic BCR (OB1) and TCR (OT-II) lymphocytes of matching antigenic specificity. Results indicated that proliferation of OB1 B cells, mediated through help from CD4+ OT-II cells, was suppressed by OB1 Bregs of similar specificity. Transcriptomic analyses indicated that Bregs-TLR suppression is associated with a block in targeted B cell differentiation controlled by PRDM1 (Blimp1). This work uncovered the regulatory properties of a new brand of Breg cells and provided mechanistic insights into potential applications of Breg therapy in transplantation.
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Linfocitos B Reguladores , Traslado Adoptivo , Animales , Técnicas de Cocultivo , Activación de Linfocitos , RatonesRESUMEN
Antibody repertoire sequencing enables researchers to acquire millions of B cell receptors and investigate these molecules at the single-nucleotide level. This power and resolution in studying humoral responses have led to its wide applications. However, most of these studies were conducted with a limited number of samples. Given the extraordinary diversity, assessment of these key features with a large sample set is demanded. Thus, we collect and systematically analyze 2,152 high-quality heavy-chain antibody repertoires. Our study reveals that 52 core variable genes universally contribute to more than 99% of each individual's repertoire; a distal interspersed preferences characterize V gene recombination; the number of public clones between two repertoires follows a linear model, and the positive selection dominates at RGYW motif in somatic hypermutations. Thus, this population-level analysis resolves some critical features of the antibody repertoire and may have significant value to the large cadre of scientists.
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Anticuerpos Antineoplásicos/inmunología , Biología/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Receptores de Antígenos de Linfocitos B/metabolismo , Recombinación V(D)J/inmunología , Conjuntos de Datos como Asunto , HumanosRESUMEN
The microbiota plays a major role in the regulation of the host immune functions thus establishing a symbiotic relationship that maintains immune homeostasis. Among immune cells, regulatory B cells (Bregs), which can inhibit effector T cell responses, may be involved in the intestinal homeostasis. Recent works suggest that the interaction between the microbiota and Bregs appears to be important to limit autoimmune diseases and help to maintain tolerance in transplantation. Short-chain fatty acids (SCFAs), recognized as major metabolites of the microbiota, seem to be involved in the generation of a pro-tolerogenic environment in the gut, particularly through the regulation of B cell differentiation, limiting mature B cells and promoting the function of Bregs. In this review, we show that this B cells-microbiota interaction may open a path toward new potential therapeutic applications not only for patients with autoimmune diseases but also in transplantation.
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Linfocitos B Reguladores , Microbiota , Humanos , Tolerancia Inmunológica , Activación de Linfocitos , Linfocitos TRESUMEN
Following solid organ transplantation, a substantial proportion of chronic allograft loss is attributed to the formation of donor-specific antibodies (DSAs) and antibody-mediated rejection (AbMR). The frequency and phenotype of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells is altered in the setting of kidney transplantation, particularly in patients who develop AbMR. However, the roles of Tfh and Tfr cells in AbMR after solid organ transplantation is unclear. We developed mouse models to inducibly and potently perturb Tfh and Tfr cells to assess the roles of these cells in the development of DSA and AbMR. We found that Tfh cells are required for both de novo DSA responses as well as augmentation of DSA following presensitization. Using orthotopic allogeneic kidney transplantation models, we found that deletion of Tfh cells at the time of transplantation resulted in less severe transplant rejection. Furthermore, using inducible Tfr cell deletion strategies we found that Tfr cells inhibit de novo DSA formation but only have a minor role in controlling kidney transplant rejection. These studies demonstrate that Tfh cells promote, whereas Tfr cells inhibit, DSA to control rejection after kidney transplantation. Therefore, targeting these cells represent a new therapeutic strategy to prevent and treat AbMR.