RESUMEN
B lymphocytes were originally described as a cell type uniquely capable of secreting Abs. The importance of T cell help in Ab production was revealed soon afterward. Following these seminal findings, investigators made great strides in delineating steps in the conventional pathway that B cells follow to produce high-affinity Abs. These studies revealed generalized, or canonical, features of B cells that include their developmental origin and paths to maturation, activation, and differentiation into Ab-producing and memory cells. However, along the way, examples of nonconventional B cell populations with unique origins, age-dependent development, tissue localization, and effector functions have been revealed. In this brief review, features of B-1a, B-1b, marginal zone, regulatory, killer, NK-like, age-associated, and atypical B cells are discussed. Emerging work on these noncanonical B cells and functions, along with the study of their significance for human health and disease, represents an exciting frontier in B cell biology.
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Linfocitos B , Linfocitos T , Humanos , Linfocitos T/metabolismo , Tejido LinfoideRESUMEN
INTRODUCTION: Post-traumatic stress disorder occurs in parents of infants with CHD, contributing to psychological distress with detrimental effects on family functioning and well-being. We sought to determine the prevalence and factors associated with post-traumatic stress disorder symptoms in parents whose infants underwent staged palliation for single ventricle heart disease. MATERIALS AND METHODS: A large longitudinal multi-centre cohort study evaluated 215 mothers and fathers for symptoms of post-traumatic stress disorder at three timepoints, including post-Norwood, post-Stage II, and a final study timepoint when the child reached approximately 16 months of age, using the self-report questionnaire Impact of Event Scale - Revised. RESULTS: The prevalence of probable post-traumatic stress disorder post-Norwood surgery was 50% of mothers and 39% of fathers, decreasing to 27% of mothers and 24% of fathers by final follow-up. Intrusive symptoms such as flashbacks and nightmares and hyperarousal symptoms such as poor concentration, irritability, and sudden physical symptoms of racing heart and difficulty breathing were particularly elevated in parents. Higher levels of anxiety, reduced coping, and decreased satisfaction with parenting were significantly associated with symptoms of post-traumatic stress disorder in parents. Demographic and clinical variables such as parent education, pre-natal diagnosis, medical complications, and length of hospital stay(s) were not significantly associated with symptoms of post-traumatic stress disorder. DISCUSSION: Parents whose infants underwent staged palliation for single ventricle heart disease often reported symptoms of post-traumatic stress disorder. Symptoms persisted over time and routine screening might help identify parents at-risk and prompt referral to appropriate supports.
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Cardiopatías , Trastornos por Estrés Postraumático , Niño , Femenino , Lactante , Humanos , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiología , Prevalencia , Estudios de Cohortes , Padres/psicología , Cardiopatías/complicaciones , Estrés Psicológico/psicologíaRESUMEN
We previously reported monophosphoryl lipid A (MPL) and synthetic cord factor trehalose-6,6'-dicorynomycolate (TDCM) significantly increase Ab responses to T cell-independent type 2 Ags (TI-2 Ags) in a manner dependent on B cell-intrinsic TLR4 expression, as well as MyD88 and TRIF proteins. Given the capacity of MPL to drive type I IFN production, we aimed to investigate the extent to which type I IFN receptor (IFNAR) signaling was required for TI-2 responses and adjuvant effects. Using Ifnar1-/- mice and IFNAR1 Ab blockade, we found that IFNAR signaling is required for optimal early B cell activation, expansion, and Ab responses to nonadjuvanted TI-2 Ags, including the pneumococcal vaccine. Further study demonstrated that B cell-intrinsic type I IFN signaling on B cells was essential for normal TI-2 Ab responses. In particular, TI-2 Ag-specific B-1b cell activation and expansion were significantly impaired in Ifnar1-/- mice; moreover, IFNAR1 Ab blockade similarly reduced activation, expansion, and differentiation of IFNAR1-sufficient B-1b cells in Ifnar1-/- recipient mice, indicating that B-1b cell-expressed IFNAR supports TI-2 Ab responses. Consistent with these findings, type I IFN significantly increased the survival of TI-2 Ag-activated B-1b cells ex vivo and promoted plasmablast differentiation. Nonetheless, MPL/TDCM adjuvant effects, which were largely carried out through innate B cells (B-1b and splenic CD23- B cells), were independent of type I IFN signaling. In summary, our study highlights an important role for B-1b cell-expressed IFNAR in promoting responses to nonadjuvanted TI-2 Ags, but it nonetheless demonstrates that adjuvants which support innate B cell responses may bypass this requirement.
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Formación de Anticuerpos , Linfocitos B , Ratones , Animales , Antígenos , Polisacáridos , Receptores de Antígenos de Linfocitos B , Adyuvantes Inmunológicos , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
Patient engagement in research, a collaborative practice of including patients and families as active and respected partners in the research process, leads to improved quality of patient care and positively affects outcomes for patients and families. There is strong support for the benefits of patient engagement. What is less clear are the methods by which organizations can achieve authentic patient engagement in research and the ways a committee structure can support an institutional research engagement need beyond the individual investigators. In this report, we describe the mechanisms needed to support the implementation of a research-focused patient engagement strategy and lessons learned from the patient and family perspective.
Patient engagement in research is a way of working in partnership with patients and members of the public to plan, manage, design and carry out health research, leading to improved patient care. Extensive research has been published on the practices individual research teams can use to positively engage patients and families in research. A current gap in existing research is the methods health care organization can use to achieve authentic patient engagement. In this report, we describe the implementation of a research-focused patient engagement strategy and the lessons learned from the patients and families involved in developing the strategy.
RESUMEN
Age-related muscle mass and strength decline (sarcopenia) impairs the performance of daily living activities and can lead to mobility disability/limitation in older adults. Biological pathways in muscle that lead to mobility problems have not been fully elucidated. Immunoglobulin G (IgG) infiltration in muscle is a known marker of increased fiber membrane permeability and damage vulnerability, but whether this translates to impaired function is unknown. Here, we report that IgG1 and IgG4 are abundantly present in the skeletal muscle (vastus lateralis) of ~ 50% (11 out of 23) of older adults (> 65 years) examined. Skeletal muscle IgG1 was inversely correlated with physical performance (400 m walk time: r = 0.74, p = 0.005; SPPB score: r = - 0.73, p = 0.006) and muscle strength (r = - 0.6, p = 0.05). In a murine model, IgG was found to be higher in both muscle and blood of older, versus younger, C57BL/6 mice. Older mice with a higher level of muscle IgG had lower motor activity. IgG in mouse muscle co-localized with cardiac troponin T (cTnT) and markers of complement activation and apoptosis/necroptosis. Skeletal muscle-inducible cTnT knockin mice also showed elevated IgG in muscle and an accelerated muscle degeneration and motor activity decline with age. Most importantly, anti-cTnT autoantibodies were detected in the blood of cTnT knockin mice, old mice, and older humans. Our findings suggest a novel cTnT-mediated autoimmune response may be an indicator of sarcopenia.
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Sarcopenia , Troponina T , Humanos , Ratones , Animales , Anciano , Troponina T/metabolismo , Autoinmunidad , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Limitación de la Movilidad , Biomarcadores/metabolismo , Inmunoglobulina G/metabolismoRESUMEN
The inability of T cell-independent type 2 (TI-2) Ags to induce recall responses is a poorly understood facet of humoral immunity, yet critically important for improving vaccines. Using normal and VHB1-8 transgenic mice, we demonstrate that B cell-intrinsic PD-1 expression negatively regulates TI-2 memory B cell (Bmem) generation and reactivation in part through interacting with PDL1 and PDL2 on non-Ag-specific cells. We also identified a significant role for PDL2 expression on Bmems in inhibiting reactivation and Ab production, thereby revealing a novel self-regulatory mechanism exists for TI-2 Bmems This regulation impacts responses to clinically relevant vaccines, because PD-1 deficiency was associated with significantly increased Ab boosting to the pneumococcal vaccine after both vaccination and infection. Notably, we found a B cell-activating adjuvant enabled even greater boosting of protective pneumococcal polysaccharide-specific IgG responses when PD-1 inhibition was relieved. This work highlights unique self-regulation by TI-2 Bmems and reveals new opportunities for significantly improving TI-2 Ag-based vaccine responses.
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Linfocitos B/inmunología , Infecciones Neumocócicas/inmunología , Vacunas Neumococicas/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/inmunología , Animales , Antígeno B7-H1/metabolismo , Homeostasis , Inmunidad Humoral , Inmunogenicidad Vacunal , Memoria Inmunológica , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Unión Proteica , Transducción de SeñalRESUMEN
CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC-/-HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted.
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Autoinmunidad , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Enfermedad Injerto contra Huésped/inmunología , Glicoproteínas de Membrana/inmunología , Animales , Linfocitos B/patología , Linfocitos T CD4-Positivos/patología , Diferenciación Celular/genética , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Humanos , Memoria Inmunológica/genética , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
The roles distinct B cell subsets play in clonal expansion, isotype switching, and memory B cell differentiation in response to T cell-independent type 2 Ags (TI-2 Ags) has been understudied. Using sorted B cells from VHB1-8 knock-in mice, we evaluated B-1b, marginal zone, and follicular B cell responses to the TI-2 Ag, NP-Ficoll. All subsets extensively divided in response to NP-Ficoll. Nonetheless, B-1b cells exhibited significantly increased IgG switching and differentiation into Ab-secreting cells (ASC)-a finding that coincided with increased AgR signaling capacity and Blimp1 expression by B-1b cells. All subsets formed memory cells and expressed markers previously identified for T cell-dependent memory B cells, including CD80, PDL2, and CD73, although B-1b cells generated the greatest number of memory cells with higher frequencies of IgG- and CD80-expressing cells. Despite memory formation, secondary immunization 4 wk after primary immunization did not increase NP-specific IgG. However, boosting occurred in B-1b cell-recipient mice when IgG levels declined. CD80+ memory B-1b cells divided, class switched, and differentiated into ASC in response to Ag in vivo, but this was inhibited in the presence of NP-specific IgG. Furthermore, CD80 blockade significantly increased memory B-1b cell division and differentiation to ASC upon Ag restimulation. Collectively, these findings demonstrate B-1b, marginal zone B, and follicular B subsets significantly contribute to the TI-2 Ag-specific memory B cell pool. In particular, we show B-1b cells generate a functional CD80-regulated memory population that can be stimulated to divide and differentiate into ASC upon Ag re-encounter when Ag-specific IgG levels decline.
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Subgrupos de Linfocitos B/inmunología , Memoria Inmunológica/inmunología , Linfocitos T/inmunología , Animales , Antígenos T-Independientes/inmunología , Antígeno B7-1/inmunología , Diferenciación Celular/inmunología , División Celular/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina G/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/inmunologíaRESUMEN
Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous studies demonstrated a toll-like receptor 4 (TLR4) and C-type lectin receptor (CLR; Mincle/MCL) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits peritoneal tumor growth and ascites development through a mechanism dependent upon B1a cell-produced natural IgM, complement, and phagocytes. In the current study, we investigated the requirement for TLR4 and Fc receptor common γ chain (FcRγ), required for Mincle/MCL signaling, in the MPL/TDCM-elicited response. MPL/TDCM significantly increased macrophages and Ly6Chi monocytes in the peritoneal cavity of both TLR4-/- and FcRγ-/- mice, suggesting redundancy in the signals required for monocyte/macrophage recruitment. However, B1 cell activation, antibody secreting cell differentiation, and tumor-reactive IgM production were defective in TLR4-/-, but not FcRγ-/- mice. TRIF was required for production of IgM reactive against tumor- and mucin-related antigens, but not phosphorylcholine, whereas TLR4 was required for production of both types of reactivities. Consistent with this, B1 cells lacking TLR4 or TRIF did not proliferate or differentiate into tumor-reactive IgM-producing cells in vitro and did not reconstitute MPL/TDCM-dependent protection against peritoneal carcinomatosis in CD19-/- mice. Our results indicate a TLR4/TRIF-dependent pathway is required by B1 cells for MPL/TDCM-elicited production of protective tumor-reactive natural IgM. The dependency on TRIF signaling for tumor-reactive, but not phosphorylcholine-reactive, IgM production reveals unexpected heterogeneity in TLR4-dependent regulation of natural IgM production, thereby highlighting important differences to consider when designing vaccines or therapies targeting these specificities.
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Proteínas Adaptadoras del Transporte Vesicular/fisiología , Subgrupos de Linfocitos B/inmunología , Factores Cordón/administración & dosificación , Inmunoglobulina M/inmunología , Lípido A/análogos & derivados , Neoplasias Peritoneales/inmunología , Receptor Toll-Like 4/fisiología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Subgrupos de Linfocitos B/efectos de los fármacos , Lípido A/administración & dosificación , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/fisiología , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/patologíaRESUMEN
Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous study demonstrated a Toll-like receptor and C-type lectin receptor agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development following TA3-Ha and EL4 challenge through a mechanism dependent on B-1a cell-produced natural IgM and complement. In this study, we investigated additional players in the MPL/TDCM-elicited response. MPL/TDCM treatment rapidly increased type I IFN levels in the peritoneal cavity along with myeloid cell numbers, including macrophages and Ly6Chi monocytes. Type I IFN receptor (IFNAR1-/-) mice produced tumor-reactive IgM following MPL/TDCM treatment, but failed to recruit Ly6C+ monocytes and were not afforded protection during tumor challenges. Clodronate liposome depletion of phagocytic cells, as well as targeted depletion of Ly6C+ cells, also ablated MPL/TDCM-induced protection. Cytotoxic mediators known to be produced by these cells were required for effects. TNFα was required for effective TA3-Ha killing and nitric oxide was required for EL4 killing. Collectively, these data reveal a model whereby MPL/TDCM-elicited antitumor effects strongly depend on innate cell responses, with B-1a cell-produced tumor-reactive IgM and complement pairing with myeloid cell-produced cytotoxic mediators to effectively eradicate tumors in the peritoneal cavity.
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Antígenos Ly/metabolismo , Factores Cordón/farmacología , Interferón Tipo I/metabolismo , Lectinas Tipo C/agonistas , Lípido A/análogos & derivados , Neoplasias Peritoneales/tratamiento farmacológico , Receptores Toll-Like/agonistas , Adyuvantes Inmunológicos/farmacología , Animales , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Quimioterapia Combinada , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lípido A/farmacología , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/secundario , Fagocitos , Receptor de Interferón alfa y beta/fisiología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.
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Antígenos Nucleares/fisiología , Roturas del ADN de Doble Cadena , Reparación del ADN/genética , Proteínas Asociadas a Matriz Nuclear/fisiología , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Proteínas de Ciclo Celular , Células Cultivadas , Reparación del ADN por Unión de Extremidades/genética , Regulación hacia Abajo , Femenino , Células HEK293 , Humanos , Unión ProteicaRESUMEN
Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the antitumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer-induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B-cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice, restored MPL/TDCM-induced protection in mice with B-cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell-produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases. SIGNIFICANCE: This work identifies a critical antitumor role for innate-like B cells localized within the peritoneal cavity and demonstrates a novel strategy to activate their tumor-killing potential.See related commentary by Tripodo, p. 5.
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Subgrupos de Linfocitos B/inmunología , Inmunidad Innata/inmunología , Inmunoglobulina M/inmunología , Activación de Linfocitos/inmunología , Neoplasias Mamarias Animales/inmunología , Cavidad Peritoneal/patología , Neoplasias Peritoneales/inmunología , Animales , Subgrupos de Linfocitos B/efectos de los fármacos , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patología , Factores Cordón/farmacología , Femenino , Inmunidad Innata/efectos de los fármacos , Inmunoglobulina M/efectos de los fármacos , Lectinas Tipo C/agonistas , Lípido A/análogos & derivados , Lípido A/farmacología , Activación de Linfocitos/efectos de los fármacos , Masculino , Neoplasias Mamarias Animales/tratamiento farmacológico , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/secundario , Receptores Toll-Like/agonistasRESUMEN
Protection against encapsulated bacteria can be elicited using polysaccharide vaccines. These antigens often behave as T-cell-independent type 2 antigens (TI-2 Ags). However, TI-2 Ags, including pneumococcal polysaccharides, often elicit weak immunoglobulin G (IgG) responses and are refractive to boosting. Conjugate vaccines have not completely overcome this challenge and hence, alternative strategies are required to enhance polysaccharide vaccine responses. Herein, we describe an adjuvant consisting of a Toll-like receptor and C-type lectin receptor agonist pairing that significantly increases primary immunoglobulin M and IgG responses to TI-2 Ags as well as enables significant boosting when coadministered with polysaccharide vaccines. Consistent with this, the adjuvant significantly increased the generation of both TI-2 memory B cells and long-lived antibody secreting cells. Adjuvant effects were highly dependent on B-cell-intrinsic MyD88, but not Trif expression. Importantly, coadministration of the adjuvant with the Pneumovax vaccine significantly increased the protective efficacy of vaccination in a lethal challenge mouse model of pneumococcal respiratory infection. Collectively, these data provide evidence that B-cell-directed adjuvants have promise in significantly improving the quality and quantity of serologic and B-cell memory responses to clinically relevant polysaccharide vaccines.
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Adyuvantes Inmunológicos/farmacología , Formación de Anticuerpos/efectos de los fármacos , Formación de Anticuerpos/inmunología , Polisacáridos/inmunología , Proteínas Adaptadoras del Transporte Vesicular/genética , Animales , Anticuerpos Antibacterianos , Células Productoras de Anticuerpos/inmunología , Linfocitos B/inmunología , Vacunas Bacterianas/inmunología , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina G/inmunología , Inmunoglobulina M , Lectinas Tipo C/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Infecciones Neumocócicas/inmunología , Vacunas Neumococicas/inmunología , Streptococcus pneumoniae/inmunología , Receptores Toll-Like/inmunología , Vacunación , Vacunas Conjugadas/inmunologíaRESUMEN
CD22 (Siglec-2) is a critical regulator of B cell activation and survival. CD22-/- mice generate significantly impaired Ab responses to T cell-independent type 2 (TI-2) Ags, including haptenated Ficoll and pneumococcal polysaccharides, Ags that elicit poor T cell help and activate BCR signaling via multivalent epitope crosslinking. This has been proposed to be due to impaired marginal zone (MZ) B cell development/maintenance in CD22-/- mice. However, mice expressing a mutant form of CD22 unable to bind sialic acid ligands generated normal TI-2 Ab responses, despite significantly reduced MZ B cells. Moreover, mice treated with CD22 ligand-binding blocking mAbs, which deplete MZ B cells, had little effect on TI-2 Ab responses. We therefore investigated the effects of CD22 deficiency on B-1b cells, an innate-like B cell population that plays a key role in TI-2 Ab responses. B-1b cells from CD22-/- mice had impaired BCR-induced proliferation and significantly increased intracellular Ca2+ concentration responses following BCR crosslinking. Ag-specific B-1b cell expansion and plasmablast differentiation following TI-2 Ag immunization was significantly impaired in CD22-/- mice, consistent with reduced TI-2 Ab responses. We generated CD22-/- mice with reduced CD19 levels (CD22-/-CD19+/-) to test the hypothesis that augmented B-1b cell BCR signaling in CD22-/- mice contributes to impaired TI-2 Ab responses. BCR-induced proliferation and intracellular Ca2+ concentration responses were normalized in CD22-/-CD19+/- B-1b cells. Consistent with this, TI-2 Ag-specific B-1b cell expansion, plasmablast differentiation, survival, and Ab responses were rescued in CD22-/-CD19+/- mice. Thus, CD22 plays a critical role in regulating TI-2 Ab responses through regulating B-1b cell signaling thresholds.
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Antígenos T-Independientes/inmunología , Linfocitos B/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD19/inmunología , Diferenciación Celular/inmunología , Proliferación Celular/fisiología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal/inmunologíaRESUMEN
B-1 cells produce natural Abs which provide an integral first line of defense against pathogens while also performing important homeostatic housekeeping functions. In this study, we demonstrate that programmed cell death 1 ligand 2 (PD-L2) regulates the production of natural Abs against phosphorylcholine (PC). Naive PD-L2-deficient (PD-L2-/-) mice produced significantly more PC-reactive IgM and IgA. This afforded PD-L2-/- mice with selectively enhanced protection against PC-expressing nontypeable Haemophilus influenzae, but not PC-negative nontypeable Haemophilus influenzae, relative to wild-type mice. PD-L2-/- mice had significantly increased PC-specific CD138+ splenic plasmablasts bearing a B-1a phenotype, and produced PC-reactive Abs largely of the T15 Id. Importantly, PC-reactive B-1 cells expressed PD-L2 and irradiated chimeras demonstrated that B cell-intrinsic PD-L2 expression regulated PC-specific Ab production. In addition to increased PC-specific IgM, naive PD-L2-/- mice and irradiated chimeras reconstituted with PD-L2-/- B cells had significantly higher levels of IL-5, a potent stimulator of B-1 cell Ab production. PD-L2 mAb blockade of wild-type B-1 cells in culture significantly increased CD138 and Blimp1 expression and PC-specific IgM, but did not affect proliferation. PD-L2 mAb blockade significantly increased IL-5+ T cells in culture. Both IL-5 neutralization and STAT5 inhibition blunted the effects of PD-L2 mAb blockade on B-1 cells. Thus, B-1 cell-intrinsic PD-L2 expression inhibits IL-5 production by T cells and thereby limits natural Ab production by B-1 cells. These findings have broad implications for the development of therapeutic strategies aimed at altering natural Ab levels critical for protection against infectious disease, autoimmunity, allergy, cancer, and atherosclerosis.
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Formación de Anticuerpos , Linfocitos B/inmunología , Inmunoglobulina M/metabolismo , Fosforilcolina/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Linfocitos T/inmunología , Animales , Anticuerpos Bloqueadores/farmacología , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Homeostasis , Inmunidad Innata , Interleucina-5/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Sindecano-1/genética , Sindecano-1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Tn is a carbohydrate antigen uniquely exposed on tumor mucins and, thus, an ideal target for immunotherapy. However, it has been difficult to elicit protective antibody responses against Tn antigen and other tumor-associated carbohydrate antigens. Our study demonstrates this can be attributed to PD-1 immuno-inhibition. Our data show a major role for PD-1 in suppressing mucin- and Tn-specific B-cell activation, expansion, and antibody production important for protection against Tn-bearing tumor cells. These Tn/mucin-specific B cells belong to the innate-like B-1b cell subset typically responsible for T cell-independent antibody responses. Interestingly, PD-1-mediated regulation is B cell-intrinsic and CD4+ cells play a key role in supporting Tn/mucin-specific B-cell antibody production in the context of PD-1 deficiency. Mucin-reactive antibodies produced in the absence of PD-1 inhibition largely belong to the IgM subclass and elicit potent antitumor effects via a complement-dependent mechanism. The identification of this role for PD-1 in regulating B cell-dependent antitumor immunity to Tn antigen highlights an opportunity to develop new therapeutic strategies targeting tumor-associated carbohydrate antigens. Cancer Immunol Res; 4(12); 1027-37. ©2016 AACR.
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Antígenos de Carbohidratos Asociados a Tumores/inmunología , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Animales , Línea Celular Tumoral , Femenino , Humanos , Inmunización , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Ratones Endogámicos C57BL , Ratones Transgénicos , Mucinas/inmunología , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/genéticaRESUMEN
A clinician-driven home monitoring program can improve interstage outcomes in single-ventricle patients. Sociodemographic factors have been independently associated with mortality in interstage patients. We hypothesized that even in a population with high-risk sociodemographic characteristics, a home monitoring program is effective in reducing interstage mortality. We defined interstage period as the time period between discharge following Norwood palliation and second-stage surgery. We reviewed the charts of patients for the three-year period before (group 1) and after (group 2) implementation of the home monitoring program. Clinical variables around Norwood palliation, during the interstage period, and at the time of second-stage surgery were analyzed. There were 74 patients in group 1 and 52 in group 2. 59 % patients were Hispanic, and 84 % lived in neighborhoods where over 5 % families lived below poverty line. There was no significant difference in pre-Norwood variables, Norwood discharge variables, age at second surgery, or outcomes at second surgery. There were more Sano shunts performed at the Norwood procedure as the source of pulmonary blood flow in group 2 (p value <0.05). There were more unplanned hospital admissions and percutaneous re-interventions in group 2. Patients in group 2 whose admission criteria included desaturation had a 45 % likelihood of having an unplanned re-intervention. Group 2 noted an 80 % relative reduction in interstage mortality (p < 0.01). In a multiple regression analysis, after accounting for ethnicity, socio-economic status, and source of pulmonary blood flow, enrollment in a home monitoring program independently predicted improved interstage survival (p < 0.01). A clinician-driven home monitoring program reduces interstage mortality even when the majority of patients has high-risk sociodemographic characteristics.
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Ventrículos Cardíacos , Humanos , Síndrome del Corazón Izquierdo Hipoplásico , Procedimientos de Norwood , Cuidados Paliativos , Alta del Paciente , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
For successful carbohydrate based anti-cancer vaccines, it is critical that B cells are activated to secret antibodies targeting the tumor associated carbohydrate antigens (TACAs). Despite the availability of many TACA based constructs, systematic understanding of the effects of structural features on anti-glycan antibody responses is lacking. In this study, a series of defined synthetic glyco-polymers bearing a representative TACA, i.e., the Thomsen-nouveau (Tn) antigen, have been prepared to probe the induction of early B cell activation and antibody production via a T cell independent mechanism. Valency and density of the antigen in the polymers turned out to be critical. An average of greater than 6 Tn per chain was needed to induce antibody production. Glycopolymers with 40 antigens per chain and backbone molecular weight of 450 kDa gave the strongest stimulation to B cells in vitro, which correlated well with its in vivo activity. Deviations from the desired valency and density led to decreased antibody production or even antigen specific B cell non-responsiveness. These findings provide important insights on how to modulate anti-TACA immune responses facilitating the development of TACA based anti-cancer vaccines using glycopolymers.