RESUMEN
Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti-cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11-Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA.
Asunto(s)
Cadherinas/metabolismo , Fibroblastos/metabolismo , Membrana Sinovial/metabolismo , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/metabolismo , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Cadherinas/genética , Adhesión Celular/genética , Fibroblastos/patología , Regulación de la Expresión Génica/genética , Humanos , Células L , Ratones , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Membrana Sinovial/citología , Membrana Sinovial/patologíaRESUMEN
Maintenance of immune tolerance in the periphery can be envisioned as a balance between autoreactive lymphocytes and regulatory mechanisms that counteract them. The naturally occurring CD4(+)CD25(+) regulatory T cells (T(REGs)) have a major role in modulating the activity of self-reactive cells. The identification of Forkhead box P3 transcription factor (FoxP3) as the critical determinant of T(REG) development and function has provided new opportunities and generated expanded interest in studying the balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. The identification of both human and mouse diseases resulting from the lack of FoxP3 expression, and consequently the absence of T(REGs), has rapidly expanded knowledge of T(REG) development and function during the past 5 years. Although it is still unclear how these regulatory cells function, they can inhibit the activation of potentially pathogenic T cells in vitro. Using in vitro functional assays and phenotypic analysis, T(REGs) isolated from patients with a variety of autoimmune diseases have been shown to exhibit reduced regulatory function as compared with those isolated from healthy controls. This Review will focus on the current state of knowledge on human T(REGs) and their association with specific autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Factores de Transcripción Forkhead/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Linfocitos T Reguladores/metabolismo , Granulomatosis con Poliangitis/inmunología , Humanos , Sarcoidosis/inmunología , Linfocitos T Reguladores/fisiologíaRESUMEN
OBJECTIVES: Economic evaluation is becoming more common and important as new biologic therapies for rheumatoid arthritis (RA) are developed. While much has been published about how to design cost-utility models for RA to conduct these evaluations, less has been written about the sources of data populating those models. The goal is to review the literature and to provide recommendations for future data collection efforts. METHODS: This study reviewed RA cost-utility models published between January 2006 and February 2014 focusing on five key sources of data (health-related quality-of-life and utility, clinical outcomes, disease progression, course of treatment, and healthcare resource use and costs). It provided recommendations for collecting the appropriate data during clinical and other studies to support modeling of biologic treatments for RA. RESULTS: Twenty-four publications met the selection criteria. Almost all used two steps to convert clinical outcomes data to utilities rather than more direct methods; most did not use clinical outcomes measures that captured absolute levels of disease activity and physical functioning; one-third of them, in contrast with clinical reality, assumed zero disease progression for biologic-treated patients; little more than half evaluated courses of treatment reflecting guideline-based or actual clinical care; and healthcare resource use and cost data were often incomplete. CONCLUSIONS: Based on these findings, it is recommended that future studies collect clinical outcomes and health-related quality-of-life data using appropriate instruments that can convert directly to utilities; collect data on actual disease progression; be designed to capture real-world courses of treatment; and collect detailed data on a wide range of healthcare resources and costs.
Asunto(s)
Antirreumáticos/economía , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factores Biológicos/economía , Factores Biológicos/uso terapéutico , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Progresión de la Enfermedad , Humanos , Modelos Econométricos , Años de Vida Ajustados por Calidad de VidaRESUMEN
OBJECTIVE: Interleukin-20 (IL-20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109-0012, a selective anti-IL-20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy. METHODS: Sixty-seven patients with RA were enrolled and randomized (2:1) to receive NNC0109-0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double-blind, 12-week trial with a 13-week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C-reactive protein level (DAS28-CRP) from baseline to week 12. RESULTS: In patients treated with NNC0109-0012, the primary end point, improvement in the DAS28-CRP at week 12, was achieved (estimated difference -0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference -1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109-0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109-0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109-0012 were observed. CONCLUSION: In this phase IIa trial, treatment with NNC0109-0012 (anti-IL-20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109-0012 administration.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Interleucinas/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Artritis Reumatoide/inmunología , Autoanticuerpos/inmunología , Anticuerpos ampliamente neutralizantes , Proteína C-Reactiva/inmunología , Método Doble Ciego , Femenino , Herpes Simple/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Nasofaringitis/inducido químicamente , Péptidos Cíclicos/inmunología , Infecciones del Sistema Respiratorio/inducido químicamente , Factor Reumatoide/inmunología , Resultado del Tratamiento , Infecciones Urinarias/inducido químicamente , Adulto JovenRESUMEN
CD4(+)CD25(+) T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4(+)CD25(high) Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE. In this study, we report a significant decrease in the suppressive function of CD4(+)CD25(high) Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE. Notably, CD4(+)CD25(high) Tregs isolated from patients with active SLE expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4(+) effector T cells in vitro. In contrast, the expression of FoxP3 mRNA and protein and in vitro suppression of the proliferation of CD4(+) effector T cells by Tregs isolated from inactive SLE patients, was comparable to that of normal individuals. In vitro activation of CD4(+)CD25(high) Tregs from patients with active SLE increased FoxP3 mRNA and protein expression and restored their suppressive function. These data are the first to demonstrate a reversible defect in CD4(+)CD25(high) Treg function in patients with active SLE, and suggest that strategies to enhance the function of these cells might benefit patients with this autoimmune disease.
Asunto(s)
Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica/inmunología , Lupus Eritematoso Sistémico/inmunología , Activación de Linfocitos/inmunología , Autotolerancia , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Proliferación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Femenino , Factores de Transcripción Forkhead/biosíntesis , Humanos , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patologíaRESUMEN
CD4+CD25+ T-regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. However, little is known about the exogenous factors that regulate their differentiation and function. Here, we report that TNF inhibits the suppressive function of both naturally occurring CD4+CD25+ Tregs and TGFbeta1-induced CD4+CD25+ T-regulatory cells. The mechanism of this inhibition involves signaling through TNFRII that is constitutively expressed selectively on unstimulated Tregs and that is up-regulated by TNF. TNF-mediated inhibition of suppressive function is related to a decrease in FoxP3 mRNA and protein expression by the Tregs. Notably, CD4+CD25hi Tregs isolated from patients with active rheumatoid arthritis (RA) expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4+ effector T cells in vitro. Treatment with anti-TNF antibody (infliximab) increased FOXP3 mRNA and protein expression by CD4+CD25hi Tregs and restored their suppressive function. Thus, TNF has a novel action in modulating autoimmunity, by inhibiting CD4+CD25+ Treg activity.
Asunto(s)
Regulación hacia Abajo/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Adulto , Anciano , Anticuerpos Monoclonales/farmacología , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/inmunología , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/efectos de los fármacos , Humanos , Infliximab , Persona de Mediana Edad , Fenotipo , ARN Mensajero/biosíntesis , ARN Mensajero/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Human CD1d molecules consist of a transmembrane CD1 (cluster of differentiation 1) heavy chain in association with beta(2)-microglobulin (beta(2)m). Assembly occurs in the endoplasmic reticulum (ER) and involves the initial glycan-dependent association of the free heavy chain with calreticulin and calnexin and the thiol oxidoreductase ERp57. Folding and disulfide bond formation within the heavy chain occurs prior to beta(2)m binding. There are four N-linked glycans on the CD1d heavy chain, and we mutated them individually to ascertain their importance for the assembly and function of CD1d-beta(2)m heterodimers. None of the four were indispensable for assembly or the ability to bind alpha-galactosyl ceramide and to present it to human NKT cells. Nor were any required for the CD1d molecule to bind and present alpha-galactosyl ceramide after lysosomal processing of a precursor lipid, galactosyl-(alpha1-2)-galactosyl ceramide. However, one glycan, glycan 2 at Asn-42, proved to be of particular importance for the stability of the CD1d-beta(2)m heterodimer. A mutant CD1d heavy chain lacking glycan 2 assembled with beta(2)m and transported from the ER more rapidly than wild-type CD1d and dissociated more readily from beta(2)m upon exposure to detergents. A mutant expressing only glycan 1 dissociated completely from beta(2)m upon exposure to the detergent Triton X-100, whereas a mutant expressing only glycan 2 at Asn-42 was more stable. In addition, glycan 2 was not processed efficiently to the complex form in mature wild-type CD1d molecules. Modeling the glycans on the published structure indicated that glycan 2 interacts significantly with both the CD1d heavy chain and beta(2)m, which may explain these unusual properties.
Asunto(s)
Antígenos CD1/metabolismo , Polisacáridos/química , Subunidades de Proteína/metabolismo , Microglobulina beta-2/metabolismo , Secuencia de Aminoácidos , Presentación de Antígeno/genética , Antígenos CD1/biosíntesis , Antígenos CD1/química , Antígenos CD1/genética , Antígenos CD1d , Conformación de Carbohidratos , Células Clonales , Dimerización , Humanos , Líquido Intracelular/enzimología , Líquido Intracelular/metabolismo , Células Asesinas Naturales/enzimología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidasa/química , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidasa/fisiología , Datos de Secuencia Molecular , Mutagénesis , Polisacáridos/fisiología , Procesamiento Proteico-Postraduccional/genética , Subunidades de Proteína/biosíntesis , Subunidades de Proteína/genética , Transporte de Proteínas/genética , Subgrupos de Linfocitos T/enzimología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Microglobulina beta-2/químicaRESUMEN
OBJECTIVE: The 2-[(18)F]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) technique provides information on uptake and metabolism of glucose in various tissues. Compared with resting cells, activated lymphocytes take up radioactively labeled glucose analog at a higher rate, which makes it possible to identify lymphoid organs with higher concentrations of activated lymphocytes. This study was undertaken to compare the pattern of PET images and quantitative FDG uptake in lymphoid organs of patients with active systemic lupus erythematosus (SLE) versus patients with inactive SLE and to correlate these findings with peripheral blood lymphocyte phenotypes. METHODS: Ten patients with active SLE and 9 patients with inactive SLE were studied. FDG-PET images were obtained from the inguinal region to above the ear, starting at 60 minutes after injection of FDG. Standardized uptake values using lean body mass were determined over areas of interest. RESULTS: Both patients with active lupus and those with inactive lupus had increased FDG uptake in lymph nodes when compared with healthy volunteers, and there was no statistically significant difference between the 2 groups of lupus patients. Thymic uptake was demonstrated in 5 of 10 patients with active lupus compared with 0 of 9 patients with inactive disease. Three of the 5 patients with active SLE who were over 29 years of age had thymic uptake. Of the activation markers tested, only the CD3/CD71 population of cells was significantly different between the patient groups, with an increased percentage in the active disease group (P = 0.0247). CONCLUSION: Increased FDG uptake in lymph nodes of both patients with active SLE and patients with inactive SLE suggests that metabolic, and probably immunologic, activity is enhanced not only in active, but also in clinically quiescent, disease. The increased thymic uptake observed only in patients with active disease suggests that the thymus plays an important role during periods of disease activity.