RESUMEN
Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.
Asunto(s)
Antígeno de Maduración de Linfocitos B , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Mieloma Múltiple , Polimorfismo de Nucleótido Simple , Mieloma Múltiple/genética , Humanos , Antígeno de Maduración de Linfocitos B/genética , Análisis de la Aleatorización Mendeliana , Linfocitos B/inmunología , Linfocitos B/metabolismo , Estudios de Casos y Controles , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Masculino , Telómero/genéticaRESUMEN
Antibody-producing plasma cells fuel humoral immune responses. They also contribute to autoimmune diseases such as systemic lupus erythematosus or IgA nephropathy. Interleukin-6 and the tumor necrosis factor (TNF) family ligands BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) participate in plasma cell survival. BAFF binds to three receptors, BAFFR (BAFF receptor), TACI (transmembrane activator and CAML interactor), and BCMA (B cell maturation antigen), while APRIL binds to TACI, BCMA, and proteoglycans. However, which ligand-receptor pair(s) are required to maintain plasma cells in different body locations remains unknown. Here, by combining mouse genetic and pharmacological approaches, we found that plasma cells required BCMA and/or TACI but not BAFFR. BCMA responded exclusively to APRIL, while TACI responded to both BAFF and APRIL, identifying three self-sufficient ligand-receptor pairs for plasma cell maintenance: BAFF-TACI, APRIL-TACI, and APRIL-BCMA. Together, these actors accounted for 90% of circulating antibodies. In BAFF-ko mice, the reduction of plasma cells upon APRIL inhibition indicated that APRIL could function in the absence of BAFF-APRIL heteromers. No evidence was found that in the absence of BCMA and TACI, binding of APRIL to proteoglycans would help maintain plasma cells. IL-6, alone or together with BAFF and APRIL, supported mainly splenic plasmablasts and plasma cells and contributed to circulating IgG but not IgA levels. In conclusion, survival factors for plasma cells can vary with body location and with the antibody isotype that plasma cells produce. To efficiently target plasma cells, in particular IgA-producing ones, dual inhibition of BAFF and APRIL is required.
Asunto(s)
Factor Activador de Células B , Receptor del Factor Activador de Células B , Antígeno de Maduración de Linfocitos B , Interleucina-6 , Proteína Activadora Transmembrana y Interactiva del CAML , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Animales , Factor Activador de Células B/inmunología , Factor Activador de Células B/metabolismo , Factor Activador de Células B/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Antígeno de Maduración de Linfocitos B/inmunología , Antígeno de Maduración de Linfocitos B/metabolismo , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismo , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Proteína Activadora Transmembrana y Interactiva del CAML/inmunología , Interleucina-6/metabolismo , Interleucina-6/inmunología , Ratones , Receptor del Factor Activador de Células B/metabolismo , Receptor del Factor Activador de Células B/inmunología , Receptor del Factor Activador de Células B/genética , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Ratones Noqueados , Células Productoras de Anticuerpos/inmunología , Células Productoras de Anticuerpos/metabolismo , Ratones Endogámicos C57BLRESUMEN
TNFRSF13B mutations are widely associated with common variable immunodeficiency. TNFRSF13B was recently counted among relevant genes associated with childhood-onset of hematological malignancies; nonetheless, its role in acute myeloid leukemia (AML) remains unexplored. We report the study of a family with two cases of AML, sharing a germline TNFRSF13B mutation favoring the formation of a more stable complex with its ligand TNFSF13: a positive regulator of AML-initiating cells. Our data turn the spotlight onto the TNFRSF13B role in AML onset, inserting a new fragment into the complex scenario of a hereditary predisposition to myeloid neoplasms.
Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Niño , Mutación , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/genética , Leucemia Mieloide Aguda/genética , Proteína Activadora Transmembrana y Interactiva del CAML/genéticaRESUMEN
Cytomegalovirus (CMV) infection is the most frequent infection episode in kidney transplant (KT) recipients. Reactivation usually occurs in the first three months after transplantation and is associated with higher cellular and/or antibody-mediated rejection rates and poorer graft performance. CMV induces the expression of BAFF (B-cell-activating factor, a cytokine involved in the homeostasis of B cells), which communicates signals for survival and growth to B cells and virus-specific plasma cells via the R-BAFF (BAFF receptor), TACI (the calcium modulator, the cyclophilin ligand interactor), and BCMA (B cell maturation antigen) receptors. These molecules of the BAFF system have also been suggested as biomarkers for the development of alloantibodies and graft dysfunction. This prospective study included 30 CMV-IgG seropositive KT recipients. The expression levels of the genes BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA) in peripheral blood leukocytes (PBL) pre-KT were determined using qPCR. qPCR was also used to monitor CMV reactivation in the first three months following KT. The remainder of the KT recipients were classified as CMV- reactivation, and those with more than 500 copies/mL in at least one sample were classified as CMV+ reactivation. There were no discernible variations in the BAFF-R and TACI transcript expression levels. In the CMV+ group, we examined the relationship between the transcript levels and peak viremia. Peak viremia levels and BCMA transcript levels showed a strong correlation. BAFF-R and TACI expressions showed no measurable differences. In patients with early CMV reactivation, high BCMA receptor expression was associated with increased plasmablast, lymphocyte B cell class-switched levels (LBCS), and viral load. Our findings demonstrate that pre-KT BCMA transcript levels increased in KT recipients with early CMV reactivation. These transcript levels positively correlate with peak viremia and weakly with plasmablast and LBCS levels in PBLs.
Asunto(s)
Antígeno de Maduración de Linfocitos B , Citomegalovirus , Humanos , Antígeno de Maduración de Linfocitos B/genética , Antígeno de Maduración de Linfocitos B/metabolismo , Estudios Prospectivos , Viremia , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Factor Activador de Células B/genética , Inmunoglobulina GRESUMEN
While many of the genes and molecular pathways in the germinal center B cell response which initiate protective antibody production are known, the contributions of individual molecular players in terminal B cell differentiation remain unclear. We have previously investigated how mutations in TACI gene, noted in about 10% of patients with common variable immunodeficiency, impair B cell differentiation and often, lead to lymphoid hyperplasia and autoimmunity. Unlike mouse B cells, human B cells express TACI-L (Long) and TACI-S (Short) isoforms, but only TACI-S promotes terminal B cell differentiation into plasma cells. Here we show that the expression of intracellular TACI-S increases with B cell activation, and colocalizes with BCMA and their ligand, APRIL. We show that the loss of APRIL impairs isotype class switch and leads to distinct metabolic and transcriptional changes. Our studies suggest that intracellular TACI-S and APRIL along with BCMA direct long-term PC differentiation and survival.
Asunto(s)
Antígeno de Maduración de Linfocitos B , Proteína Activadora Transmembrana y Interactiva del CAML , Ratones , Animales , Humanos , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Linfocitos B , Células Plasmáticas , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Factor Activador de Células BRESUMEN
The BAFF/APRIL-system with the two cytokines BAFF and APRIL and their three receptors, transmembrane activator and CAML interactor (TACI), BAFF receptor, and B-cell maturation Ag, is important for B cell maintenance. The BAFF/APRIL system is a therapeutic target in B cell-derived malignancies and autoimmune diseases. However, unexpected outcomes of clinical trials with atacicept (TACI-Fc) underline our incomplete understanding of this system. Shedding of the three receptors is one important regulatory element. In humans, TACI exists in two isoforms generated through alternative splicing in their extracellular portion: TACI-long (l) has two cysteine-rich domains, whereas TACI-short (s) lacks the first low-affinity one. In this study, we discriminated soluble (s) forms of TACI-l and TACI-s with newly generated mAbs and found that both were spontaneously released from activated human B cells, with a predominance of sTACI-l. Furthermore, sTACI-l was also the dominant isoform in human serum. Vaccination with the mRNA vaccine from BioNTech does not significantly affect the serum levels of sTACI-l. Both TACI-s and TACI-l were shed by a disintegrin and metalloproteinase domain-containing protein 10. TACI-l and TACI-s formed homo- and hetero-oligomers in soluble and membrane-bound forms. Both sTACI-l and sTACI-s acted as decoy receptors for BAFF, but only sTACI-l also efficiently inhibited APRIL. Dimerization of sTACI-l enhanced its decoy functions only slightly. Together, we extend our knowledge of the complexity of the BAFF/APRIL system by identifying and characterizing the two soluble isoforms of TACI.
Asunto(s)
Linfocitos B , Proteína Activadora Transmembrana y Interactiva del CAML , Humanos , Empalme Alternativo , Factor Activador de Células B/metabolismo , Receptor del Factor Activador de Células B/genética , Citocinas/genética , Isoformas de Proteínas/genética , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismoRESUMEN
BACKGROUND: The pathogenesis of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) remains still inconclusive. Recent studies identified an increased expression of BAFF (a B cell-activating factor) and its receptor TACI (Transmembrane Activator and cAML Interactor) in nasal polyp samples, while TNFRSF13B/TACI mutations have been found in patients with benign lymphoproliferative disorders and primary antibody deficiencies. OBJECTIVE: The aim of our study was to evaluate the possible contribution of TNFRSF13B/TACI mutations in CRSwNP pathogenesis. METHODS: Forty-four (44) patients with CRSwNP (male/female: 33/11, mean age: 52.5 years, range: 16-83) were analyzed for TNFRSF13B/TACI mutations by PCR-sequencing. RESULTS: No pathogenic TNFRSF13B/TACI mutations were identified in our cohort study of CRSwNP patients. We detected two common missense mutations (p.P251L and p.V220A), along with other common silent mutations and intronic polymorphisms in an identical prevalence to healthy control population. CONCLUSION: TNFRSF13B/TACI mutations might not play a role in the pathogenesis of CRSwNP.
Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Proteína Activadora Transmembrana y Interactiva del CAML , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Crónica , Estudios de Cohortes , Mutación , Pólipos Nasales/genética , Rinitis/genética , Sinusitis/genética , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Adolescente , Adulto Joven , Adulto , Anciano , Anciano de 80 o más AñosRESUMEN
Antibodies directed against organ transplants are thought to pose the most vexing hurdle to enduring function and survival of the transplants, particularly organ xenotransplants, and accordingly basic and clinical investigation has focused on elucidating the specificity and pathogenicity of graft-specific antibodies. While much has been learned about these matters, far less is known about the B cells producing graft-specific antibodies and why these antibodies appear to injure some grafts but not others. With the goal of addressing those questions, we have investigated the properties of tumor necrosis factor receptor super family-13B (TNFRSF13B), which regulates various aspects of B cell responses. A full understanding of the functions of TNFRSF13B however is hindered by extreme polymorphism and by diversity of interactions of the protein. Nevertheless, TNFRSF13B variants have been found to exert distinct impact on natural and elicited antibody responses and host defense and mutations of TNFRSF13B have been found to influence the propensity for development of antibody-mediated rejection of organ transplants. Because B cell responses potentially limit application of xenotransplantation, understanding how TNFRSF13B diversity and TNFRSF13B variants govern immunity in xenotransplantation could inspire development of novel therapeutics that could in turn accelerate clinical implementation of xenotransplantation.
Asunto(s)
Linfocitos B , Trasplante de Órganos , Humanos , Polimorfismo Genético , Mutación , Anticuerpos , Trasplante Heterólogo , Rechazo de Injerto/genética , Proteína Activadora Transmembrana y Interactiva del CAML/genéticaRESUMEN
AIM: Immune pathogenesis of nephrotic syndrome (NS) is not completely understood. We aimed to evaluate the expression of B-cell activating factor (BAFF) and its receptors in renal samples from pediatric NS patients and its relationship with renal function survival. MATERIALS AND METHODS: We conducted an ambispective study on 33 patients with pediatric NS. Immunohistochemistry for BAFF, TACI, BCMA and BR3 was performed. Markers were evaluated on podocytes and interstitial inflammatory infiltrates (III). We performed Kaplan-Meier curves to describe renal function survival according to markers' expression. RESULTS: Thirty-three NS patients were included. Minimal change disease was seen in 21 (63.6%) patients, and focal segmental glomerulosclerosis in 12 (36.4%). BAFF was found in podocytes (18.2% of samples) and III (36.4% of samples), BAFF-R in one sample, TACI in 4 (podocytes and III), and BCMA in 5 samples of podocytes and 7 of III. BAFF on podocytes and III was associated with worst renal function at follow-up; those patients had 25% probability of having GFR >90 mL/min/1.73m2, versus 84.9% when absent (p = 0.0067). Patients with BAFF in III had 42.9% probability of having GFR>90 mL/min/1.73 m2, versus 94.1% when absent (p = 0.0063). CONCLUSION: BAFF expression in renal biopsies could be a prognostic factor for renal function.
Asunto(s)
Factor Activador de Células B , Síndrome Nefrótico , Humanos , Niño , Factor Activador de Células B/metabolismo , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Antígeno de Maduración de Linfocitos B , Interleucina-4 , Biomarcadores , PronósticoRESUMEN
The role of B-cell-activating factor (BAFF) in B-lymphocyte biology has been comprehensively studied, but its contributions to innate immunity remain unclear. Natural killer (NK) cells form the first line of defense against viruses and tumors, and have been shown to be defective in patients with systemic lupus erythematosus (SLE). The link between BAFF and NK cells in the development and progression of SLE remains unstudied. By assessing NK cell numbers in wild-type (WT), BAFF-/- (BAFF deficient), BAFF-R-/- (BAFF receptor deficient), TACI-/- (transmembrane activator and calcium modulator and cyclophilin ligand interactor deficient), BCMA-/- (B-cell maturation antigen deficient) and BAFF transgenic (Tg) mice, we observed that BAFF signaling through BAFF-R was essential for sustaining NK cell numbers in the spleen. However, according to the cell surface expression of CD27 and CD11b on NK cells, we found that BAFF was dispensable for NK cell maturation. Ex vivo and in vivo models showed that NK cells from BAFF-/- and BAFF Tg mice produced interferon-γ and killed tumor cells at a level similar to that in WT mice. Finally, we established that NK cells do not express receptors that interact with BAFF in the steady state or in the BAFF Tg mouse model of SLE. Our findings demonstrate that BAFF has an indirect effect on NK cell homeostasis and no effect on NK cell function.
Asunto(s)
Lupus Eritematoso Sistémico , Proteína Activadora Transmembrana y Interactiva del CAML , Ratones , Animales , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Densidad de Población , Interleucina-4 , Ratones Transgénicos , Células Asesinas Naturales/metabolismoRESUMEN
In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations.
Asunto(s)
Inmunodeficiencia Variable Común , Proteína Activadora Transmembrana y Interactiva del CAML , Linfocitos B , Proliferación Celular , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/metabolismo , Humanos , Ligandos , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismoRESUMEN
B cell-activating factor (BAFF) binds the three receptors BAFF-R, BCMA, and TACI, predominantly expressed on mature B cells. Almost all B cell cancers are reported to express at least one of these receptors. Here we develop a BAFF ligand-based chimeric antigen receptor (CAR) and generate BAFF CAR-T cells using a non-viral gene delivery method. We show that BAFF CAR-T cells bind specifically to each of the three BAFF receptors and are effective at killing multiple B cell cancers, including mantle cell lymphoma (MCL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL), in vitro and in vivo using different xenograft models. Co-culture of BAFF CAR-T cells with these tumor cells results in induction of activation marker CD69, degranulation marker CD107a, and multiple proinflammatory cytokines. In summary, we report a ligand-based BAFF CAR-T capable of binding three different receptors, minimizing the potential for antigen escape in the treatment of B cell cancers.
Asunto(s)
Factor Activador de Células B/genética , Receptor del Factor Activador de Células B/genética , Antígeno de Maduración de Linfocitos B/genética , Linfoma de Células del Manto/terapia , Mieloma Múltiple/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Factor Activador de Células B/inmunología , Receptor del Factor Activador de Células B/inmunología , Antígeno de Maduración de Linfocitos B/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Activación de Linfocitos , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/patología , Proteína 1 de la Membrana Asociada a los Lisosomas/genética , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Masculino , Ratones , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Unión Proteica , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/trasplante , Proteína Activadora Transmembrana y Interactiva del CAML/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Genetic variants in PIK3CD, PIK3R1 and NFKB1 cause the primary immune deficiencies, activated PI3Kδ syndrome (APDS) 1, APDS2 and NFκB1 haploinsufficiency, respectively. We have identified a family with known or potentially pathogenic variants NFKB1, TNFRSF13B and PIK3R1. The study's aim was to describe their associated immune and cellular phenotypes and compare with individuals with monogenic disease. NFκB1 pathway function was measured by immunoblotting and PI3Kδ pathway activity by phospho-flow cytometry. p105/p50 expression was absent in two individuals but elevated pS6 only in the index case. Transfection of primary T cells demonstrated increased basal pS6 signalling due to mutant PIK3R1, but not mutant NFKB1 or their wildtype forms. We report on the presence of pathogenic variant NFKB1, with likely modifying variants in TNFRSF13B and PIK3R1 in a family. We describe immune features of both NFκB1 haploinsufficiency and APDS2, and the inhibition of excessive PI3K signalling by rapamycin in vitro.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ia/genética , Haploinsuficiencia , Síndromes de Inmunodeficiencia/genética , Subunidad p50 de NF-kappa B/genética , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Adolescente , Adulto , Femenino , Humanos , Síndromes de Inmunodeficiencia/etiología , Síndromes de Inmunodeficiencia/inmunología , Masculino , Mutación , Adulto JovenRESUMEN
Our understanding of inflammatory bowel disease is changing as we identify genetic variants associated with immune dysregulation. Inflammatory bowel disease undetermined, even when diagnosed in older children and adolescents, in the setting of multiple inflammatory and infectious diseases should raise the suspicion of complex immune dysregulation with a monogenic basis. We report a case of inflammatory bowel disease undetermined triggered by exposure to a nonsteroidal antiinflammatory drug in a 16-year-old girl with a background history of juvenile idiopathic arthritis, cytopenias, recurrent respiratory tract and middle ear infections, and esophageal candidiasis. Immunologic assessment included measurement of immunoglobulin levels, lymphocyte immunophenotyping, B-cell functional tests, and whole-exome sequencing. Laboratory investigation revealed defects of humoral immunity, including mild persistent hypogammaglobulinemia affecting all 3 isotypes and absent isohemagglutinins. Whole exome sequencing revealed a heterozygous TNFRSF13B (Tumor Necrosis Factor Receptor Superfamily Member 13B, or Transmembrane Activator and Calcium-modulating cyclophilin ligand Interactor, TACI) gene variant, which is associated with common variable immunodeficiency and the development of autoimmune diseases. In conclusion, a clinical history of recurrent infections, atypical histologic features of inflammatory bowel disease, additional autoimmune manifestations, and an inadequate response to conventional therapy should prompt the physician to refer to an immunologist with the query of inborn error of immunity. We report how extensive immune evaluation and genetic diagnosis can individualize care and facilitate a multidisciplinary team approach.
Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Inflamatorias del Intestino/genética , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Adolescente , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/inmunología , Antiinflamatorios no Esteroideos/efectos adversos , Artritis Juvenil/diagnóstico , Enfermedades Autoinmunes/inmunología , Celecoxib/efectos adversos , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Femenino , Heterocigoto , Humanos , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/inmunología , Secuenciación del ExomaRESUMEN
Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNF receptor superfamily member 13B (TNFRSF13B) variants, which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells' functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of those with antibody-mediated rejection (AMR) but fewer than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses, we investigated alloimmunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice were not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased "natural" IgM and compromised complement regulation, leading to complement deposition in allografted hearts and autogenous kidneys. Thus, WT TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhance morbidity associated with immune responses.
Asunto(s)
Linfocitos B/inmunología , Rechazo de Injerto/genética , Inmunidad Innata , Isoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Mutación Missense , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Animales , Linfocitos B/patología , ADN/genética , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Femenino , Genotipo , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Humanos , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismoRESUMEN
TACI promotes T-cell independent antibody responses and plasma cell differentiation and counteracts BAFF driven B-cell activation. Mutations in TNFRSF13B (encoding TACI) are associated with common variable immunodeficiency (CVID) but are also found in 1-2% of the general population. Although not diseases causing, certain TNFRSF13B mutations predispose CVID patients to autoimmunity and lymphoproliferation. Recently, studies of TACI-deficient humans and murine models revealed novel aspects of TACI, especially its crosstalk with the TLR pathways, differential expression of TACI isoforms, and its role in the generation of autoreactive B-cells. Vice versa, these studies are instrumental for a better understanding of TACI deficiency in humans and suggest that gene dosage, mutation type, and additional clinical or laboratory abnormalities influence the relevance of TNFRSF13B variants in individual CVID patients. TACI is embedded in a complex and well-balanced system, which is vulnerable to genetic and possibly also environmental hits.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/inmunología , Inmunodeficiencia Variable Común/genética , Humanos , Proteína Activadora Transmembrana y Interactiva del CAML/deficiencia , Proteína Activadora Transmembrana y Interactiva del CAML/genéticaRESUMEN
Although fingolimod and interferon-ß are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-ß, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-ß treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-ß and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.
Asunto(s)
Factor Activador de Células B/metabolismo , Subgrupos de Linfocitos B/inmunología , Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Células Precursoras de Linfocitos B/inmunología , Transducción de Señal/efectos de los fármacos , Adulto , Anciano , Factor Activador de Células B/genética , Receptor del Factor Activador de Células B/genética , Receptor del Factor Activador de Células B/metabolismo , Subgrupos de Linfocitos B/efectos de los fármacos , Células Cultivadas , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Interleucina-10/metabolismo , Interleucinas , Masculino , Persona de Mediana Edad , Células Precursoras de Linfocitos B/efectos de los fármacos , ARN Mensajero/genética , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismo , Resultado del TratamientoRESUMEN
Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.
Asunto(s)
Autoinmunidad/genética , Factor Activador de Células B/inmunología , Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Autoinmunidad/inmunología , Factor Activador de Células B/antagonistas & inhibidores , Factor Activador de Células B/genética , Receptor del Factor Activador de Células B/genética , Linfocitos B/inmunología , Quimera , Femenino , Haploinsuficiencia/genética , Inmunosupresores/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/genética , Transducción de Señal/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/inmunologíaRESUMEN
TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.
Asunto(s)
Citrobacter rodentium/inmunología , Colitis/inmunología , Infecciones por Enterobacteriaceae/inmunología , Inmunoglobulina A/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Alelos , Animales , Linfocitos B , Colitis/microbiología , Modelos Animales de Enfermedad , Resistencia a la Enfermedad/genética , Infecciones por Enterobacteriaceae/microbiología , Femenino , Humanos , Inmunoglobulina A/metabolismo , Mutación con Pérdida de Función , Activación de Linfocitos/genética , Masculino , Polimorfismo de Nucleótido Simple/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismoRESUMEN
Immunocompromised patients, including those with inborn errors of immunity (IEI), may be at increased risk for severe or prolonged infections with SARS-CoV-2 (Zhu et al. N Engl J Med. 382:727-33, 2020; Guan et al. 2020; Minotti et al. J Infect. 81:e61-6, 2020). While antibody and T cell responses to SARS-CoV-2 structural proteins are well described in healthy convalescent donors, adaptive humoral and cellular immunity has not yet been characterized in patients with antibody deficiency (Grifoni et al. Cell. 181:1489-1501 e1415, 2020; Burbelo et al. 2020; Long et al. Nat Med. 26:845-8, 2020; Braun et al. 2020). Herein, we describe the clinical course, antibody, and T cell responses to SARS-CoV-2 structural proteins in a cohort of adult and pediatric patients with antibody deficiencies (n = 5) and controls (related and unrelated) infected with SARS-CoV-2. Five patients within the same family (3 with antibody deficiency, 2 immunocompetent controls) showed antibody responses to nucleocapsid and spike proteins, as well as SARS-CoV-2 specific T cell immunity at days 65-84 from onset of symptoms. No significant difference was identified between immunocompromised patients and controls. Two additional unrelated, adult patients with common variable immune deficiency were assessed. One did not show antibody response, but both demonstrated SARS-CoV-2-specific T cell immunity when evaluated 33 and 76 days, respectively, following SARS-CoV-2 diagnosis. This report is the first to show robust T cell activity and humoral immunity against SARS-CoV-2 structural proteins in some patients with antibody deficiency. Given the reliance on spike protein in most candidate vaccines (Folegatti et al. Lancet. 396:467-78, 2020; Jackson et al. N Engl J Med. 383:1920-31, 2020), the responses are encouraging. Additional studies will be needed to further define the timing of onset of immunity, longevity of the immune response, and variability of response in immunocompromised patients.