RESUMEN
Several disturbances in T-cell mediated immunity have been described during aging, but immunosenescence of the B-cell compartment is less well elucidated. The peripheral blood B-cell compartment (CD19+) can be split into six main subpopulations according to the cell surface markers IgD, CD27, CD24, and CD38: Transitional, naïve, unswitched, switched, double negative and plasmablasts. We thus aimed to verify whether shifts in these subsets occur during healthy and pathological aging. We recruited three groups of aged people (> 60 years old), healthy, COPD patients, and smokers without altered pulmonary function test, and a fourth group of individuals 18-40 years old (youngs). Total B-cells percentage and absolute number were similar among the healthy aged, COPD patients, and youngs, but the smokers showed significantly higher absolute numbers. While all six B-cell subset percentages were comparable among the healthy aged, COPD patients, and youngs, smokers showed significantly higher percentages of switched B-cells and reduced naïve B-cells than the other three groups, resulting in an inverted naive:switched ratio. Analysis of the cell subset absolute numbers showed a similar trend. Overall, our results suggest that aging drives milder alterations in the distribution of peripheral blood B-cell subpopulations than in the T-cell compartment. We suggest that it is the T-cell immunosenescence that most contributes to the poor humoral immune responses in the elderly, vaccine responses included. Surprisingly it was the smokers who showed significant alterations when compared with the youngs, healthy aged, and aged COPD patients, probably as a result of the chronic immune stimulation described in active smoking subjects.
Asunto(s)
Subgrupos de Linfocitos B , Enfermedad Pulmonar Obstructiva Crónica , Anciano , Humanos , Linfocitos B , Envejecimiento , Subgrupos de Linfocitos B/química , Antígenos CD19/análisisRESUMEN
Immune aplastic anaemia (AA) is caused by cytotoxic T lymphocytes (CTLs) that destroy haematopoietic stem and progenitor cells. Enhanced type 1 T helper (Th1) responses and reduced regulatory T cells (Tregs) are involved in the immune pathophysiology. CD24hi CD38hi regulatory B cells (Bregs) suppress CTLs and Th1 responses, and induce Tregs via interleukin 10 (IL-10). We investigated circulating B-cell subpopulations, including CD24hi CD38hi Bregs, as well as total B cells, CD4+ T cells, CD8+ T cells and natural killer cells in 104 untreated patients with severe and very severe AA, aged ≥18 years. All patients were treated with standard immunosuppressive therapy (IST) plus eltrombopag. CD24hi CD38hi Bregs were markedly reduced in patients with AA compared to healthy individuals, especially in very severe AA, but residual Bregs remained functional, capable of producing IL-10; total B-cell counts and the other B-cell subpopulations were similar to those of healthy individuals. CD24hi CD38hi Bregs did not correlate with responses to IST, and they recovered to levels present in healthy individuals after therapy. Mature naïve B-cell counts were unexpectedly associated with IST response. Markedly reduced CD24hi CD38hi Bregs, especially in very severe AA, with recovery after IST suggest Breg deficits may contribute to the pathophysiology of immune AA.
Asunto(s)
ADP-Ribosil Ciclasa 1/análisis , Anemia Aplásica/sangre , Antígenos CD19/análisis , Subgrupos de Linfocitos B/patología , Linfocitos B Reguladores/patología , Antígeno CD24/análisis , Linfopenia/etiología , Glicoproteínas de Membrana/análisis , Adolescente , Adulto , Anciano , Anemia Aplásica/complicaciones , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/patología , Suero Antilinfocítico/uso terapéutico , Subgrupos de Linfocitos B/química , Linfocitos B Reguladores/química , Benzoatos/uso terapéutico , Médula Ósea/patología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Ciclosporina/uso terapéutico , Femenino , Humanos , Hidrazinas/uso terapéutico , Inmunosupresores/uso terapéutico , Interleucina-10/biosíntesis , Interleucina-10/genética , Células Asesinas Naturales/patología , Recuento de Linfocitos , Linfopenia/sangre , Linfopenia/patología , Masculino , Persona de Mediana Edad , Pirazoles/uso terapéutico , Receptores de Trombopoyetina/agonistas , Adulto JovenRESUMEN
BACKGROUND: CD3 and CD19 are the characteristic surface markers of mature T lymphocytes and B lymphocytes of human respectively. A special subset of immune cells that characteristically expressed the surface markers CD19+ of B lymphocytes and CD3+ of T lymphocytes simultaneously (CD19+CD3+ cells, hereinafter referred to as B-T cells) was found in the peripheral blood of human, yet it has not been reported in cancer research before. Our aims were to characterize the expression and possible value of B-T cells in cancer patients. METHODS: Flow cytometry was applied to analyse the CD19+CD3+ cells, and laser scanning confocal microscope was utilized to prove co-expressing CD19+ of B lymphocytes and CD3+ of T lymphocytes simultaneously on the surface of the cells. Then a total of 523 patients with malignant tumor were enrolled in this study, and 177 healthy donors were recruited as the control group. The levels of CD19+CD3+ cells in peripheral blood were measured by flow cytometry, and the differences between the two groups were compared. RESULTS: The healthy donors and cancer patients all had B-T cells in their peripheral blood, but the percentage of B-T cells was 0.16 % ± 0.11 % and 0.58 % ± 0.38 % respectively, showing statistically significant (P < 0.0001). There was no significant correlation between the percentage of B-T cells and lymphocyte subsets (P > 0.05). The percentages of B-T cells in different tumor species were different. The proportion of B-T cells was high in esophageal cancer, non-Hodgkin's lymphoma and lung cancer, but it was low in pancreatic cancer, ovarian cancer and kidney cancer. Meanwhile, there was significant difference between esophageal cancer and kidney cancer (P < 0.001). The distribution of B-T cells in pancreatic cancer and kidney cancer was more concentrated, yet more dispersed in other cancers. Although there was a trend of increase in clinical stage â ¢+â £ and a trend of decrease in age above 60 years for breast cancer, gastric cancer and liver cancer, there was no significant difference in the percentage of B-T cells in age, gender, different clinical stages, tumor metastasis, lymph node metastasis, and splenomegaly (P > 0.05). CONCLUSION: The percentage of B-T cells in cancer patients was significantly higher than that of healthy donors. B-T cells maybe play a very complicated role in tumor, whether it could be a potential tumor immune marker or not and what are the specific phenotypes and functions of it to need be further verified.
Asunto(s)
Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Subgrupos de Linfocitos B/inmunología , Neoplasias/inmunología , Subgrupos de Linfocitos T/inmunología , Anciano , Antígenos CD19/sangre , Subgrupos de Linfocitos B/química , Complejo CD3/análisis , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/químicaRESUMEN
Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.
Asunto(s)
Subgrupos de Linfocitos B/fisiología , Diferenciación Celular , Epigénesis Genética , Interferón gamma/metabolismo , Interleucinas/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Subgrupos de Linfocitos B/química , Subgrupos de Linfocitos B/efectos de los fármacos , Redes Reguladoras de Genes , Humanos , Lupus Eritematoso Sistémico/patología , Proteínas de Dominio T Box/análisisRESUMEN
BACKGROUND: The pathogenesis of immunological tolerance caused by avian leukosis virus subgroup J (ALV-J), an oncogenic retrovirus, is largely unknown. RESULTS: In this study, the development, differentiation, and immunological capability of B cells and their progenitors infected with ALV-J were studied both morphologically and functionally by using a model of ALV-J congenital infection. Compared with posthatch infection, congenital infection of ALV-J resulted in severe immunological tolerance, which was identified as the absence of detectable specific antivirus antibodies. In congenitally infected chickens, immune organs, particularly the bursa of Fabricius, were poorly developed. Moreover, IgM-and IgG-positive cells and total immunoglobulin levels were significantly decreased in these chickens. Large numbers of bursa follicles with no differentiation into cortex and medulla indicated that B cell development was arrested at the early stage. Flow cytometry analysis further confirmed that ALV-J blocked the differentiation of CD117+chB6+ B cell progenitors in the bursa of Fabricius. Furthermore, both the humoral immunity and the immunological capability of B cells and their progenitors were significantly suppressed, as assessed by (a) the antibody titres against sheep red blood cells and the Marek's disease virus attenuated serotype 1 vaccine; (b) the proliferative response of B cells against thymus-independent antigen lipopolysaccharide (LPS) in the spleen germinal centres; and (c) the capacities for proliferation, differentiation and immunoglobulin gene class-switch recombination of B cell progenitors in response to LPS and interleukin-4(IL-4) in vitro. CONCLUSIONS: These findings suggested that the anergy of B cells in congenitally infected chickens is caused by the developmental arrest and dysfunction of B cell progenitors, which is an important factor for the immunological tolerance induced by ALV-J.
Asunto(s)
Virus de la Leucosis Aviar/inmunología , Leucosis Aviar/congénito , Subgrupos de Linfocitos B/patología , Anergia Clonal , Enfermedades de las Aves de Corral/congénito , Células Madre/patología , Animales , Anticuerpos Antivirales/sangre , Leucosis Aviar/patología , Virus de la Leucosis Aviar/patogenicidad , Subgrupos de Linfocitos B/química , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/virología , Bolsa de Fabricio/patología , Diferenciación Celular , Proliferación Celular , Pollos , Citometría de Flujo , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Enfermedades de las Aves de Corral/patología , Proteínas Proto-Oncogénicas c-kit/análisis , Células Madre/química , Células Madre/inmunología , Células Madre/virologíaRESUMEN
A subset of atypical memory B cells accumulates in malaria and several infections, autoimmune disorders and aging in both humans and mice. It has been suggested these cells are exhausted long-lived memory B cells, and their accumulation may contribute to poor acquisition of long-lasting immunity to certain chronic infections, such as malaria and HIV. Here, we generated an immunoglobulin heavy chain knock-in mouse with a BCR that recognizes MSP1 of the rodent malaria parasite, Plasmodium chabaudi. In combination with a mosquito-initiated P. chabaudi infection, we show that Plasmodium-specific atypical memory B cells are short-lived and disappear upon natural resolution of chronic infection. These cells show features of activation, proliferation, DNA replication, and plasmablasts. Our data demonstrate that Plasmodium-specific atypical memory B cells are not a subset of long-lived memory B cells, but rather short-lived activated cells, and part of a physiologic ongoing B-cell response.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Memoria Inmunológica , Proteína 1 de Superficie de Merozoito/inmunología , Plasmodium chabaudi/inmunología , Animales , Subgrupos de Linfocitos B/química , Linfocitos B/química , Citometría de Flujo , Técnicas de Sustitución del Gen , Inmunoglobulina G/genética , Malaria/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Enfermedades de los Roedores/inmunologíaRESUMEN
OBJECTIVE: Recently, a seemingly novel innate immune cell subset bearing features of natural killer and B cells was identified in mice. So-called NKB cells appear as first responders to infections, but whether this cell population is truly novel or is in fact a subpopulation of B cells and exists in higher primates remains unclear. The objective of this study was to identify NKB cells in primates and study the impact of HIV/SIV infections. DESIGN AND METHODS: NKB cells were quantified in both naive and lentivirus infected rhesus macaques and humans by excluding lineage markers (CD3, CD127) and positive Boolean gating for CD20, NKG2A/C and/or NKp46. Additional phenotypic measures were conducted by RNA-probe and traditional flow cytometry. RESULTS: Circulating cytotoxic NKB cells were found at similar frequencies in humans and rhesus macaques (range, 0.01-0.2% of total lymphocytes). NKB cells were notably enriched in spleen (median, 0.4% of lymphocytes), but were otherwise systemically distributed in tonsil, lymph nodes, colon, and jejunum. Expression of immunoglobulin was highly variable, but heavily favoured IgM and IgA rather than IgG. Interestingly, NKB cell frequencies expanded in PBMC and colon during SIV infection, as did IgG expression, but were generally unaltered in HIV-infected humans. CONCLUSION: These results suggest a cell type expressing both natural killer and B-cell features exists in rhesus macaques and humans and are perturbed by HIV/SIV infection. The full functional niche remains unknown, but the unique phenotype and systemic distribution could make NKB cells unique targets for immunotherapeutics or vaccine strategies.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Tracto Gastrointestinal/patología , Infecciones por VIH/patología , Receptores de Células Asesinas Naturales/análisis , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Adulto , Animales , Subgrupos de Linfocitos B/química , Linfocitos B/química , Humanos , Inmunoglobulina A/metabolismo , Inmunoglobulina M/metabolismo , Recuento de Linfocitos , Macaca mulatta , Persona de Mediana EdadRESUMEN
BACKGROUND: Chronic antigen exposure and/or ageing increases the frequency of T-box expressed in T cells (T-bet)-expressing B-lymphocytes in mice. The frequency and significance of B-cell T-bet expression during chronic hepatitis C (HCV) infection in human subjects has never been described. METHODS: Healthy controls, cirrhotic and noncirrhotic HCV-infected patients, and non-HCV patients with cirrhosis were recruited. Peripheral blood mononuclear cells were phenotyped for expression of T-bet and related markers by flow cytometry. In a subset of patients who underwent antiviral therapy and were cured of HCV infection (sustained virological response), the dynamics of T-bet expression in B cells was monitored. After cure, convalescent B cells were tested for T-bet expression after re-exposure to infected plasma or recombinant HCV proteins. RESULTS: Forty-nine patients including 11 healthy donors, 30 hepatitis C-infected individuals (nine with liver cancer, 13 with cirrhosis, eight without cirrhosis) and eight patients with cirrhosis due to non-HCV-related cause were recruited. We found that B cells in patients with chronic HCV exhibited increased frequency of T-bet+ B cells relative to noninfected individuals (median 11.5% v. 2.2%, P<.0001) but that there were no significant differences between noncirrhotic, cirrhotic and cancer-bearing infected individuals. T-Bet+ B cells expressed higher levels of CD95, CXCR3, CD11c, CD267 and FcRL5 compared to T-bet- B cells and predominantly exhibit a tissue-like memory CD27- CD21- phenotype independent of HCV infection. T-bet+ B cells in HCV-infected patients were more frequently class-switched IgD- IgG+ (40.4% vs. 26.4%, P=.012). Resolution of HCV infection with direct-acting antiviral (DAA) therapy leads to a marked reduction in the frequency of T-bet+ B cells (median 14.1% pretreatment v. 6.7% end of treatment v. 6.1% SVR12, P≤.01). Re-exposure of convalescent (cured) B cells to viremic plasma and recombinant HCV E2 protein led to re-expression of T-bet. CONCLUSION: Chronic antigenemia in chronic HCV infection induces and maintains an antigen-specific T-bet+ B cell. These B cells share markers with tissue-like memory B cells. Antigen-driven T-bet expression may be a critical suppressor of B-cell activation in chronic HCV infection.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Hepatitis C Crónica/inmunología , Memoria Inmunológica , Proteínas de Dominio T Box/análisis , Viremia/inmunología , Adulto , Anciano , Subgrupos de Linfocitos B/química , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana EdadRESUMEN
The host acquired immune response, especially the humoral immunity, plays key roles in preventing bacterial pneumonia in the lung. Our previous research demonstrated that interleukin 17-producing γδ T cells (IL17-γδ T cells) have a protective effect on the early innate immune response during acute pulmonary Pseudomonas aeruginosa infection. However, whether IL17-γδ T cells also play a role in humoral immunity is unknown. In this study, an acute pulmonary P. aeruginosa infection model was established in wild-type and γδ TCR-/- C57BL/6 mice. The expression of IL-17 on γδ T cells isolated from infected lung tissues increased rapidly and peaked at day 7 after acute infection with P. aeruginosa. Compared with wild-type infected mice, the levels of total immunoglobulins including IgA, IgG, and IgM in the serum and BALF were significantly decreased in γδ TCR-/- mice, with the exception of IgM in the BALF. Moreover, CD69 expression in B cells from the lungs and spleen and the level of BAFF in the plasma were also decreased in γδ TCR-/- mice. IL17-γδ T cell transfusion significantly improved the production of immunoglobulins, B cell activation and BAFF levels in γδ TCR-/- mice compared with γδ TCR-/- mice without transfusion; this effect was blocked when cells were pretreated with an IL-17 antibody. Together, these data demonstrate that IL17-γδ T cells are involved in CD19+ B cell activation and the production of immunoglobulins during acute pulmonary P. aeruginosa infection. Thus, we conclude that IL17-γδ T cells may facilitate the elimination of bacteria and improve survival through not only innate immunity but also humoral immunity.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Subgrupos de Linfocitos B/inmunología , Neumonía Bacteriana/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Factor Activador de Células B/sangre , Subgrupos de Linfocitos B/química , Análisis Químico de la Sangre , Líquido del Lavado Bronquioalveolar/química , Inmunoglobulina A/análisis , Inmunoglobulina A/sangre , Inmunoglobulina G/análisis , Inmunoglobulina G/sangre , Inmunoglobulina M/análisis , Inmunoglobulina M/sangre , Interleucina-17/metabolismo , Lectinas Tipo C/análisis , Pulmón/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Bazo/inmunologíaRESUMEN
IL-10-competent subset within CD1d(hi)CD5(+) B cells, also known as B10 cells, has been shown to regulate autoimmune diseases. In our previous study, adoptive transfer of CD1d(hi)CD5(+) B cells expanded in vivo by GM-CSF prevented and suppressed experimental autoimmune myasthenia gravis (EAMG). The goal of this study was to further examine the role and mechanism of IL-10 in the regulatory function of B10 cells in EAMG. We found that only IL-10 competent CD1d(hi)CD5(+) B cells sorted from WT mice, but not IL-10 deficient CD1d(hi)CD5(+) B cells exhibited regulatory function in vitro and in vivo. Adoptive transfer of IL-10 competent CD1d(hi)CD5(+) B cells led to higher frequency of Tregs and B10 cells, and low levels of proinflammatory cytokines and autoantibody production. We conclude that IL-10 production within CD1d(hi)CD5(+) B cells plays an important role in immune regulation of EAMG.
Asunto(s)
Antígenos CD1d/metabolismo , Subgrupos de Linfocitos B/química , Antígenos CD5/metabolismo , Interleucina-10/metabolismo , Miastenia Gravis Autoinmune Experimental/inmunología , Miastenia Gravis Autoinmune Experimental/patología , Traslado Adoptivo/métodos , Animales , Proliferación Celular/fisiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Interleucina-10/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/metabolismo , Miastenia Gravis Autoinmune Experimental/inducido químicamente , Miastenia Gravis Autoinmune Experimental/fisiopatología , Fragmentos de Péptidos/inmunología , Receptores Nicotínicos/inmunologíaRESUMEN
OBJECTIVES: In antiretroviral therapy (ART)-treated patients, to determine if AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is preceded by: elevated frequency of potentially malignant abnormal activated/germinal center-like B cells, elevated serum prevalence of B-cell stimulatory Toll-like receptor (TLR) ligands resulting from HIV infection-associated microbial translocation, dysregulated B-cell TLR expression/signaling, and perturbations in the frequency of immunoregulatory cells. DESIGN: A case-control study nested with a cohort study of HIV-infected women. METHODS: Prediagnostic AIDS-NHL cases (nâ=â12, collected 1-12 months before diagnosis) and controls (nâ=â42) from the Women's Interagency HIV Study cohort, were matched for HIV and ART status, age, race, and CD4 lymphocyte count. Serum levels of TLR ligands, the prevalence of malignancy-associated abnormal activated/germinal center-like (CD19CD10CD71CD86AID) B cells, TLR2 expression on B cells, expression of TLR2-modulating micro-RNA, and the frequency of regulatory T and B cells were assessed. RESULTS: Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/germinal center-like CD19CD10CD71CD86AID B cells (Pâ=â0.0072), elevated serum prevalence of the TLR2 ligand, and significantly elevated B-cell TLR2 expression (Pâ=â0.0015), positively correlating with the frequency of activated/germinal center-like B cells (rhoâ=â0.7273, Pâ=â0.0144). In cases, a purified subset of activated/germinal center-like B cells exhibited decreased expression of microRNAs that modulate TLR2 signaling, including miR-21, 146a, 146b, and 155. Finally, cases also exhibited significantly elevated frequencies of antitumor immunity inhibitory regulatory B cells (Pâ=â0.0024), but not regulatory T cells. CONCLUSIONS: Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of regulatory B cells, precede the diagnosis of AIDS-NHL in HIV-infected ART-treated patients.
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Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/patología , Subgrupos de Linfocitos B/inmunología , Linfoma no Hodgkin/diagnóstico , Receptor Toll-Like 2/análisis , Adulto , Subgrupos de Linfocitos B/química , Traslocación Bacteriana/inmunología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , MicroARNs/análisis , MicroARNs/genéticaRESUMEN
The role of CD19(+) CD5(+) and CD19(+) CD5(-) B cell subpopulations in the antibody response to pneumococcal capsular polysaccharides (caps-PSs) is controversial. In the present study, we evaluated the role of human CD19(+) CD5(+) and CD19(+) CD5(-) cell populations in the serotype-specific antibody response to caps-PS. After vaccination of 5 healthy human adults with Pneumovax (23-valent pneumococcal polysaccharide vaccine [PPV23]), IgG anti-caps-PS serotype 4 antibody-producing cells resided mainly in the CD19(+) CD5(-) B cell subset, as assessed by enzyme-linked immunosorbent spot (ELISpot) analysis. Moreover, in a humanized SCID mouse model, CD19(+) CD5(-) B cells were more effective than CD19(+) CD5(+) cells in producing IgG anti-cap-PS antibodies. Finally, an association was found between the level of IgG anti-caps-PS antibodies and the number of CD19(+) CD5(-) B cells in 33 humans vaccinated with PPV23. Taken together, our data suggest that CD5 defines a functionally distinct population of B cells in humans in the anti-caps-PS immune response.
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Anticuerpos Antibacterianos/sangre , Formación de Anticuerpos , Subgrupos de Linfocitos B/inmunología , Antígenos CD5/análisis , Vacunas Neumococicas/inmunología , Streptococcus pneumoniae/inmunología , Adolescente , Adulto , Animales , Antígenos CD19/análisis , Subgrupos de Linfocitos B/química , Niño , Preescolar , Femenino , Humanos , Inmunoglobulina G/sangre , Masculino , Ratones SCID , Vacunas Neumococicas/administración & dosificación , Adulto JovenRESUMEN
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19(+) B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient's leukemia.
Asunto(s)
Agammaglobulinemia/terapia , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre de Sangre Periférica , Agammaglobulinemia/complicaciones , Aloinjertos , Anticuerpos Antibacterianos/biosíntesis , Antígenos CD19/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Subgrupos de Linfocitos B/química , Preescolar , Terapia Combinada , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Recuento de Linfocitos , Masculino , Vacunas Neumococicas , Recurrencia , Inducción de Remisión , Streptococcus pneumoniae/inmunología , Acondicionamiento PretrasplanteRESUMEN
Francisella tularensis, a facultative intracellular Gram-negative bacterium, causes the illness tularemia. The infection of mice with live vaccine strain is considered to be a model of human tularemia. F. tularensis infects predominantly such phagocytic cells as macrophages or neutrophils, but it also infects non-phagocytic hepatocytes, epithelial cells, and murine and human B cell lines. Based on work with the murine tularemia model, we report here that F. tularensis LVS infects peritoneal CD19(+) cells - exclusively B-1a cells - early after intraperitoneal infection in vivo. The peritoneal and consequently spleen CD19(+) cells are activated by the F. tularensis LVS infection to express the activation markers from MHC class II, CD25, CD54, CD69, and the co-stimulatory molecules CD80 and CD86. As early as 12 h post-infection, the peritoneal CD19(+) cells produce IFN-γ, IL-1ß, IL-4, IL-6, IL-12, IL-17, IL-23, and TNF-α. The spleen CD19(+) cells respond to infection with some delay. Moreover, the F. tularensis infected A20 B cell line activates CD3(+) spleen cells isolated from naïve mice. Thus, the data presented here suggest that B cells have all the attributes to actively participate in the induction and regulation of the adaptive immune response during early stages of F. tularensis infection.
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Subgrupos de Linfocitos B/inmunología , Citocinas/metabolismo , Activación de Linfocitos , Tularemia/inmunología , Animales , Antígenos CD/análisis , Subgrupos de Linfocitos B/química , Modelos Animales de Enfermedad , Femenino , Antígenos de Histocompatibilidad Clase II/análisis , Ratones Endogámicos BALB C , Peritoneo/inmunología , Bazo/inmunología , Factores de TiempoRESUMEN
Whereas NO is known to regulate T cell responses, its role in regulating B cell responses remains unclear. Previous studies suggested that inducible NO synthase 2 (NOS2/iNOS) is required for normal IgA Ab responses but inhibits antiviral IgG2a Ab responses. In this study we used NOS2(-/-) mice to determine the role of NO in T cell-dependent and T cell-independent (TI)-2 Ab responses. Whereas T cell-dependent Ab responses were only modestly increased in NOS2(-/-) mice, IgM and IgG3 Ab responses as well as marginal zone B cell plasma cell numbers and peritoneal B1b B cells were significantly elevated after immunization with the TI-2 Ag 4-hydroxy-3-nitrophenyl acetyl (NP)-Ficoll. The elevated TI-2 responses in NOS2(-/-) mice were accompanied by significant increases in serum levels of BAFF/BLyS and by increases in BAFF-producing Ly6C(hi) inflammatory monocytes and monocyte-derived dendritic cells (DCs), suggesting that NO normally inhibits BAFF expression. Indeed, we found that NOS2(-/-) DCs produced more BAFF than did wild-type DCs, and addition of a NO donor to NOS2(-/-) DCs reduced BAFF production. Bone marrow chimeric mice that lack NOS2 in either nonhematopoietic or hematopoietic cells had intermediate IgM and IgG3 Ab responses after NP-Ficoll immunization, suggesting that NOS2 from both hematopoietic and nonhematopoietic sources regulates TI-2 Ab responses. Similar to NOS2(-/-) mice, depletion of Ly6C(hi) inflammatory monocytes and monocyte-derived DCs enhanced NP-specific IgM and IgG3 responses to NP-Ficoll. Thus, NO produced by inflammatory monocytes and their derivative DC subsets plays an important role in regulating BAFF production and TI-2 Ab responses.
Asunto(s)
Formación de Anticuerpos/inmunología , Factor Activador de Células B/biosíntesis , Factor Activador de Células B/genética , Óxido Nítrico Sintasa de Tipo II/fisiología , Óxido Nítrico/química , Subgrupos de Linfocitos T/inmunología , Animales , Formación de Anticuerpos/genética , Factor Activador de Células B/inmunología , Subgrupos de Linfocitos B/química , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Ficoll/química , Ficoll/inmunología , Haptenos/inmunología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Óxido Nítrico/inmunología , Óxido Nítrico Sintasa de Tipo II/deficiencia , Óxido Nítrico Sintasa de Tipo II/genética , Nitrofenoles/inmunología , Fenilacetatos/inmunología , Subgrupos de Linfocitos T/químicaRESUMEN
The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MNC) infiltrates of exocrine glands and overactivity of B lymphocytes. Although T cells have long been perceived as the prime effectors, increasing evidence indicates that the key role is rather served by B cells. Among related abnormalities are rheumatoid factor (RF), anti-SSA/Ro, and anti-SSB/La antibodies (Ab). Also, supporting this view is our finding of an increase in the number of circulating naïve mature B (Bm) cells, with a reciprocal decrease in that of memory B cells. Furthermore, a ratio of Bm2-plus-Bm2' cells to early Bm5-plus-late Bm5 above 5 is diagnostic. This variation partly reflects the migration of active memory B cells into the exocrine glands of the patients, as well as into their skin. More recently, the B-cell-activating factor of the TNF family (BAFF) has been endorsed with a pivotal role in B-cell survival and hence implicated in the pathogenesis of autoimmunity. In practice, B cells have turned quite attractive as a target for biotherapy. For example, treatment with anti-CD20 Ab has afforded some benefits in this disease, while BAFF blockers are still on the way, but should expand our armamentarium for treating SS. With such B-cell-directed biotherapies in mind, we delineate herein the distinguishing traits of B lymphocytes in SS.
Asunto(s)
Subgrupos de Linfocitos B/clasificación , Glándulas Salivales/patología , Síndrome de Sjögren/inmunología , Antígenos CD/análisis , Subgrupos de Linfocitos B/química , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Citocinas/metabolismo , Humanos , Recuento de Linfocitos , Glándulas Salivales/inmunología , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/tratamiento farmacológicoRESUMEN
B cells are required for development of spontaneous autoimmune thyroiditis (SAT) in NOD.H-2h4 mice where they function as important APCs for activation of CD4(+) T cells. Depletion of B cells using anti-CD20 effectively inhibits SAT development. The goals of this study were to characterize the B cells that migrate to thyroids in SAT, and to determine whether anti-CD20 effectively targets those B cells in mice with established SAT. The results showed that most thyroid-infiltrating B cells in mice with SAT are follicular (FO) B cells. Expression of CD80, CD86, and CD40 was significantly increased on FO, but not marginal zone, splenic B cells after SAT development. Thyroid-infiltrating and peripheral blood B cells had lower expresion of CD20 and CD24 compared with splenic and lymph node FO B cells. Despite reduced CD20 expression, anti-CD20 depleted most B cells in thyroids of mice with established SAT within 3 d. B cell depletion in thyroids of mice given anti-CD20 was more complete and longer lasting than in spleen and lymph nodes and was comparable to that in blood. Circulation of B cells was required for effective and rapid removal of B cells in thyroids because preventing lymphocyte egress by administration of FTY720 abrogated the effects of anti-CD20 on thyroid B cells. Therefore, the FO subset of B cells preferentially contributes to SAT development and persistence, and anti-CD20 targeting of FO B cells effectively eliminates B cells in the target organ even though thyroid B cells have decreased CD20 expression.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/inmunología , Subgrupos de Linfocitos B/inmunología , Depleción Linfocítica , Glándula Tiroides/inmunología , Tiroiditis Autoinmune/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Antígenos CD20/efectos de los fármacos , Subgrupos de Linfocitos B/química , Subgrupos de Linfocitos B/efectos de los fármacos , Antígeno B7-1/análisis , Antígeno B7-2/análisis , Recuento de Linfocito CD4 , Quimiotaxis de Leucocito , Femenino , Inmunoglobulina G/farmacología , Inmunoglobulina G/uso terapéutico , Inmunofenotipificación , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Ratones , Ratones Endogámicos NOD , Bazo/inmunología , Bazo/ultraestructura , Glándula Tiroides/patología , Tiroiditis Autoinmune/patología , Tiroiditis Autoinmune/terapiaAsunto(s)
Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Subgrupos de Linfocitos B/química , Enfermedad de Hodgkin/patología , Sialiltransferasas/análisis , Antígenos CD20/análisis , Subgrupos de Linfocitos B/patología , Biomarcadores de Tumor , Enfermedad de Hodgkin/metabolismo , Humanos , Inmunofenotipificación , Factor 2 de Transcripción de Unión a Octámeros/análisisRESUMEN
Bcl-3 is an atypical member of the family of IκB proteins. Unlike the classic members, Bcl-3 functions as a nuclear transcriptional cofactor that may, depending on context, promote or suppress genes via association with p50/NF-κB1 or p52/NF-κB2 homodimers. Bcl-3 is also an oncogene, because it is a partner in recurrent translocations in B cell tumors, resulting in deregulated expression. Bcl-3 functions, however, remain poorly understood. We have investigated the role of Bcl-3 in B cells and discovered a previously unknown involvement in the splenic development of these cells. Loss of Bcl-3 in B cells resulted in significantly more marginal zone (MZ) and fewer follicular (FO) B cells. Conversely, transgenic expression of Bcl-3 in B cells generated fewer MZ and more FO B cells. Both Bcl-3(-/-) FO and MZ B cells were more responsive to LPS stimulation compared with their wild-type counterparts, including increased proliferation. By contrast, Bcl-3(-/-) FO B cells were more prone to apoptosis upon BCR stimulation, also limiting their expansion. The data reveal Bcl-3 as a regulator of B cell fate determination, restricting the MZ path and favoring the FO pathway, at least in part, via increased signal-specific survival of the latter, a finding of relevance to its tumorigenic activity.
Asunto(s)
Subgrupos de Linfocitos B/citología , Linfopoyesis/fisiología , Proteínas Proto-Oncogénicas/fisiología , Bazo/citología , Factores de Transcripción/fisiología , Animales , Antígenos de Diferenciación de Linfocitos B/análisis , Proteínas del Linfoma 3 de Células B , Subgrupos de Linfocitos B/química , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linaje de la Célula , Inmunidad Innata , Inmunoglobulina M/inmunología , Inmunofenotipificación , Integrina alfa4beta1/biosíntesis , Integrina alfa4beta1/genética , Lipopolisacáridos/farmacología , Activación de Linfocitos/efectos de los fármacos , Recuento de Linfocitos , Antígeno-1 Asociado a Función de Linfocito/biosíntesis , Antígeno-1 Asociado a Función de Linfocito/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Quimera por Radiación , Bazo/ultraestructura , Factores de Transcripción/deficiencia , Factores de Transcripción/genéticaRESUMEN
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) represents 5% of all Hodgkin lymphoma and has distinct clinico-pathological features. It is typified by the presence of lymphocyte predominant cells, which are CD20(+) , CD15(-) and CD30(-) and are found scattered amongst small B-lymphocytes arranged in a nodular pattern. Patients typically are males presenting with localized, peripheral lymphadenopathy. Despite frequent and often late or multiple relapses the prognosis is favourable. Deaths due to NLPHL are uncommon, but secondary malignancies and other treatment toxicities contribute appreciably to overall mortality. Secondary aggressive non-Hodgkin lymphoma can occur in approximately 7-14% of cases of NLPHL. Given this diseases' rarity, the optimal management is unclear and opinions differ as to whether treatment paradigms should be similar to or differ from those for classical Hodgkin lymphoma. This review provides an overview of the existing literature describing of the outcome and treatment approaches for limited and advanced stage NLPHL.