RESUMEN
BACKGROUND: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ability of a combination immunosuppression (IS) treatment with bortezomib and a mouse-specific CD20 monoclonal antibody to suppress anti-AAV NAbs and enable readministration of AAV vectors of the same capsid in mice. METHODS: An AAV8 vector (AAV8-CB-hGAA) that ubiquitously expresses human α-glucosidase was used for initial gene therapy and a second AAV8 vector (AAV8-LSP-hSEAP) that contains a liver-specific promoter to express human secreted embryonic alkaline phosphatase (hSEAP) was used for AAV readministration. Plasma samples were used for determination of anti-AAV8 NAb titers. Cells isolated from whole blood, spleen, and bone marrow were analyzed for B-cell depletion by flow cytometry. The efficiency of AAV readministration was determined by the secretion of hSEAP in blood. RESULTS: In näive mice, an 8-week IS treatment along with AAV8-CB-hGAA injection effectively depleted CD19+ B220+ B cells from blood, spleen, and bone marrow and prevented the formation of anti-AAV8 NAbs. Following administration of AAV8-LSP-hSEAP, increasing levels of hSEAP were detected in blood for up to 6 weeks, indicating successful AAV readministration. In mice pre-immunized with AAV8-CB-hGAA, comparison of IS treatment for 8, 12, 16, and 20 weeks revealed that the 16-week IS treatment demonstrated the highest plasma hSEAP level following AAV8-LSP-hSEAP readministration. CONCLUSIONS: Our data suggest that this combination treatment is an effective IS approach that will allow retreatment of patients with AAV-mediated gene therapy. A combination IS treatment with bortezomib and a mouse-specific CD20 monoclonal antibody effectively suppressed anti-AAV NAbs in naïve mice and in mice with pre-existing antibodies, allowing successful readministration of the same AAV capsid vector.
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Anticuerpos Neutralizantes , Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Ratones , Animales , Bortezomib/farmacología , Bortezomib/uso terapéutico , Cápside , Anticuerpos Antivirales , Vectores Genéticos/genética , Retratamiento , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Dependovirus/genéticaRESUMEN
D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8+ T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6+CD8+ T cells with a progenitor phenotype and decreased terminally exhausted CD8+ T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8+ T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Inmunotoxinas , Humanos , Animales , Ratones , Glioblastoma/patología , Inmunotoxinas/genética , Linfocitos T CD8-positivos , Inmunidad Adaptativa , Receptores ErbB/metabolismo , Línea Celular Tumoral , Neoplasias Encefálicas/terapiaRESUMEN
Pediatric patients with constitutively active mutations in the cytosolic double-stranded-DNA-sensing adaptor STING develop an autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients have elevated interferon-stimulated gene expression and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus-associated lymphoid tissue (BALT). Mice harboring SAVI mutations (STING V154M [VM]) that recapitulate human disease also develop lymphocyte-rich BALT. Ablation of either T or B lymphocytes prolongs the survival of SAVI mice, but lung immune aggregates persist, indicating that T cells and B cells can independently be recruited as BALT. VM T cells produced IFNγ, and IFNγR deficiency prolonged the survival of SAVI mice; however, T-cell-dependent recruitment of infiltrating myeloid cells to the lung was IFNγ independent. Lethally irradiated VM recipients fully reconstituted with wild type bone-marrow-derived cells still developed ILD, pointing to a critical role for VM-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes. We identified lung endothelial cells as radioresistant cells that express STING. Transcriptional analysis of VM endothelial cells revealed up-regulation of chemokines, proinflammatory cytokines, and genes associated with antigen presentation. Together, our data show that VM-expressing radioresistant cells play a key role in the initiation of lung disease in VM mice and provide insights for the treatment of SAVI patients, with implications for ILD associated with other connective tissue disorders.
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Células Endoteliales , Enfermedades Pulmonares Intersticiales , Proteínas de la Membrana , Linfocitos T , Enfermedades Vasculares , Animales , Niño , Células Endoteliales/inmunología , Células Endoteliales/efectos de la radiación , Mutación con Ganancia de Función , Humanos , Interferón gamma/genética , Interferón gamma/metabolismo , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/inmunología , Depleción Linfocítica , Tejido Linfoide/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Tolerancia a Radiación , Linfocitos T/inmunología , Enfermedades Vasculares/genética , Enfermedades Vasculares/inmunologíaRESUMEN
The protein tyrosine phosphatase CD45 plays a crucial role in B cell antigen receptor (BCR) signaling by activating Src family kinases. Cd45-/- mice show altered B cell development and a phenotype likely due to reduced steady-state signaling; however, Cd45-/- B cells show relatively normal BCR ligation-induced signaling. In our investigation of how BCR signaling was restored in Cd45-/- cells, we found that the coreceptor CD22 switched from an inhibitory to a stimulatory function in these cells. We disrupted the ability of CD22 to interact with its ligands in Cd45-/- B cells by generating Cd45-/-St6galI-/- mice, which cannot synthesize the glycan ligand of CD22, or by treating Cd45-/- B cells in vitro with the sialoside GSC718, which inhibits ligand binding to CD22. BCR ligation-induced signaling was reduced by ST6GalI deficiency, but not by GSC718 treatment, suggesting that CD22 restored BCR ligation-induced signaling in Cd45-/- mature B cells by altering cellular phenotypes during development. CD22 was required for the increase in the surface amount of IgM-BCR on Cd45-/- B cells, which augmented signaling. Because B cell survival depends on steady-state BCR signaling, IgM-BCR abundance was likely increased by the selective survival of IgM-BCRhi Cd45-/- B cells because of CD22-mediated signaling under conditions of substantially reduced steady-state signaling. Because the amount of surface IgM-BCR is increased on B cells from patients with other BCR signaling deficiencies, including X-linked agammaglobulinemia, our findings suggest that CD22 may contribute to the partial restoration of B cell function in these patients.
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Linfocitos B , Receptores de Antígenos de Linfocitos B , Animales , Linfocitos B/metabolismo , Antígenos Comunes de Leucocito , Activación de Linfocitos , Ratones , Receptores de Antígenos de Linfocitos B/metabolismo , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Transducción de Señal , Familia-src Quinasas/metabolismoAsunto(s)
Linfocitos B Reguladores/efectos de los fármacos , Inmunosupresores/administración & dosificación , Pénfigo/tratamiento farmacológico , Rituximab/administración & dosificación , Azatioprina/administración & dosificación , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Quimioterapia Combinada/métodos , Glucocorticoides/administración & dosificación , Humanos , Interleucina-10/metabolismo , Recuento de Linfocitos , Ácido Micofenólico/administración & dosificación , Pénfigo/sangre , Pénfigo/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: Local type III hypersensitivity reactions are acute inflammatory events induced by immune complex (IC) deposition. CD22 and CD72 are B cell-specific cell surface molecules that negatively regulate B cell function. OBJECTIVE: To elucidate the roles of CD22 and CD72 in the development of IgG-mediated type III hypersensitivity reactions. METHOD: The reverse Arthus reaction model in the skin was induced in mice lacking CD22 (CD22-/-), CD72 (CD72-/-), and both of them (CD22-/-/CD72-/-). Edema at 4h and hemorrhage at 8h after IC challenge were evaluated. Inflammatory cell infiltration and cytokine and chemokine expression were also examined. RESULTS: Edema and hemorrhage were significantly reduced in CD22-/-/CD72-/- mice compared with wild-type mice. The loss of both membrane proteins resulted in a greater decrease in edema at 4h, but not hemorrhage at 8h, than the loss of each protein alone. Infiltration of neutrophils, macrophages, and T cells, and the expression of TNF-α, IL-6, MIP-1α, and CCR5 mRNA were also diminished in the knockout mice compared to wild-type mice, and most significantly reduced in CD22-/-/CD72-/- mice. Regulatory T (Treg) cells in the spleen were significantly increased in all knockout mice at 4h. Significant differences in the severity of edema and hemorrhage between wild-type and knockout mice were lost when Treg cells were depleted in the knockout mice. CONCLUSION: These results demonstrate that CD22 and CD72 expression contribute to the development of the reverse Arthus reaction model and CD22 and CD72 might be therapeutic targets for human IC-mediated diseases.
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Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/inmunología , Reacción de Arthus/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Piel/inmunología , Animales , Complejo Antígeno-Anticuerpo/administración & dosificación , Complejo Antígeno-Anticuerpo/inmunología , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos B/genética , Reacción de Arthus/patología , Biopsia , Inyecciones Intradérmicas , Ratones , Ratones Noqueados , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , Piel/patologíaRESUMEN
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed in various immune cells and most of them carry signaling functions. High-affinity synthetic sialoside ligands have been developed for various Siglecs. Therapeutic potentials of the nanoparticles and compounds that contain multiple numbers of these sialosides and other reagents such as toxins and antigens have been demonstrated. However, whether immune responses can be regulated by monomeric sialoside ligands has not yet been known. CD22 (also known as Siglec-2) is an inhibitory molecule preferentially expressed in B lymphocytes (B cells) and is constitutively bound and functionally regulated by α2,6 sialic acids expressed on the same cell (cis-ligands). Here, we developed synthetic sialosides GSC718 and GSC839 that bind to CD22 with high affinity (IC50 ~100 nM), and inhibit ligand binding of CD22. When B cells are activated by B cell antigen receptor (BCR) ligation, both GSC718 and GSC839 downregulate proliferation of B cells, and this regulation requires both CD22 and α2,6 sialic acids. This result suggests that these sialosides regulate BCR ligation-induced B cell activation by reversing endogenous ligand-mediated regulation of CD22. By contrast, GSC718 and GSC839 augment B cell proliferation induced by TLR ligands or CD40 ligation, and this augmentation requires CD22 but not α2,6 sialic acids. Thus, these sialosides appear to enhance B cell activation by directly suppressing the inhibitory function of CD22 independently of endogenous ligand-mediated regulation. Moreover, GSC839 augments B cell proliferation that depends on both BCR ligation and CD40 ligation as is the case for in vivo B cell responses to antigens, and enhanced antibody production to the extent comparable to CpG oligonuleotides or a small amount of alum. Although these known adjuvants induce production of the inflammatory cytokines or accumulation of inflammatory cells, CD22-binding sialosides do not. Thus, synthetic sialosides that bind to CD22 with high-affinity modulate B cell activation through endogenous ligand-dependent and independent pathways, and carry an adjuvant activity without inducing inflammation.
Asunto(s)
Formación de Anticuerpos , Linfocitos B/inmunología , Proliferación Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Ácidos Siálicos/metabolismo , Adyuvantes Inmunológicos , Animales , Linfocitos B/efectos de los fármacos , Ligandos , Ratones , Ratones Endogámicos C57BL , Polisacáridos/inmunología , Unión Proteica , Receptores de Antígenos de Linfocitos B/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Transducción de SeñalRESUMEN
Angiotensin II (AngII) promotes hypertension, atherogenesis, vascular aneurysm and impairs post-ischemic cardiac remodeling through concerted roles on vascular cells, monocytes and T lymphocytes. However, the role of AngII in B lymphocyte responses is largely unexplored. Here, we show that chronic B cell depletion (Baffr deficiency) significantly reduces atherosclerosis in Apoe -/- mice infused with AngII. While adoptive transfer of B cells in Apoe -/- /Baffr -/- mice reversed atheroprotection in the absence of AngII, infusion of AngII in B cell replenished Apoe -/- /Baffr -/- mice unexpectedly prevented the progression of atherosclerosis. Atheroprotection observed in these mice was associated with a significant increase in regulatory CD1dhiCD5+ B cells, which produced high levels of interleukin (IL)-10 (B10 cells). Replenishment of Apoe -/- /Baffr -/- mice with Il10 -/- B cells reversed AngII-induced B cell-dependent atheroprotection, thus highlighting a protective role of IL-10+ regulatory B cells in this setting. Transfer of AngII type 1A receptor deficient (Agtr1a -/-) B cells into Apoe -/- /Baffr -/- mice substantially reduced the production of IL-10 by B cells and prevented the AngII-dependent atheroprotective B cell phenotype. Consistent with the in vivo data, AngII synergized with BAFF to induce IL-10 production by B cells in vitro via AngII type 1A receptor. Our data demonstrate a previously unknown synergy between AngII and BAFF in inducing IL-10 production by B cells, resulting in atheroprotection.
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Angiotensina II/metabolismo , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Factor Activador de Células B/genética , Linfocitos B Reguladores/metabolismo , Animales , Aterosclerosis/patología , Linfocitos B Reguladores/inmunología , Biomarcadores , Células Cultivadas , Modelos Animales de Enfermedad , Inmunohistoquímica , Interleucina-10/biosíntesis , Ratones , Ratones Noqueados , Fenotipo , Receptor de Angiotensina Tipo 1/deficienciaRESUMEN
OBJECTIVE: Regulatory B cells that inhibit immune responses through interleukin-10 (IL-10) secretion (B10 cells) have been characterized in adult subjects with autoimmune disease. The aim of this study was to characterize B10 cells in individuals across the entire age range of normal human development and changes in their frequency and numbers in children with autoimmunity. METHODS: The phenotype and numbers of B10 cells in blood were examined in healthy individuals and children with autoimmunity, using flow cytometry. B10 cell function was assessed by measuring the effect of B cell-derived IL-10 on interferon-γ (IFNγ) expression by CD4+ T cells. Serum cytokine levels were measured by enzyme-linked immunosorbent assay. RESULTS: The frequency of B10 cells transiently increased during childhood, when up to 30% of B cells were competent to produce IL-10, compared with the low frequencies in healthy newborns (3-4%) and adults (7-9%). The surface phenotype of B10 cells in children revealed age-dependent variability. B10 cells from children were distinct from proinflammatory cytokine-producing B cells and down-regulated IFNγ production by CD4+ T cells in vitro. Compared with age-matched healthy controls, children with autoimmunity had lower numbers and frequencies of B10 cells (decreased by 39% and 48%, respectively), higher IFNγ levels, and lower IL-21 levels in serum. IFNγ inhibited, whereas IL-21 promoted, B cell IL-10 competence in vitro. CONCLUSION: B10 cells, a functionally defined cell subset with a variable surface phenotype reflective of overall B cell development, transiently expand during childhood. B10 cell frequencies and numbers were decreased in children with autoimmunity, which may be explained in part by alterations in serum IFNγ and IL-21 that differentially regulate B10 cell development.
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Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Linfocitos B Reguladores/fisiología , Interleucina-10 , Adolescente , Adulto , Factores de Edad , Enfermedades Autoinmunes/sangre , Niño , Preescolar , Femenino , Humanos , Interferón gamma/sangre , Interleucinas/sangre , Masculino , Persona de Mediana EdadRESUMEN
Non-Hodgkin lymphoma (NHL) is the most commonly diagnosed hematologic cancer of adults in the United States, with the vast majority of NHLs deriving from malignant B lymphocytes that express cell surface CD20. CD20 immunotherapy (rituximab) is widely used to treat NHL, even though the initial effectiveness of rituximab varies widely among patients and typically wanes over time. The mechanisms through which lymphomas initially resist or gain resistance to immunotherapy are not well established. To address this, a preclinical mouse model system was developed to comprehensively identify lymphoma transcriptomic changes that confer resistance to CD20 immunotherapy. The generation of spontaneous primary and familial lymphomas revealed that sensitivity to CD20 immunotherapy was not regulated by differences in CD20 expression, prior exposure to CD20 immunotherapy, or serial in vivo passage. An unbiased forward exome screen of these primary lymphomas was used to validate the utility of this expansive lymphoma cohort, which revealed that increased lymphoma galectin-1 (Gal-1) expression strongly correlated with resistance to immunotherapy. Genetically induced lymphoma Gal-1 expression ablated antibody-dependent lymphoma phagocytosis in vitro and lymphoma sensitivity to CD20 immunotherapy in vivo. Human NHLs also express elevated Gal-1 compared with nonmalignant lymphocytes, demonstrating the ability of this preclinical model system to identify molecular targets that could be relevant to human therapy. This study therefore established a powerful preclinical model system that permits the comprehensive identification of the dynamic lymphoma molecular network that drives resistance to immunotherapy.
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Antígenos CD20/genética , Resistencia a Antineoplásicos , Galectina 1/fisiología , Inmunoterapia/métodos , Linfoma de Células B/inmunología , Animales , Antineoplásicos/uso terapéutico , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/metabolismo , Hemicigoto , Humanos , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Fagocitosis , Rituximab/uso terapéuticoRESUMEN
Calcium ion (Ca(2+)) signaling is a typical phenomenon mediated through immune receptors, such as the B-cell antigen receptor (BCR), and it is important for their biological activities. To analyze the signaling of immune receptors together with their in vivo dynamics, we generated stable transgenic mice with the Föster/fluorescence resonance energy transfer (FRET)-based Ca(2+) indicator yellow cameleon 3.60 (YC3.60), based on the Cre/loxP system (YC3.60(flox)). We successfully obtained mice with specific YC3.60 expression in immune or nerve cells as well as mice with ubiquitous expression of this indicator. We established five-dimensional (5D) (x, y, z, time, and Ca(2+)) intravital imaging of lymphoid tissues, including the bone marrow. Furthermore, in autoimmune-prone models, the CD22(-/-) and C57BL/6- lymphoproliferation (lpr)/lpr mouse, Ca(2+) fluxes were augmented, although they did not induce autoimmune disease. Intravital imaging of Ca(2+) signals in lymphocytes may improve assessment of the risk of autoimmune diseases in model animals.
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Técnicas Biosensibles/métodos , Señalización del Calcio , Calcio/metabolismo , Linfocitos/metabolismo , Imagen Molecular/métodos , Animales , Antígenos CD19/genética , Antígenos CD19/metabolismo , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Autoinmunidad , Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Genes Reporteros , Ratones , Ratones Transgénicos , Ganglios Linfáticos Agregados/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Bazo/metabolismoRESUMEN
OBJECTIVE: To determine the serum levels of nucleosome in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc. METHODS: Serum nucleosome levels in 91 patients with SSc were examined by ELISA. The expression of Toll-like receptor (TLR) 9 in T and B cells was quantified by flow cytometric intracellular protein analysis. The effects of nucleosomes on lymphocytes were also analysed. Moreover, we assessed the effects of nucleosomes on fibrosis, using wild type and CD19-deficient bleomycin-treated mice, an experimental model for human SSc. RESULTS: Serum nucleosome levels were elevated in SSc compared with healthy controls and correlated positively with the extent of skin and pulmonary fibrosis and immunological abnormalities. The retrospective longitudinal analysis showed the serum nucleosome levels to be attenuated during the follow-up period. TLR9, which can be stimulated by nucleosome expression was upregulated in the affected T and B cells of patients with SSc. Moreover, nucleosome stimulation strongly increased interleukin (IL)-4 and IL-17 expression of T cells, B-cell IgG production and proliferation of lymphocytes in SSc compared with those in healthy controls. In bleomycin-induced SSc model mice, serum nucleosome levels were elevated compared with control mice. Furthermore, nucleosomes increased IgG production and proliferation of mouse B cells. Although TLR9 expression was similar between wild type and CD19-deficient splenic B cells, CD19 deficiency reduced these nucleosome effects. CONCLUSION: These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.
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Linfocitos B/metabolismo , Nucleosomas/metabolismo , Esclerodermia Sistémica/sangre , Linfocitos T/metabolismo , Animales , Linfocitos B/inmunología , Bleomicina , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoglobulina G/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Estudios Longitudinales , Masculino , Ratones , Estudios Retrospectivos , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/inmunología , Transducción de Señal , Linfocitos T/inmunología , Receptor Toll-Like 9/metabolismoRESUMEN
We have previously shown that polyclonal natural IgM protects mice from renal ischemia/reperfusion injury (IRI) by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells (DC), as we observed high IgM binding to splenic DC. To test this hypothesis, we pretreated bone marrow-derived DC (BMDC) with polyclonal murine or human IgM prior to LPS activation and demonstrated that 0.5 × 10(6) IgM/LPS-pretreated BMDC, when injected into wild-type C57BL/6 mice 24 h before renal ischemia, protect mice from developing renal IRI. We show that this switching of LPS-activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to nonapoptotic BMDC receptors. Regulatory BMDC require IL-10 and programmed death 1 as well as downregulation of CD40 and p65 NF-κB phosphorylation to protect in renal IRI. Blocking the programmed death ligand 1 binding site just before i.v. injection of IgM/LPS-pretreated BMDC or using IL-10 knockout BMDC fails to induce protection. Similarly, IgM/LPS-pretreated BMDC are rendered nonprotective by increasing CD40 expression and phosphorylation of p65 NF-κB. How IgM/LPS regulatory BMDC suppress in vivo ischemia-induced innate inflammation remains to be determined. However, we show that suppression is dependent on other in vivo regulatory mechanisms in the host, that is, CD25(+) T cells, B cells, IL-10, and circulating IgM. There was no increase in Foxp3(+) regulatory T cells in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leukocyte Abs can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation.
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Células de la Médula Ósea/inmunología , Células Dendríticas/inmunología , Inmunoglobulina M/inmunología , Inflamación/inmunología , Riñón/irrigación sanguínea , Daño por Reperfusión/prevención & control , Animales , Linfocitos B/inmunología , Antígenos CD40/metabolismo , Células Cultivadas , Interleucina-10/inmunología , Lipopolisacáridos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Receptor de Muerte Celular Programada 1/inmunología , Daño por Reperfusión/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Factor de Transcripción ReIA/metabolismoAsunto(s)
Artritis Experimental/inmunología , Linfocitos B Reguladores/inmunología , Colitis/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Hipersensibilidad Tardía/inmunología , Lupus Eritematoso Sistémico/inmunología , Presentación de Antígeno , Artritis Experimental/genética , Artritis Experimental/patología , Linfocitos B Reguladores/patología , Colitis/genética , Colitis/patología , Citocinas/genética , Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Regulación de la Expresión Génica/inmunología , Humanos , Hipersensibilidad Tardía/genética , Hipersensibilidad Tardía/patología , Tolerancia Inmunológica , Inmunidad Humoral , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Citocinas/genética , Receptores de Citocinas/inmunología , Transducción de SeñalRESUMEN
Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.
RESUMEN
B cells are known to instigate and promulgate immune responses by producing antibodies and presenting antigens to T cells. However, a rare but potent B-cell subset in both humans and mice is capable of inhibiting immune responses through the production of the anti-inflammatory cytokine IL-10. Regulatory B cells do not express any unique combination of surface markers but instead represent a small population of B cells that have acquired the unique ability to produce IL-10. This numerically rare B-cell subset is therefore functionally referred to as 'B10 cells' to reflect both their molecular program and the fact that their anti-inflammatory effects in models of autoimmunity, infection and cancer are solely attributable to IL-10 production. As with most B cells, B10 cell development and function appear to be predominantly, if not exclusively, driven by antigen-receptor signals. Once generated, B10 cells respond to both innate and adaptive immune signals, with a requirement for antigen-specific local interactions with T cells to induce IL-10 production and to provide optimal immune suppression in mouse models of autoimmune disease. B10 cells therefore provide an antigen-specific mechanism for delivering IL-10 locally to sites of immune activation and inflammation. The ability of B10 cells to regulate innate and adaptive immune responses makes them an ideal therapeutic target for the treatment of many immune-related disorders.
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Presentación de Antígeno , Linfocitos B Reguladores/inmunología , Dermatitis por Contacto/inmunología , Inmunidad Humoral , Interleucina-10/inmunología , Animales , Linfocitos B Reguladores/patología , Comunicación Celular , Dermatitis por Contacto/genética , Dermatitis por Contacto/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/inmunología , Humanos , Inmunidad Innata , Interleucina-10/genética , Ratones , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal , Bazo/inmunología , Bazo/patología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
B cells have diverse functions during immune responses, including antibody production, antigen presentation, and cytokine secretion. Multiple lymphomas and leukemias derive from malignant B cells, so therapies that deplete B cells are clinically important, particularly antibodies targeting the B cell-specific surface molecules CD19 and CD20. Macrophages are the principal mediators of CD19 and CD20 monoclonal antibody-dependent B-cell and lymphoma depletion in mice through Fcγ receptor-dependent phagocytosis. Thereby, the extent of CD19 or CD20 antibody-induced B cell and tumor depletion in vivo is influenced by molecular changes within tumors and genetic variations between individuals. In addition to Fcγ receptor polymorphisms, lymphoma- and regulatory B cell-derived cytokine production and macrophage localization and function within tumor microenvironments influence tumor clearance. Given the dynamic interactions of these factors, the identification of effector cell and tumor microenvironment genetic alterations will identify molecular targets that enhance immunotherapies for the treatment of human diseases.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD19/inmunología , Antígenos CD20/inmunología , Antineoplásicos/uso terapéutico , Linfocitos B/inmunología , Inmunoterapia , Linfoma de Células B/tratamiento farmacológico , Rituximab/uso terapéutico , Microambiente Tumoral/inmunología , Animales , Humanos , Linfoma de Células B/inmunología , Macrófagos/inmunología , Ratones , Receptores de IgG/inmunologíaRESUMEN
Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the CNS that predominantly affects the spinal cord and optic nerves. A majority (approximately 75%) of patients with NMO are seropositive for autoantibodies against the astrocyte water channel aquaporin-4 (AQP4). These autoantibodies are predominantly IgG1, and considerable evidence supports their pathogenicity, presumably by binding to AQP4 on CNS astrocytes, resulting in astrocyte injury and inflammation. Convergent clinical and laboratory-based investigations have indicated that B cells play a fundamental role in NMO immunopathology. Multiple mechanisms have been hypothesized: AQP4 autoantibody production, enhanced proinflammatory B cell and plasmablast activity, aberrant B cell tolerance checkpoints, diminished B cell regulatory function, and loss of B cell anergy. Accordingly, many current off-label therapies for NMO deplete B cells or modulate their activity. Understanding the role and mechanisms whereby B cells contribute to initiation, maintenance, and propagation of disease activity is important to advancing our understanding of NMO pathogenesis and developing effective disease-specific therapies.