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1.
Immunology ; 151(3): 349-362, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28369800

RESUMEN

Marginal zone (MZ) B cells are positioned within the spleen to capture blood-borne antigen and immune complexes and deliver them to follicular dendritic cells in the B-cell follicles. We show that within the spleens of aged mice antigen capture by MZ B cells, and their ability to shuttle between the follicle and MZ, were impaired. The ability of aged MZ B cells to migrate towards the MZ chemoattractant sphingosine-1-phosphate was increased, suggesting that aged MZ B cells had a greater propensity to be retained within the MZ. An extrinsic impairment in aged B-cell migration towards the MZ was demonstrated using bone marrow chimeras. The follicular shuttling of MZ B cells derived from either young or aged bone marrow was similarly reduced in aged recipient spleens, showing that ageing effects on splenic stromal cells were responsible for the impaired follicular shuttling of MZ B cells. MZ B cells rapidly mount T-cell-independent (TI) antibody-responses to microbial polysaccharide antigen. In aged mice the ability to produce immunoglobulins in response to the TI type 1 antigen TNP-LPS was impaired. These ageing-related changes to the MZ and MZ B cells have implications for the clearance of blood-borne pathogens. Indeed elderly people have increased susceptibility to Streptococcus pneumoniae, a TI antigen, and decreased responses to vaccination. A thorough analysis of the mechanisms that underpin the ageing-related decline in the status of the MZ and MZ B cells will help the design of novel treatments to improve immunity in the elderly.


Asunto(s)
Envejecimiento/inmunología , Subgrupos de Linfocitos B/inmunología , Quimiotaxis , Activación de Linfocitos , Bazo/inmunología , Factores de Edad , Envejecimiento/sangre , Animales , Antígenos T-Independientes/sangre , Antígenos T-Independientes/inmunología , Subgrupos de Linfocitos B/efectos de los fármacos , Subgrupos de Linfocitos B/metabolismo , Trasplante de Médula Ósea , Proliferación Celular , Células Cultivadas , Quimiocina CXCL13/farmacología , Quimiotaxis/efectos de los fármacos , Femenino , Lipopolisacáridos/farmacología , Activación de Linfocitos/efectos de los fármacos , Lisofosfolípidos/farmacología , Ratones Endogámicos C57BL , Fenotipo , Esfingosina/análogos & derivados , Esfingosina/farmacología , Bazo/efectos de los fármacos , Bazo/metabolismo , Células del Estroma/inmunología , Quimera por Trasplante
2.
Immunology ; 151(2): 239-247, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28207940

RESUMEN

Lymph nodes (LN) are secondary lymphoid organs spread throughout the lymphatic system. They function to filter pathogenic material from the lymphatic fluid to maintain the health of the organism. Subcapsular sinus macrophages (SCSM) are among the first-responders within the LN due to their strategic location within the subcapsular sinus region. These macrophages aid the delivery of immune complexes to B cells and follicular dendritic cells (FDC) within the LN. Here we show an increase in SCSM and other macrophage populations within aged LN. However, immune complex uptake by macrophages within LN was not altered with age, nor was immune complex uptake by B cells. LN stromal cell populations, important in immune responses and the localization and survival of leucocytes, were altered in their representation and distribution in aged LN. In particular, FDC regions were decreased in size and had decreased chemokine CXCL13 expression. Furthermore, the retention of immune complexes by FDC was decreased in aged LN at 24 hr post-injection. As FDC are important in the maintenance of germinal centre responses, the decreased retention of immune complex in aged LN may contribute to the reduced germinal centre responses observed in aged mice.


Asunto(s)
Envejecimiento/inmunología , Ganglios Linfáticos/anatomía & histología , Ganglios Linfáticos/inmunología , Animales , Femenino , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL
3.
Biogerontology ; 18(5): 723-738, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28501894

RESUMEN

The elderly have a decreased response to vaccination and an increased susceptibility to infectious diseases. The spleen and lymph nodes are important secondary lymphoid organs where immune cells can rapidly respond to pathogenic material in the blood and lymph in order to mount long-term adaptive immune responses to those pathogens. In aged mice and humans structural changes occur to both the spleen and lymph nodes. These structural changes affect the functioning of the immune cells within, which may ultimate result in less effective or decreased immune responses. This review describes our current understanding of the structural changes that occur to the spleen and lymph nodes of elderly mice. However, where data are available, we also discuss whether similar changes occur in tissues from elderly humans. A particular focus is made on how these structural changes are considered to impact on the functioning of the immune cells within. The world's population is currently living longer than ever before. The increased incidence and severity of infectious diseases in the elderly has the potential to have a significant impact on the health care system if solutions are not identified. A thorough understanding of the molecular causes of these ageing-related structural changes to the spleen and lymph nodes may help to identify novel treatments that could repair them, and in doing so, improve immune responses and vaccine efficacy in the elderly.


Asunto(s)
Envejecimiento/fisiología , Ganglios Linfáticos/anatomía & histología , Bazo/anatomía & histología , Anciano , Animales , Humanos , Ganglios Linfáticos/inmunología , Ratones , Bazo/inmunología
4.
Immunol Rev ; 237(1): 90-103, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20727031

RESUMEN

Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes controlling B-cell survival and responsiveness, but also from the manipulation of antigen specificity made possible by targeting endogenous immunoglobulin loci. In this review, we discuss recent results obtained from our laboratory using gene-targeted mouse models to investigate the in vivo regulation of B-cell survival and responsiveness. The control of BAFF-dependent survival signals by the TRAF2- and TRAF3-signaling proteins is discussed as is the potential involvement of these molecules in B-lineage malignancies. We also outline the development and use of the SW(HEL) model for analyzing antigen-specific B-cell responses in vivo. This includes insights into the control of early decision-making during T-dependent B-cell differentiation, the affinity maturation and plasma cell differentiation of germinal center B cells, and the identification of EBI2 as a key regulator of B-cell migration and differentiation.


Asunto(s)
Linfocitos B/inmunología , Animales , Linfocitos B/citología , Supervivencia Celular , Centro Germinal/citología , Centro Germinal/inmunología , Ratones , Modelos Inmunológicos , Factor 2 Asociado a Receptor de TNF/metabolismo , Factor 3 Asociado a Receptor de TNF/metabolismo
5.
Blood ; 117(15): 4041-51, 2011 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-21300983

RESUMEN

B cells require signals delivered through B-cell activating factor of the TNF family receptor (BAFF-R) and CD40 to survive and produce antibody responses in vivo. In vitro data indicate that these signals are controlled by the homologous RING finger proteins cIAP1 and cIAP2, in collaboration with TRAF2 and TRAF3. There is also mounting evidence that all 4 of these signaling molecules can act as tumor suppressors in human B-lineage malignancies. However, it has not been possible to identify the roles of cIAP1 and cIAP2 in controlling B-cell physiology because of the absence of an appropriate in vivo model. Here we describe a unique genetically modified mouse in which the linked cIap1 and cIap2 genes can be independently inactivated. Deletion of cIAP1 plus cIAP2 (but not either protein alone) rendered primary B cells independent of BAFF-R for their survival and led to their uncontrolled accumulation in vivo. B cells deficient in cIAP1 and cIAP2 were also incapable of forming germinal centers, a key step in antibody-mediated immunity. These data define a fundamental role for cIAP1/cIAP2 in regulating B-cell survival and responsiveness, show this requires direct binding to TRAF2, and suggest how mutations of TRAF2, TRAF3, and cIAP1/cIAP2 contribute to B-lineage malignancies, such as multiple myeloma.


Asunto(s)
Linfocitos B/citología , Linfocitos B/fisiología , Centro Germinal/citología , Proteínas Inhibidoras de la Apoptosis/genética , Animales , Factor Activador de Células B/metabolismo , Receptor del Factor Activador de Células B/metabolismo , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Antígenos CD40/metabolismo , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Supervivencia Celular/inmunología , Eliminación de Gen , Centro Germinal/fisiología , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/inmunología , Factor 2 Asociado a Receptor de TNF/genética , Factor 2 Asociado a Receptor de TNF/metabolismo , Factor 3 Asociado a Receptor de TNF/genética , Factor 3 Asociado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligasas
6.
J Immunol ; 187(10): 5032-42, 2011 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-22003205

RESUMEN

Krüppel-like factor 3 (Klf3) is a member of the Klf family of transcription factors. Klfs are widely expressed and have diverse roles in development and differentiation. In this study, we examine the function of Klf3 in B cell development by studying B lymphopoiesis in a Klf3 knockout mouse model. We show that B cell differentiation is significantly impaired in the bone marrow, spleen, and peritoneal cavity of Klf3 null mice and confirm that the defects are cell autonomous. In the bone marrow, there is a reduction in immature B cells, whereas recirculating mature cells are noticeably increased. Immunohistology of the spleen reveals a poorly structured marginal zone (MZ) that may in part be caused by deregulation of adhesion molecules on MZ B cells. In the peritoneal cavity, there are significant defects in B1 B cell development. We also report that the loss of Klf3 in MZ B cells is associated with reduced BCR signaling strength and an impaired ability to respond to LPS stimulation. Finally, we show increased expression of a number of Klf genes in Klf3 null B cells, suggesting that a Klf regulatory network may exist in B cells.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Factores de Transcripción de Tipo Kruppel/deficiencia , Factores de Transcripción de Tipo Kruppel/genética , Linfopoyesis/genética , Linfopoyesis/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Peritoneo/inmunología , Peritoneo/metabolismo , Peritoneo/patología , Quimera por Radiación/genética , Quimera por Radiación/inmunología , Bazo/inmunología , Bazo/metabolismo , Bazo/patología
7.
J Exp Med ; 218(2)2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33119033

RESUMEN

The TNF superfamily ligand BAFF maintains the survival of naive B cells by signaling through its surface receptor, BAFFR. Activated B cells maintain expression of BAFFR after they differentiate into germinal center (GC) or memory B cells (MBCs). However, the functions of BAFFR in these antigen-experienced B cell populations remain unclear. Here, we show that B cell-intrinsic BAFFR does not play a significant role in the survival or function of GC B cells or in the generation of the somatically mutated MBCs derived from them. Instead, BAFF/BAFFR signaling was required to generate the unmutated, GC-independent MBCs that differentiate directly from activated B cell blasts early in the response. Furthermore, amplification of BAFFR signaling in responding B cells did not affect GCs or the generation of GC-derived MBCs but greatly expanded the GC-independent MBC response. Although BAFF/BAFFR signaling specifically controlled the formation of the GC-independent MBC response, both types of MBCs required input from this pathway for optimal long-term survival.


Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Memoria Inmunológica/inmunología , Animales , Factor Activador de Células B/inmunología , Factor Activador de Células B/metabolismo , Receptor del Factor Activador de Células B/inmunología , Receptor del Factor Activador de Células B/metabolismo , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiología
8.
J Immunol Methods ; 360(1-2): 162-6, 2010 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-20600080

RESUMEN

Transduction of bone marrow stem cells with retroviral expression vectors represents a cheaper and more rapid alternative to conventional transgenesis for studies of in vivo gene function. However, achieving tissue-specific expression of genes inserted into retroviral vectors is notoriously difficult. We have developed a single tri-cistronic retroviral vector (MG(f)I4) that facilitates Cre-dependent, lineage-specific gene expression within hematopoietic cells. Bone marrow stem cells transduced with MG(f)I4 co-express a loxP-flanked (floxed) eGFP cDNA together with truncated human CD4 (hCD4Delta). Open reading frames (ORFs) cloned between these two cDNAs are not constitutively translated but are activated upon Cre-mediated removal of the eGFP cDNA. Mice reconstituted with transduced bone marrow stem cells obtained from Cd19-Cre, Cr2-Cre or Lck-Cre, donors were shown to specifically express an ORF insert in the appropriate lymphocyte subsets. Cells that had activated ORF expression were identifiable by transition from a GFP+, hCD4+ to a GFP(-), hCD4+ phenotype. The use of this novel vector in conjunction with the wide range of well-characterized Cre-transgenic lines will be a versatile tool for exploring gene function within the immune system. In particular, this approach will provide a convenient way to test the functional significance of naturally occurring genetic mutations linked to human disease.


Asunto(s)
Vectores Genéticos , Células Madre Hematopoyéticas/metabolismo , Integrasas/metabolismo , Subgrupos Linfocitarios/metabolismo , Retroviridae/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Antígenos CD19/genética , Antígenos CD19/metabolismo , Células de la Médula Ósea/patología , Trasplante de Médula Ósea , Antígenos CD4/genética , Antígenos CD4/metabolismo , Linaje de la Célula/genética , Proteínas Fluorescentes Verdes/genética , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/patología , Humanos , Integrasas/genética , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Receptores de Complemento 3d/genética , Receptores de Complemento 3d/metabolismo , Eliminación de Secuencia
9.
Cancer Res ; 70(18): 7273-82, 2010 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-20807818

RESUMEN

Tumor angiogenesis is essential for malignant growth and metastasis. Bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute to angiogenesis-mediated tumor growth. EPC ablation can reduce tumor growth; however, the lack of a marker that can track EPCs from the BM to tumor neovasculature has impeded progress in understanding the molecular mechanisms underlying EPC biology. Here, we report the use of transgenic mouse and lentiviral models to monitor the BM-derived compartment of the tumor stroma; this approach exploits the selectivity of the transcription factor inhibitor of DNA binding 1 (Id1) for EPCs to track EPCs in the BM, blood, and tumor stroma, as well as mature EPCs. Acute ablation of BM-derived EPCs using Id1-directed delivery of a suicide gene reduced circulating EPCs and yielded significant defects in angiogenesis-mediated tumor growth. Additionally, use of the Id1 proximal promoter to express microRNA-30-based short hairpin RNA inhibited the expression of critical EPC-intrinsic factors, confirming that signaling through vascular endothelial growth factor receptor 2 is required for EPC-mediated tumor biology. By exploiting the selectivity of Id1 gene expression in EPCs, our results establish a strategy to track and target EPCs in vivo, clarifying the significant role that EPCs play in BM-mediated tumor angiogenesis.


Asunto(s)
Carcinoma Pulmonar de Lewis/genética , Células Endoteliales/fisiología , Proteína 1 Inhibidora de la Diferenciación/genética , Células Madre/fisiología , Animales , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Procesos de Crecimiento Celular/genética , Línea Celular Tumoral , Pollos , Células Endoteliales/patología , Perfilación de la Expresión Génica , Proteína 1 Inhibidora de la Diferenciación/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Células Madre/patología , Células del Estroma/patología , Regulación hacia Arriba
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