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1.
Mol Cell Biol ; 31(1): 63-80, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20974805

RESUMEN

An early lesion in many kidney diseases is damage to podocytes, which are critical components of the glomerular filtration barrier. A number of proteins are essential for podocyte filtration function, but the signaling events contributing to development of nephrotic syndrome are not well defined. Here we show that class II phosphoinositide 3-kinase C2α (PI3KC2α) is expressed in podocytes and plays a critical role in maintaining normal renal homeostasis. PI3KC2α-deficient mice developed chronic renal failure and exhibited a range of kidney lesions, including glomerular crescent formation and renal tubule defects in early disease, which progressed to diffuse mesangial sclerosis, with reduced podocytes, widespread effacement of foot processes, and modest proteinuria. These findings were associated with altered expression of nephrin, synaptopodin, WT-1, and desmin, indicating that PI3KC2α deficiency specifically impacts podocyte morphology and function. Deposition of glomerular IgA was observed in knockout mice; importantly, however, the development of severe glomerulonephropathy preceded IgA production, indicating that nephropathy was not directly IgA mediated. PI3KC2α deficiency did not affect immune responses, and bone marrow transplantation studies also indicated that the glomerulonephropathy was not the direct consequence of an immune-mediated disease. Thus, PI3KC2α is critical for maintenance of normal glomerular structure and function by supporting normal podocyte function.


Asunto(s)
Glomérulos Renales/anatomía & histología , Glomérulos Renales/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Animales , Antígenos de Superficie/metabolismo , Trasplante de Médula Ósea , Glomerulonefritis/etiología , Glomerulonefritis/patología , Glomerulonefritis/fisiopatología , Glomerulonefritis por IGA/etiología , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/fisiopatología , Humanos , Inmunoglobulina A/metabolismo , Inmunoglobulina G/metabolismo , Glomérulos Renales/enzimología , Glomérulos Renales/patología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/metabolismo , Fosfatidilinositol 3-Quinasas/deficiencia , Fosfatidilinositol 3-Quinasas/genética , Podocitos/enzimología , Podocitos/patología , Podocitos/fisiología , Insuficiencia Renal/etiología , Insuficiencia Renal/patología , Insuficiencia Renal/fisiopatología , Quimera por Trasplante
2.
Immunity ; 30(3): 421-33, 2009 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-19249230

RESUMEN

Immunity to the intestinal parasite Heligomosomoides polygyrus is dependent on the successful generation of T helper 2 (Th2) memory cells. We showed that B cells contribute to immunity against H. polygyrus by producing antibody (Ab) and by promoting expansion and differentiation of primary and memory Th2 cells. We also demonstrated that cytokine-producing effector B cells were essential for effective immunity to H. polygyrus. Tumor necrosis factor alpha production by B cells was necessary for sustained Ab production, whereas interleukin 2 production by B cells was necessary for Th2 cell expansion and differentiation. These results show that B cells mediate protection from pathogens not only by presenting antigen and secreting antibody but also by producing cytokines that regulate the quality and magnitude of humoral and cellular immune responses.


Asunto(s)
Antígenos Helmínticos/inmunología , Linfocitos B/inmunología , Citocinas/metabolismo , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/prevención & control , Células Th2/inmunología , Animales , Formación de Anticuerpos , Ensayo de Inmunoadsorción Enzimática , Inmunidad Celular , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
3.
J Immunol ; 175(11): 7103-7, 2005 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16301612

RESUMEN

Although IL-4-producing B cells (B effector 2 cells) are found following infection and immunization, the signals regulating IL-4 production by Be2 cells are unknown. We show that culturing naive B cells with Th2 cells induces up-regulation of IL-4 in the B cells with a concomitant down-regulation of T-bet, IL-12Rbeta2, and IFN-gamma. Up-regulation of IL-4 in the Be2 cells is dependent on both T cells and IL-4 as IL-4Ralpha-deficient B cells primed with Th2 cells did not transcribe IL-4, and B cells primed in the presence of IL-4-deficient Th2 cells produced IFN-gamma instead of IL-4. Likewise, the in vivo development of IL-4-expressing B cells in a nematode infection model was dependent on both T cells and IL-4Ralpha-mediated signals. Thus, the differentiation of naive B cells into IL-4-expressing Be2 cells is regulated by a combination of T cell-dependent signals and the cytokine environment and this process is critically dependent upon the IL-4/IL-4R signaling pathway.


Asunto(s)
Linfocitos B/citología , Linfocitos B/inmunología , Interleucina-4/inmunología , Receptores de Superficie Celular/inmunología , Células Th2/inmunología , Animales , Linfocitos B/metabolismo , Diferenciación Celular/inmunología , Células Cultivadas , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-4/biosíntesis , Ratones , Nematospiroides dubius/inmunología , Receptores de Interleucina/biosíntesis , Receptores de Interleucina/inmunología , Receptores de Interleucina-12 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
J Immunol ; 175(8): 5306-13, 2005 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16210636

RESUMEN

Oral infection with the nematode parasite Heligmosomoides polygyrus H. polygyrus is entirely restricted to the small intestine. Although the evoked Th2 response has been extensively studied in secondary lymphoid organs, little is known about the systemic dissemination of Th2 cells or type 2 associated eosinophils and basophils. In this study we use bicistronic 4get IL-4 reporter mice to directly visualize the type 2 response to H. polygyrus infection. We observed that CD4(+)/GFP(+) Th2 cells spread systemically and found that these cells accumulated in nonlymphoid "hot spots" in the liver, the lung airways, and the peritoneal cavity. Interestingly, the total number of Th2 cells in the peritoneal cavity was comparable to those found in the draining mesenteric lymph node or the spleen. Peritoneal Th2 cells were distinguished by an exceptionally low apoptotic potential and high expression of the intestinal homing receptor alpha(4)beta(7) integrin. CD4(+)/GFP(+) Th2 cells from these peripheral sites were fully functional as indicated by rapid IL-4 production upon polyclonal or Ag-specific restimulation. Th2 cells persisted in the intestinal tissue and the peritoneal cavity of drug-cured mice for weeks. The presence of peripheral memory Th2 cells in the intestine might be crucial for immunity to recall infections. These findings have important implications for the design of vaccination strategies because it may be necessary to establish and maintain memory CD4(+) T cells at the potential future site of infection.


Asunto(s)
Parasitosis Intestinales/inmunología , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Células Th2/inmunología , Animales , Apoptosis/fisiología , Células Cultivadas , Memoria Inmunológica/inmunología , Interleucina-4/biosíntesis , Parasitosis Intestinales/tratamiento farmacológico , Tejido Linfoide/citología , Tejido Linfoide/metabolismo , Tejido Linfoide/parasitología , Ratones , Ratones Endogámicos BALB C , Cavidad Peritoneal/parasitología , Fenotipo , Infecciones por Strongylida/tratamiento farmacológico , Células Th2/metabolismo
5.
J Immunol ; 174(11): 6781-90, 2005 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-15905519

RESUMEN

This manuscript systematically identifies the molecular mechanisms that regulate the ability of B cells to produce the critical type 1 cytokine, IFN-gamma. B cells produce IFN-gamma in response to IL-12 and IL-18 and when primed by Th1 cells. We show that development of IFN-gamma-producing B cells by either Th1 cells or IL-12/IL-18 is absolutely dependent on expression of the IFN-gammaR and the T-box transcription factor, T-bet. Interestingly, although T-bet up-regulation in developing B effector 1 (Be1) cells is controlled by IFN-gammaR-mediated signals, STAT1-deficient B cells up-regulate T-bet and produce IFN-gamma, indicating that additional transcriptional activators must be coupled to the IFN-gammaR in B cells. Finally, we show that although IL-12/IL-18 or IFN-gamma-producing Th1 cells are required to initiate transcription of the IFN-gamma gene in B cells, sustained expression of IFN-gamma and T-bet by B cells is dependent on an IFN-gamma/IFN-gammaR/T-bet autocrine feedback loop. These findings have significant implications, because they suggest that IFN-gamma-producing B cells not only amplify Th1 responses, but also imprint a type 1 phenotype on B cells themselves. In the case of immune responses to bacterial or viral pathogens, this B cell-driven autocrine feedback loop is likely to be beneficial; however, in the case of B cell responses to autoantigens, it may result in amplification of the autoimmune loop and increased pathology.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Interferón gamma/biosíntesis , Interferón gamma/metabolismo , Receptores de Interferón/fisiología , Factores de Transcripción/fisiología , Animales , Subgrupos de Linfocitos B/citología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Interleucina-12/antagonistas & inhibidores , Interleucina-12/inmunología , Interleucina-12/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Interferón/biosíntesis , Receptores de Interferón/deficiencia , Receptores de Interferón/genética , Factor de Transcripción STAT1 , Factor de Transcripción STAT4 , Transducción de Señal/genética , Transducción de Señal/inmunología , Proteínas de Dominio T Box , Células TH1/inmunología , Células TH1/metabolismo , Transactivadores/deficiencia , Transactivadores/genética , Transactivadores/fisiología , Factores de Transcripción/biosíntesis , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Receptor de Interferón gamma
6.
Curr Dir Autoimmun ; 8: 25-54, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15564716

RESUMEN

Recent experiments have revealed that B cells can regulate the course of immune responses to pathogens and autoantigens by antibody-independent mechanisms. One antibody-independent function of B cells is to produce cytokines. In this review we describe the identification of IL-10-producing 'regulatory' B cells as well as IFNgamma-producing 'effector' Bel cells and IL-4-producing 'effector' Be2 cells. We discuss the roles of antigen, pathogen-derived molecules and T cell and dendritic cell-derived factors in regulating the differentiation of mature B cells into cytokine-producing effector B cells. We also review the recent experiments showing that B cell-derived cytokines play pathologic as well as protective roles in immune responses to autoantigens, and demonstrate that cytokine-producing B cells play unexpectedly complex and potentially opposing roles in autoimmune disease.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Linfocitos B/inmunología , Citocinas/biosíntesis , Infecciones/inmunología , Animales , Antígenos , Linfocitos B/citología , Diferenciación Celular , Células Dendríticas/inmunología , Humanos , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Interleucina-4/biosíntesis , Interleucina-6/biosíntesis , Linfotoxina-alfa/biosíntesis , Macrófagos/inmunología , Ratones , Modelos Inmunológicos , Transducción de Señal , Linfocitos T/inmunología
7.
Mech Ageing Dev ; 124(2): 155-65, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12633935

RESUMEN

Systemic and mucosal humoral immune responses have been reported to exhibit an age related decline. However, differences in primary and memory responses at mucosal sites in aged mice have been noted. In an effort to begin characterizing deficiencies in the mucosal system of aged mice, we examined the B cell compartment of gut associated Peyer's patch lymphoid tissue. To our surprise, we found that germinal center (GC) B cells from aged B6D2F1 mice (24-26 months) were present at similar frequencies and exhibited a normal activation phenotype such as upregulation of B7.1, B7.2 and CD44, and downregulation of CD23, CD62L and CD38 as that observed in younger mice (2.5-4 months). As expected, Peyer's patch GC B cells from aged mice expressing V(H)X24 genes displayed higher somatic mutation frequencies compared with younger mice. However, this was particularly striking in IgM sequences where high mutational loads suggested we were sampling memory cells. It is conceivable that B-cells expressing these genes reflect the presence of a mucosal memory compartment in aged mice that either retains flexibility in effector function or is committed to the secretion of IgM antibody.


Asunto(s)
Envejecimiento/fisiología , Centro Germinal/citología , Inmunoglobulina M/genética , Ganglios Linfáticos Agregados/citología , Hipermutación Somática de Inmunoglobulina/fisiología , Animales , Linfocitos B/citología , Linfocitos B/fisiología , Secuencia de Bases , Región Variable de Inmunoglobulina/genética , Memoria Inmunológica/genética , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Fenotipo
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