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1.
N Engl J Med ; 388(8): 694-705, 2023 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-36812433

RESUMEN

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. CONCLUSIONS: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).


Asunto(s)
Factor VIII , Hemofilia A , Humanos , Masculino , Factor VIII/uso terapéutico , Técnicas de Transferencia de Gen , Semivida , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Hemorragia/etiología , Hemorragia/prevención & control , Proteínas Recombinantes de Fusión/uso terapéutico
2.
J Immunol ; 194(6): 2482-5, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25681343

RESUMEN

B cells require CD4(+) T follicular helper (Tfh) cells to progress through the germinal center and provide protective Ab responses. In this article, we reveal a reciprocal interaction whereby circulating human plasmablasts are potent inducers of the Tfh cell-differentiation program, including the expression of their key transcription factor Bcl-6. The markedly increased propensity of plasmablasts, compared with naive B cells, to induce Tfh cell differentiation was due to their increased production of IL-6. Specific targeting of IL-6 using tocilizumab therapy in patients with rheumatoid arthritis led to a significant reduction in circulating Tfh cell numbers and IL-21 production, which was correlated with reduced plasmablast formation. Our data uncover a positive-feedback loop between circulating plasmablasts and Tfh cells that could sustain autoimmunity and spread Ab-driven inflammation to unaffected sites; this represents an important therapeutic target, as well as reveals a novel mechanism of action for tocilizumab.


Asunto(s)
Diferenciación Celular/inmunología , Interleucina-6/inmunología , Células Plasmáticas/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Citometría de Flujo , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Interleucina-6/metabolismo , Interleucinas/inmunología , Interleucinas/metabolismo , Células Plasmáticas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores CXCR5/inmunología , Receptores CXCR5/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo
3.
Ann Rheum Dis ; 74(1): 294-302, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24249811

RESUMEN

OBJECTIVE: To investigate whether regulatory T cells (Treg) can control B cell function in rheumatoid arthritis (RA) and if not to explore the basis for this defect. METHODS: Suppression of B cell responses by Treg was analysed in vitro by flow cytometry and ELISA using peripheral blood mononuclear cells from 65 patients with RA and 41 sex-matched and aged-matched healthy volunteers. Blocking and agonistic antibodies were used to define the role of Fas-mediated apoptosis in B cell regulation. RESULTS: Treg failed to restrain B cell activation, proinflammatory cytokine and antibody production in the presence of responder T cells in RA patients. This lack of suppression was not only caused by impaired Treg function but was also due to B cell resistance to regulation. In healthy donors, control by Treg was associated with increased B cell death and relied upon Fas-mediated apoptosis. In contrast, RA B cells had reduced Fas expression compared with their healthy counterparts and were resistant to Fas-mediated apoptosis. CONCLUSIONS: These studies demonstrate that Treg are unable to limit B cell responses in RA. This appears to be primarily due to B cell resistance to suppression, but Treg defects also contribute to this failure of regulation. Our data identify the Fas pathway as a novel target for Treg-mediated suppression of B cells and highlight a potential therapeutic approach to restore control of B cells by Treg in RA patients.


Asunto(s)
Apoptosis/fisiología , Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Linfocitos T Reguladores/inmunología , Receptor fas/metabolismo , Linfocitos B/metabolismo , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Humanos , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/inmunología , Masculino
4.
Kidney Int ; 83(6): 1150-8, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23423260

RESUMEN

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) commonly results in glomerulonephritis, in which neutrophils and monocytes have important roles. The heterodimer calprotectin (S100A8/S100A9, mrp8/14) is a Toll-like receptor-4 ligand found in neutrophils and monocytes and is elevated in inflammatory conditions. By immunohistochemistry of renal biopsies, patients with focal or crescentic glomerular lesions were found to have the highest expression of calprotectin and those with sclerotic the least. Serum levels of calprotectin as measured by ELISA were elevated in patients with active AAV and the levels decreased but did not normalize during remission, suggesting subclinical inflammation. Calprotectin levels in patients with limited systemic disease increased following treatment withdrawal and were significantly elevated in patients who relapsed compared with those who did not. As assessed by flow cytometry, patients with AAV had higher monocyte and neutrophil cell surface calprotectin expression than healthy controls, but this was not associated with augmented mRNA expression in CD14(+) monocytes or CD16(+) neutrophils. Thus, serum calprotectin is a potential disease biomarker in patients with AAV, and may have a role in disease pathogenesis.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Calgranulina A/sangre , Calgranulina B/sangre , Glomerulonefritis/inmunología , Mediadores de Inflamación/sangre , Riñón/inmunología , Leucocitos/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Biomarcadores/sangre , Biopsia , Estudios de Casos y Controles , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Glomerulonefritis/sangre , Glomerulonefritis/patología , Glomerulonefritis/terapia , Humanos , Inmunohistoquímica , Riñón/patología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Valor Predictivo de las Pruebas , Pronóstico , Multimerización de Proteína , Inducción de Remisión , Adulto Joven
5.
Rheumatology (Oxford) ; 51(7): 1208-15, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22337941

RESUMEN

OBJECTIVES: To correlate the kinetics of B-cell repopulation with relapse after B-cell depletion therapy in SLE patients and address whether variation in relapse rate, B-cell numbers and phenotype are related to anti-dsDNA antibody levels. METHODS: Sixty-one patients with refractory SLE were treated with a standard rituximab regimen. Clinical and serological measures of disease activity and B-cell numbers were assessed. B-cell phenotype was examined in a subgroup of patients by flow cytometry. RESULTS: Disease relapse was substantially delayed beyond B-cell repopulation, and early relapse was associated with a faster rate of repopulation. At relapse, B-cell numbers were significantly lower than at baseline in patients with high anti-dsDNA antibody levels (> 100 IU/ml) but not in patients with low anti-dsDNA antibody levels. Of the patients with high anti-dsDNA antibodies at baseline, levels fell significantly only in those patients who remained in remission after repopulation. Relapse with high anti-dsDNA antibody levels was associated with an increased percentage of IgD(-)CD27(hi) plasmablasts, whereas relapse with low anti-dsDNA antibody levels was accompanied by an increased percentage of IgD(-)CD27(-) B cells. CONCLUSION: Anti-dsDNA antibody levels distinguished two patient groups, which differ in their B-cell number and phenotype at relapse following rituximab, and suggest that different B-cell pathologies exist in SLE. The data imply that B-cell numbers should be kept very low for a sustained period in patients with high dsDNA binding, therefore justifying a more aggressive regimen.


Asunto(s)
Anticuerpos Antinucleares/sangre , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Linfocitos B/patología , Endopeptidasas/inmunología , Inmunidad Celular , Lupus Eritematoso Sistémico/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Antinucleares/inmunología , Antígenos CD20 , Linfocitos B/inmunología , Linfocitos B/metabolismo , Niño , Endopeptidasas/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Factores Inmunológicos/uso terapéutico , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/patología , Masculino , Persona de Mediana Edad , Fenotipo , Rituximab , Resultado del Tratamiento , Adulto Joven
6.
Arthritis Rheum ; 62(5): 1539-48, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20155828

RESUMEN

OBJECTIVE: T lymphocytes have been implicated in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients with myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) experience relapses less frequently than those with proteinase 3 ANCA, suggesting greater immune regulation. This study was undertaken to investigate MPO-specific T cell reactivity during disease remission and the factors regulating their responsiveness. METHODS: MPO-specific T cells were quantified by enzyme-linked immunospot assay with additional Treg cell depletion or exogenous interleukin-2. Serum tryptophan and its metabolites were measured. In vivo blockade of indoleamine 2,3-dioxygenase (IDO) was performed, and its effect on MPO reactivity was assessed. RESULTS: During disease remission, MPO-specific interferon-gamma-producing T cell frequencies were comparable with those found in healthy controls and significantly lower than those found in patients with acute disease. CD4+CD25+ regulatory cells did not play a role in maintaining these low MPO-specific T cell frequencies, since depletion of Treg cells did not augment MPO-specific responses, and FoxP3 levels were diminished in patients compared with controls. Treg cell function, however, was comparable in patients and controls, suggesting numerical rather than functional deficiency. We found diminished serum tryptophan levels and elevated levels of its metabolite kynurenine in patients with MPO AAV as compared with controls. To confirm the effect of tryptophan degradation on MPO responses in vivo, we inhibited degradation in MPO-immunized WKY rats and found greater immune responsiveness to MPO and a tendency to more severe glomerulonephritis. CONCLUSION: Our findings indicate that MPO-specific T cell frequencies are regulated during disease remission in association with tryptophan degradation. The tryptophan regulatory pathway is induced during active disease and persists during disease remission.


Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Linfocitos T Reguladores/inmunología , Triptófano/sangre , Vasculitis/inmunología , Vasculitis/metabolismo , Enfermedad Aguda , Anciano , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunosupresores/uso terapéutico , Quinurenina/sangre , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neopterin/sangre , Peroxidasa/metabolismo , Inducción de Remisión , Linfocitos T Reguladores/enzimología , Vasculitis/tratamiento farmacológico
7.
Nephrol Dial Transplant ; 25(7): 2209-17, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20100727

RESUMEN

BACKGROUND: The Th17 subset has been implicated in the pathogenesis of a number of autoimmune diseases. However, little is known about its role in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). We measured serum levels of IL-17A and associated upstream cytokines and the frequency of IL-17-producing autoantigen-specific T cells in patients with AAV. METHODS: ELISA on sera from acute (n = 28) and convalescent (n = 65) patients with AAV from Hammersmith Hospital was performed for IL-17A and the associated upstream cytokines IL-23, IL-6 and IL-1beta, as well as the Th1 cytokine IFN-gamma. ELISPOT was performed to measure autoantigen-specific recall T cell responses in convalescent patients and the frequency of IL-17- and IFN-gamma-producing cells. RESULTS: Serum IL-17A and IL-23 levels were significantly elevated in acute AAV patients compared to healthy controls (P < 0.01 and P < 0.001, respectively), but importantly, remained elevated in a proportion of convalescent patients. By contrast, no significant differences in IFN-gamma levels were detected between patient groups and controls. Patients with elevated levels of IL-23 compared to those with low IL-23 had more active disease as measured by Birmingham Vasculitis Activity Score (P < 0.05) and had higher ANCA titres (P < 0.05). Critically, immunosuppressive therapy did not always effectively suppress IL-23 or IL-17 production. Additionally, autoantigen-specific IL-17-producing, but not IFN-gamma-producing, cells were significantly elevated in patients during disease convalescence compared to healthy controls. CONCLUSIONS: These data implicate the Th17 axis and specifically IL-23 as mediators of more severe disease in AAV. Their persistence despite conventional treatment may contribute to high relapse rates.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Interleucina-17/sangre , Interleucina-23/sangre , Subgrupos de Linfocitos T/patología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Estudios de Casos y Controles , Femenino , Humanos , Interferón gamma/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología
8.
Rheumatology (Oxford) ; 48(12): 1502-5, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19815671

RESUMEN

OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNPs) within cytotoxic T-lymphocyte antigen-4 (CTLA-4) are associated with ANCA-associated small vessel vasculitis (SVV). METHODS: The CTLA-4 CT60 (exon 4), +49 (exon 1) and -318 (promoter region) genotypes were determined by PCR and restriction fragment length polymorphism (RFLP) in 222 white Caucasians of UK origin with SVV and 670 ethnically matched controls. RESULTS: The CTLA-4 exon 1 (+49) and 4 (CT60) polymorphisms are associated with SVV (+49: chi(2) = 10.965, P = 0.004; CT60: chi(2) = 12.017, P = 0.002). Both disease-susceptible and disease-protective haplotypes have been identified in this cohort, and their frequencies are similar in the subtypes of WG and microscopic polyangiitis. CONCLUSION: This study provides further evidence that CTLA-4, a susceptibility locus for a number of common autoimmune diseases, may also be involved in the development of ANCA-associated SVV.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Antígenos CD/genética , Polimorfismo de Nucleótido Simple , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Antígeno CTLA-4 , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos
9.
Front Immunol ; 10: 361, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30891036

RESUMEN

The intestinal mucosa in inflammatory bowel disease (IBD) contains increased frequencies of lymphocytes and a disproportionate increase in plasma cells secreting immunoglobulin (Ig)G relative to other isotypes compared to healthy controls. Despite consistent evidence of B lineage cells in the mucosa in IBD, little is known of B cell recruitment to the gut in IBD. Here we analyzed B cells in blood of patients with Crohn's disease (CD) and ulcerative colitis (UC) with a range of disease activities. We analyzed the frequencies of known B cell subsets in blood and observed a consistent reduction in the proportion of CD27-IgD- B cells expressing all Ig isotypes in the blood in IBD (independent of severity of disease and treatment) compared to healthy controls. Successful treatment of patients with biologic therapies did not change the profile of B cell subsets in blood. By mass cytometry we demonstrated that CD27-IgD- B cells were proportionately enriched in the gut-associated lymphoid tissue (GALT) in IBD. Since production of TNFα is a feature of IBD relevant to therapies, we sought to determine whether B cells in GALT or the CD27-IgD- subset in particular could contribute to pathology by secretion of TNFα or IL-10. We found that donor matched GALT and blood B cells are capable of producing TNFα as well as IL-10, but we saw no evidence that CD27-IgD- B cells from blood expressed more TNFα compared to other subsets. The reduced proportion of CD27-IgD- B cells in blood and the increased proportion in the gut implies that CD27-IgD- B cells are recruited from the blood to the gut in IBD. CD27-IgD- B cells have been implicated in immune responses to intestinal bacteria and recruitment to GALT, and may contribute to the intestinal inflammatory milieu in IBD.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Colitis Ulcerosa/sangre , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/inmunología , Inmunoglobulina D/metabolismo , Mucosa Intestinal/inmunología , Ganglios Linfáticos Agregados/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biopsia , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/patología , Femenino , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/uso terapéutico , Interleucina-10/metabolismo , Mucosa Intestinal/patología , Masculino , Ganglios Linfáticos Agregados/patología , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/metabolismo , Ustekinumab/uso terapéutico
10.
Nat Commun ; 9(1): 3857, 2018 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-30242242

RESUMEN

Human memory B cells and marginal zone (MZ) B cells share common features such as the expression of CD27 and somatic mutations in their IGHV and BCL6 genes, but the relationship between them is controversial. Here, we show phenotypic progression within lymphoid tissues as MZ B cells emerge from the mature naïve B cell pool via a precursor CD27-CD45RBMEM55+ population distant from memory cells. By imaging mass cytometry, we find that MZ B cells and memory B cells occupy different microanatomical niches in organised gut lymphoid tissues. Both populations disseminate widely between distant lymphoid tissues and blood, and both diversify their IGHV repertoire in gut germinal centres (GC), but nevertheless remain largely clonally separate. MZ B cells are therefore not developmentally contiguous with or analogous to classical memory B cells despite their shared ability to transit through GC, where somatic mutations are acquired.


Asunto(s)
Linfocitos B , Tejido Linfoide/citología , Humanos , Memoria Inmunológica , Tejido Linfoide/inmunología , Fenotipo
11.
J Bone Miner Res ; 21(11): 1770-7, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17002582

RESUMEN

UNLABELLED: Intestinal absorption of calcium affects bone mineralization and varies greatly. In human duodenum, expression of the calcium channel TRPV6 was directly related to blood 1,25-dihydroxyvitamin D in men, but effects of age with lower median vitamin D receptor levels were more significant in women. INTRODUCTION: The TRPV6 calcium channel/transporter is implicated in animal studies of intestinal calcium absorption, but in humans, its role and relationship to differences in mineral metabolism is unclear. We aimed to characterize TRPV6 expression in human intestine including defining relationships to the vitamin D endocrine system. MATERIALS AND METHODS: TRPV6 transcript expression was determined in endoscopic mucosal biopsies obtained from normal duodenum. Expression was compared with that in ileum and with in situ hybridization in archival tissues and related to sequence variants in genomic DNA. TRPV6 expression was related in 33 subjects to other transcripts involved in calcium absorption including the vitamin D receptor (VDR) and to blood vitamin D metabolites including 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. RESULTS: TRPV6 transcripts were readily detected in duodenum but not in ileum. Expression was highest in villous epithelial cells. Sequence variants in the coding and upstream regions of the gene did not affect TRPV6 expression. The relationship between duodenal TRPV6 expression and 1,25(OH)(2)D differed in men and women. In men, linear regression showed a strong association with 1,25(OH)(2)D (r = 0.87, p < 0.01), which was unaffected by age. In women, there was no significant overall relationship with 1,25(OH)(2)D, but there was a significant decrease with age (r = -0.69, p < 0.001). Individual expression of TRPV6 and VDR was significantly correlated. The group of older women (>50) had lower median levels of both TRPV6 and VDR transcripts than younger women (p < 0.001 and 0.02, respectively). CONCLUSIONS: Duodenal TRPV6 expression is vitamin D dependent in men, but not in older women, where expression of TRPV6 and VDR are both reduced. These findings can explain, at least in part, the lower fractional calcium absorption seen in older postmenopausal women.


Asunto(s)
Envejecimiento , Duodeno/metabolismo , Regulación de la Expresión Génica , Receptores de Calcitriol/metabolismo , Canales Catiónicos TRPV/fisiología , Vitamina D/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Calcio/metabolismo , Femenino , Humanos , Íleon/metabolismo , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Factores Sexuales , Canales Catiónicos TRPV/metabolismo
12.
FEBS Lett ; 585(23): 3603-10, 2011 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-21827750

RESUMEN

Regulatory T-cells (Tregs) are the guardians of peripheral tolerance acting to prevent autoimmune diseases such as systemic lupus erythomatosus (SLE) and rheumatoid arthritis (RA). Defects in Tregs have been reported in these two diseases despite significant differences in their clinical phenotype and pathogenesis. In both diseases the potency of Treg fails to keep pace with the activation of effector cells and are unable to resist the ensuing inflammation. This review will discuss the phenotypic, numeric, and functional abnormalities in Tregs and their role in patients and murine models of SLE and RA.


Asunto(s)
Artritis Reumatoide/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T Reguladores/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Modelos Inmunológicos
13.
J Clin Invest ; 120(5): 1469-78, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20407205

RESUMEN

Crescentic glomerulonephritis (CGN), which frequently results in acute and chronic kidney disease, is characterized by and dependent on glomerular infiltration by macrophages. The mannose receptor (MR) is a pattern recognition receptor implicated in the uptake of endogenous and microbial ligands by macrophages, mesangial cells (MCs), and selected endothelial cells. It is upregulated on alternatively activated macrophages (i.e., macrophages associated with tissue repair and humoral immunity) and involved in antigen presentation to T cells. We used the mouse model of nephrotoxic nephritis to investigate the role of MR in CGN. Our results demonstrate what we believe to be a novel role for MR in the promotion of CGN that is independent of adaptive immune responses. MR-deficient (Mr-/-) mice were protected from CGN despite generating humoral and T cell responses similar to those of WT mice, but they demonstrated diminished macrophage and MC Fc receptor-mediated (FcR-mediated) functions, including phagocytosis and Fc-mediated oxygen burst activity. Mr-/- MCs demonstrated augmented apoptosis compared with WT cells, and this was associated with diminished Akt phosphorylation. Macrophage interaction with apoptotic MCs induced a noninflammatory phenotype that was more marked in Mr-/- macrophages than in WT macrophages. Our results demonstrate that MR augments Fc-mediated function and promotes MC survival. We suggest that targeting MR may provide an alternative therapeutic approach in CGN while minimizing the impact on adaptive immune responses, which are affected by conventional immunosuppressive approaches.


Asunto(s)
Regulación de la Expresión Génica , Glomerulonefritis/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Unión a Manosa/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Fc/metabolismo , Animales , Apoptosis , Femenino , Macrófagos/metabolismo , Masculino , Receptor de Manosa , Células Mesangiales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Biológicos , Oxígeno/metabolismo , Fagocitosis , Fosforilación , Linfocitos T/metabolismo
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