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1.
Cell ; 168(5): 789-800.e10, 2017 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-28235196

RESUMEN

The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Lipopolisacáridos/metabolismo , Glicoproteínas de Membrana/deficiencia , Receptores de Interleucina-1/deficiencia , Infecciones Estafilocócicas/genética , Infecciones Estafilocócicas/inmunología , Ácidos Teicoicos/metabolismo , Inmunidad Adaptativa , Niño , Femenino , Fibroblastos/metabolismo , Humanos , Inmunidad Innata , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Masculino , Glicoproteínas de Membrana/análisis , Glicoproteínas de Membrana/genética , Monocitos/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Linaje , Fagocitos/metabolismo , Mutación Puntual , Isoformas de Proteínas/análisis , Isoformas de Proteínas/genética , Receptores de Interleucina-1/análisis , Receptores de Interleucina-1/genética , Infecciones Estafilocócicas/tratamiento farmacológico , Ácidos Teicoicos/inmunología , Receptor Toll-Like 2/metabolismo , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo
2.
Med Sci (Paris) ; 31(6-7): 647-53, 2015.
Artículo en Francés | MEDLINE | ID: mdl-26152169

RESUMEN

In humans, CD27+ blood B cells with mutated immunoglobulin (Ig) receptors comprise two major populations: isotype-switched memory cells (IgG+ or IgA+CD27+) and IgM+IgD+CD27+ cells. While switched CD27+ cells are generated in germinal centers (GC) by T-dependent (TD) responses, the origin of IgM+IgD+CD27+ cells is still controversial. Data including ours support the view that these cells can develop and mutate along a GC-independent pathway and that they represent circulating marginal zone B (MZB) cells involved in T-independent (TI) responses. Our data provide evidence for a developmental diversification of these MZB cells, at least in very young children, outside of TD and TI immune responses. The identification of a human MZB cell precursor with NOTCH2-dependent differentiation properties further argue in favor of the existence of a MZB cell lineage in humans, like in rodents. At last, a role for Toll-like receptors in the development and/or maintenance of IgM+IgD+CD27+ B cells is proposed.


Asunto(s)
Linfocitos B/fisiología , Bacterias/inmunología , Cápsulas Bacterianas/inmunología , Inmunidad Celular/fisiología , Animales , Linfocitos B/metabolismo , Bacterias/patogenicidad , Diferenciación Celular/inmunología , Humanos , Inmunoglobulina D/metabolismo , Inmunoglobulina M/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
3.
Cell Mol Life Sci ; 69(10): 1625-34, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22481437

RESUMEN

Humoral memory is maintained by two types of persistent cells, memory B cells and plasma cells, which have different phenotypes and functions. Long-lived plasma cells can survive for a lifespan within a complex niche in the bone marrow and provide continuous protective serum antibody levels. Memory B cells reside in secondary lymphoid organs, where they can be rapidly mobilized upon a new antigenic encounter. Surface IgG has long been taken as a surrogate marker for memory in the mouse. Recently, however, we have brought evidence for a long-lived IgM memory B cell population in the mouse, while we have also argued that, in humans, these same cells are not classical memory B cells but marginal zone (MZ) B cells which, as opposed to their mouse MZ counterpart, recirculate and carry a mutated B cell receptor. In this review, we will discuss these apparently paradoxical results.


Asunto(s)
Linfocitos B/inmunología , Inmunoglobulina M/química , Memoria Inmunológica , Animales , Linfocitos B/fisiología , Humanos , Ratones , Receptores de Antígenos de Linfocitos B/genética , Especificidad de la Especie
4.
Cell Rep ; 42(4): 112378, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37060566

RESUMEN

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27- and memory IgD-CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans.


Asunto(s)
Linfocitos B , Proteínas Proto-Oncogénicas c-akt , Humanos , Ratones , Animales , Tejido Linfoide , Transducción de Señal , Bazo
5.
Cell Rep ; 38(10): 110474, 2022 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-35263577

RESUMEN

A main feature of Wiskott-Aldrich syndrome (WAS) is increased susceptibility to autoimmunity. A key contribution of B cells to development of these complications has been demonstrated through studies of samples from affected individuals and mouse models of the disease, but the role of the WAS protein (WASp) in controlling peripheral tolerance has not been specifically explored. Here we show that B cell responses remain T cell dependent in constitutive WASp-deficient mice, whereas selective WASp deletion in germinal center B cells (GCBs) is sufficient to induce broad development of self-reactive antibodies and kidney pathology, pointing to loss of germinal center tolerance as a primary cause leading to autoimmunity. Mechanistically, we show that WASp is upregulated in GCBs and regulates apoptosis and plasma cell differentiation in the germinal center and that the somatic hypermutation-derived diversification is the basis of autoantibody development.


Asunto(s)
Avispas , Síndrome de Wiskott-Aldrich , Animales , Apoptosis , Autoanticuerpos , Centro Germinal/patología , Ratones , Ratones Noqueados , Síndrome de Wiskott-Aldrich/patología
6.
Cell Rep ; 37(2): 109814, 2021 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-34599871

RESUMEN

Control of the ongoing SARS-CoV-2 pandemic is endangered by the emergence of viral variants with increased transmission efficiency, resistance to marketed therapeutic antibodies, and reduced sensitivity to vaccine-induced immunity. Here, we screen B cells from COVID-19 donors and identify P5C3, a highly potent and broadly neutralizing monoclonal antibody with picomolar neutralizing activity against all SARS-CoV-2 variants of concern (VOCs) identified to date. Structural characterization of P5C3 Fab in complex with the spike demonstrates a neutralizing activity defined by a large buried surface area, highly overlapping with the receptor-binding domain (RBD) surface necessary for ACE2 interaction. We further demonstrate that P5C3 shows complete prophylactic protection in the SARS-CoV-2-infected hamster challenge model. These results indicate that P5C3 opens exciting perspectives either as a prophylactic agent in immunocompromised individuals with poor response to vaccination or as combination therapy in SARS-CoV-2-infected individuals.


Asunto(s)
Anticuerpos ampliamente neutralizantes/uso terapéutico , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/inmunología , Línea Celular , Cricetinae , Modelos Animales de Enfermedad , Epítopos/inmunología , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Pruebas de Neutralización , Unión Proteica/inmunología , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/ultraestructura , Relación Estructura-Actividad , Vacunación
7.
Front Immunol ; 8: 1265, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29067025

RESUMEN

Experimental infection with the protozoan parasite Leishmania major has been extensively used to understand the mechanisms involved in T helper cell differentiation. Following infection, C57BL/6 mice develop a small self-healing cutaneous lesion and they are able to control parasite burden, a process linked to the development of T helper (Th) 1 cells. The local presence of IL-12 has been reported to be critical in driving Th1 cell differentiation. In addition, the early secretion of IL-4 was reported to potentially contribute to Th1 cell differentiation. Following infection with L. major, early keratinocyte-derived IL-4 was suggested to contribute to Th1 cell differentiation. To investigate a putative autocrine role of IL-4 signaling on keratinocytes at the site of infection, we generated C57BL/6 mice deficient for IL-4Rα expression selectively in keratinocytes. Upon infection with L. major, these mice could control their inflammatory lesion and parasite load correlating with the development of Th1 effector cells. These data demonstrate that IL-4 signaling on keratinocytes does not contribute to Th1 cell differentiation. To further investigate the source of IL-4 in the skin during the first days after L. major infection, we used C57BL/6 IL-4 reporter mice allowing the visualization of IL-4 mRNA expression and protein production. These mice were infected with L. major. During the first 3 days after infection, skin IL-4 mRNA expression was observed selectively in mast cells. However, no IL-4 protein production was detectable locally. In addition, early IL-4 blockade locally had no impact on subsequent Th1 cell differentiation and control of the disease. Taken together, the present data rule out a major role for skin IL-4 and keratinocyte IL-4Rα signaling in the development of a Th1 protective immune response following experimental infection with L. major.

8.
J Exp Med ; 211(5): 987-1000, 2014 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-24733829

RESUMEN

Mouse splenic marginal zone precursors (MZPs) differentiate into marginal zone B (MZB) cells under a signaling pathway involving Notch2 and its ligand, delta-like 1 ligand (Dll1). We report the identification of an MZP subset in the spleen of young children. These MZPs differentiate into MZ-like B cells in vitro in the presence of OP9 cells expressing human DLL1, as demonstrated by the up-regulation of classical MZB cell markers. A set of diagnostic genes discriminating IgM(+)IgD(+)CD27(+) blood and splenic MZB cells from switched B cells was identified (up-regulation of SOX7, down-regulation of TOX, COCH, and HOPX), and their expression during the induction assay mirrored the one of MZB cells. Moreover, Alagille patients with a NOTCH2 haploinsufficiency display a marked reduction of IgM(+)IgD(+)CD27(+) B cells in blood, whereas their switched memory B cells are not affected. Altogether, these results argue in favor of the existence of a rodent-like MZB cell lineage in humans.


Asunto(s)
Diferenciación Celular/inmunología , Células Precursoras de Linfocitos B/inmunología , Receptor Notch2/metabolismo , Transducción de Señal/inmunología , Bazo/citología , Proteínas de Unión al Calcio , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Análisis por Micromatrices , Microscopía Fluorescente , Células Precursoras de Linfocitos B/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Bazo/inmunología
9.
J Clin Invest ; 123(1): 432-42, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23241960

RESUMEN

Primary immune thrombocytopenia (ITP) is a disorder caused by autoantibody-mediated platelet destruction and decreased platelet production. Rituximab, a B cell-depleting agent, has become the first-line treatment for ITP; however, patients with refractory disease usually require splenectomy. We identified antibody-secreting cells as the major splenic B cell population that is resistant to rituximab. The phenotype, antibody specificity, and gene expression profile of these cells were characterized and compared to those of antibody-secreting cells from untreated ITP spleens and from healthy tissues. Antiplatelet-specific plasma cells (PC) were detected in the spleens of patients with ITP up to 6 months after rituximab treatment, and the PC population displayed a long-lived program similar to the one of bone marrow PC, thus explaining for most of these patients the absence of response to rituximab and the response to splenectomy. When analyzed by multiplex PCR at the single-cell level, normal splenic PC showed a markedly different gene expression profile, with an intermediate signature, including genes characteristic of both long-lived PC and proliferating plasmablasts. Surprisingly, long-lived PC were not detected in untreated ITP spleens. These results suggest that the milieu generated by B cell depletion promotes the differentiation and settlement of long-lived PC in the spleen.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Factores Inmunológicos/administración & dosificación , Depleción Linfocítica , Células Plasmáticas/metabolismo , Púrpura Trombocitopénica Idiopática/metabolismo , Púrpura Trombocitopénica Idiopática/terapia , Bazo/metabolismo , Adulto , Anciano , Autoanticuerpos/sangre , Proliferación Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , Células Plasmáticas/patología , Púrpura Trombocitopénica Idiopática/patología , Rituximab , Bazo/patología , Bazo/cirugía , Esplenectomía , Factores de Tiempo , Transcriptoma
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