Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
2.
J Cell Sci ; 124(Pt 21): 3568-80, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-22045735

RESUMEN

Mutations in sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) underlie Darier disease (DD), a dominantly inherited skin disorder characterized by loss of keratinocyte adhesion (acantholysis) and abnormal keratinization (dyskeratosis) resulting in characteristic mucocutaneous abnormalities. However, the molecular pathogenic mechanism by which these changes influence keratinocyte adhesion and viability remains unknown. We show here that SERCA2 protein is extremely sensitive to endoplasmic reticulum (ER) stress, which typically results in aggregation and insolubility of the protein. Depletion of ER calcium stores is not necessary for the aggregation but accelerates the progression. Systematic analysis of diverse mutants identical to those found in DD patients demonstrated that the ER stress initiator is the SERCA2 mutant protein itself. These SERCA2 proteins were found to be less soluble, to aggregate and to be more polyubiquitinylated. After transduction into primary human epidermal keratinocytes, mutant SERCA2 aggregates elicited ER stress, caused increased numbers of cells to round up and detach from the culture plate, and induced apoptosis. These mutant induced events were exaggerated by increased ER stress. Furthermore, knockdown SERCA2 in keratinocytes rendered the cells resistant to apoptosis induction. These features of SERCA2 and its mutants establish a mechanistic base to further elucidate the molecular pathogenesis underlying acantholysis and dyskeratosis in DD.


Asunto(s)
Apoptosis , Enfermedad de Darier/enzimología , Estrés del Retículo Endoplásmico , Queratinocitos/citología , Mutación , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/química , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Células Cultivadas , Enfermedad de Darier/genética , Enfermedad de Darier/metabolismo , Enfermedad de Darier/fisiopatología , Humanos , Queratinocitos/enzimología , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Solubilidad
3.
J Immunol ; 187(1): 490-500, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21606249

RESUMEN

IL-17 and IL-23 are known to be absolutely central to psoriasis pathogenesis because drugs targeting either cytokine are highly effective treatments for this disease. The efficacy of these drugs has been attributed to blocking the function of IL-17-producing T cells and their IL-23-induced expansion. However, we demonstrate that mast cells and neutrophils, not T cells, are the predominant cell types that contain IL-17 in human skin. IL-17(+) mast cells and neutrophils are found at higher densities than IL-17(+) T cells in psoriasis lesions and frequently release IL-17 in the process of forming specialized structures called extracellular traps. Furthermore, we find that IL-23 and IL-1ß can induce mast cell extracellular trap formation and degranulation of human mast cells. Release of IL-17 from innate immune cells may be central to the pathogenesis of psoriasis, representing a fundamental mechanism by which the IL-23-IL-17 axis mediates host defense and autoimmunity.


Asunto(s)
Espacio Extracelular/metabolismo , Interleucina-17/metabolismo , Mastocitos/metabolismo , Neutrófilos/metabolismo , Psoriasis/metabolismo , Psoriasis/patología , Quimasas/biosíntesis , Humanos , Inmunidad Innata , Recuento de Leucocitos , Mastocitos/enzimología , Mastocitos/patología , Neutrófilos/enzimología , Neutrófilos/patología , Piel/inmunología , Piel/metabolismo , Piel/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Triptasas/biosíntesis
4.
J Immunol ; 187(1): 538-52, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21613614

RESUMEN

An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils. LDGs significantly overexpress mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus and control neutrophils. In contrast, gene profiles of lupus normal-density neutrophils do not differ from those of controls. LDGs have heightened capacity to synthesize neutrophils extracellular traps (NETs), which display increased externalization of bactericidal, immunostimulatory proteins, and autoantigens, including LL-37, IL-17, and dsDNA. Through NETosis, LDGs have increased capacity to kill endothelial cells and to stimulate IFN-α synthesis by plasmacytoid dendritic cells. Affected skin and kidneys from lupus patients are infiltrated by netting neutrophils, which expose LL-37 and dsDNA. Tissue NETosis is associated with increased anti-dsDNA in sera. These results expand the potential pathogenic roles of aberrant lupus neutrophils and suggest that dysregulation of NET formation and its subsequent responses may play a prominent deleterious role.


Asunto(s)
Adyuvantes Inmunológicos/toxicidad , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Infiltración Neutrófila/inmunología , Autoantígenos/inmunología , Autoantígenos/toxicidad , Línea Celular , Pruebas Inmunológicas de Citotoxicidad , Humanos , Recuento de Leucocitos , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Análisis de Secuencia por Matrices de Oligonucleótidos
5.
J Immunol ; 181(7): 4733-41, 2008 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-18802076

RESUMEN

Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-gamma inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4(+) and CD8(+) IL-17(+) T cells in skin lesions of psoriasis. Furthermore, we show that myeloid APCs potently support induction of IL-17(+) T cells, and that this activity is greatly increased in psoriasis. We tested stimuli that might account for this activity. Th1 cells and IFN-gamma are increased in psoriatic blood and lesional skin. We show that IFN-gamma programs myeloid APCs to induce human IL-17(+) T cells via IL-1 and IL-23. IFN-gamma also stimulates APC production of CCL20, supporting migration of IL-17(+) T cells, and synergizes with IL-17 in the production of human beta-defensin 2, an antimicrobial and chemotactic protein highly overexpressed by psoriatic keratinocytes. This study reveals a novel mechanistic interaction between Th1 and IL-17(+) T cells, challenges the view that Th1 cells suppress Th17 development through IFN-gamma, and suggests that Th1 and IL-17(+) T cells may collaboratively contribute to human autoimmune diseases.


Asunto(s)
Movimiento Celular/inmunología , Interferón gamma/fisiología , Interleucina-17/biosíntesis , Psoriasis/inmunología , Psoriasis/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Comunicación Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Humanos , Inmunofenotipificación , Interleucina-17/metabolismo , Interleucina-17/fisiología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Células Mieloides/patología , Psoriasis/metabolismo , Piel/citología , Piel/inmunología , Piel/metabolismo , Subgrupos de Linfocitos T/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/patología
6.
J Interferon Cytokine Res ; 26(11): 804-19, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17115899

RESUMEN

Herein we report the generation of mouse monoclonal antibodies (mAbs) specific for the IFNAR-1 subunit of the mouse interferon-alpha/beta (IFN-alpha/beta) receptor (MAR1 mAbs) that block type I IFN receptor signaling and biologic response induction in vitro and in vivo. These mAbs were generated from Ifnar1 (/) mice immunized by in vivo hydrodynamic transfection with a plasmid encoding the extracellular domain (ECD) of murine IFNAR-1. All MAR1 mAbs bound native receptor expressed on cell surfaces and immunoprecipitated IFNAR-1 from solubilized cells, and two mAbs also detected IFNAR-1 by Western blot analysis. in vitro, the mAbs prevented ligand-induced intracellular signaling and induction of a variety of type I IFN-induced biologic responses but had no effect on IFN-gamma-induced responses. The most effective in vitro blocker, MAR1-5A3, also blocked type I IFN-induced antiviral, antimicrobial, and antitumor responses in vivo. We also explored whether murine IFNAR-1 surface expression required the presence of Tyk2. In contrast to Tyk2-deficient human cell lines, comparable IFNAR-1 expression was found on primary cells derived either from wild-type or Tyk2 (/) mice. These mAbs represent much needed tools to more clearly elucidate the biochemistry, cell biology, and physiologic function of the type I IFNs and their receptor in mediating host-protective immunity and immunopathology.


Asunto(s)
Anticuerpos Bloqueadores/inmunología , Anticuerpos Monoclonales/inmunología , Receptor de Interferón alfa y beta/inmunología , Animales , Anticuerpos Bloqueadores/aislamiento & purificación , Anticuerpos Monoclonales/aislamiento & purificación , Especificidad de Anticuerpos , Expresión Génica , Inmunización/métodos , Ratones , Ratones Noqueados , Plásmidos/genética , Plásmidos/inmunología , Receptor de Interferón alfa y beta/antagonistas & inhibidores , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/genética , TYK2 Quinasa/deficiencia , TYK2 Quinasa/inmunología , Transfección/métodos
7.
Immunol Res ; 32(1-3): 231-45, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16106075

RESUMEN

Over the last 12 yr, we have shown that interferon-gamma and lymphocytes collaborate to regulate tumor development in mice. Specifically, we found that the immune system not only prevents the growth of primary (carcinogen-induced and spontaneous) and transplanted tumors but also sculpts the immunogenicity of tumors that form. These observations led us to refine the old and controversial "cancer immunosurveillance" hypothesis of Burnet and Thomas into one that we termed cancer immunoediting that better emphasizes the paradoxical host-protective and tumor-sculpting roles of immunity on developing tumors. Our current work focuses on defining the molecular mechanisms that underlie cancer immunoediting and exploring the implications of this process for cancer immunotherapy.


Asunto(s)
Interferón gamma/inmunología , Neoplasias/inmunología , Animales , Genes p53 , Rechazo de Injerto/inmunología , Humanos , Inmunoterapia , Linfocitos/inmunología , Ratones , Ratones Noqueados , Modelos Inmunológicos , Monitorización Inmunológica , Trasplante de Neoplasias , Neoplasias/prevención & control , Neoplasias/terapia , Transducción de Señal/inmunología , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/inmunología
8.
J Invest Dermatol ; 130(5): 1213-26, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-19812592

RESUMEN

Psoriasis is a common and debilitating disease of the skin, nails, and joints, with an acknowledged but complex genetic basis. Early genome-wide linkage studies of psoriasis focused on segregation of microsatellite markers in families; however, the only locus consistently identified resided in the major histocompatibility complex. Subsequently, several groups mapped this locus to the vicinity of HLA-C, and two groups have reported HLA-Cw6 itself to be the major susceptibility allele. More recently, the development of millions of single-nucleotide polymorphisms, coupled with the development of high-throughput genotyping platforms and a comprehensive map of human haplotypes, has made possible a genome-wide association approach using cases and controls rather than families. Taking advantage of these developments, we participated in a collaborative genome-wide association study of psoriasis involving thousands of cases and controls. Initial analysis of these data revealed and/or confirmed association between psoriasis and seven genetic loci-HLA-C, IL12B, IL23R, IL23A, IL4/IL13, TNFAIP3, and TNIP1-and ongoing studies are revealing additional loci. Here, we review the epidemiology, immunopathology, and genetics of psoriasis, and present a disease model integrating its genetics and immunology.


Asunto(s)
Marcadores Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Psoriasis , Humanos , Psoriasis/epidemiología , Psoriasis/genética , Psoriasis/inmunología
9.
Nat Immunol ; 6(7): 722-9, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15951814

RESUMEN

'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-gamma (IFN-gamma) is known to be involved in this process, the involvement of type I interferons (IFN-alpha/beta) has not been elucidated. We now show that, like IFN-gamma, endogenously produced IFN-alpha/beta was required for the prevention of the growth of primary carcinogen-induced and transplantable tumors. Although tumor cells are important IFN-gamma targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-alpha/beta targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-gamma.


Asunto(s)
Interferón-alfa/inmunología , Proteínas de la Membrana/inmunología , Neoplasias Experimentales/inmunología , Receptores de Interferón/inmunología , Sarcoma/inmunología , Escape del Tumor/inmunología , Animales , Proteínas de Unión al ADN/inmunología , Hematopoyesis/inmunología , Metilcolantreno , Ratones , Ratones Noqueados , Quimera por Radiación , Receptor de Interferón alfa y beta
10.
Nat Immunol ; 3(11): 991-8, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12407406

RESUMEN

The concept that the immune system can recognize and destroy nascent transformed cells was originally embodied in the cancer immunosurveillance hypothesis of Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of the absence of strong experimental evidence supporting the concept. New data, however, clearly show the existence of cancer immunosurveillance and also indicate that it may function as a component of a more general process of cancer immunoediting. This process is responsible for both eliminating tumors and sculpting the immunogenic phenotypes of tumors that eventually form in immunocompetent hosts. In this review, we will summarize the historical and experimental basis of cancer immunoediting and discuss its dual roles in promoting host protection against cancer and facilitating tumor escape from immune destruction.


Asunto(s)
Antígenos de Neoplasias/inmunología , Vigilancia Inmunológica , Modelos Inmunológicos , Neoplasias/inmunología , Escape del Tumor , Animales , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Humanos , Huésped Inmunocomprometido , Vigilancia Inmunológica/genética , Vigilancia Inmunológica/inmunología , Terapia de Inmunosupresión/efectos adversos , Incidencia , Ratones , Ratones Endogámicos , Ratones Noqueados , Ratones Desnudos , Ratones SCID , Neoplasias/epidemiología , Neoplasias/genética , Complicaciones Posoperatorias/inmunología , Selección Genética , Inmunología del Trasplante
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA