Implicación de los linfocitos B en la patogenia de la artritis crónica.

La depleción de células B que produce el rituximab (RTX), un anticuerpo monoclonal anti-CD20, ha mostrado una respuesta clínica positiva e inesperada en pacientes con artritis reumatoide (AR). Este hallazgo, junto con las propiedades artritogénicas que han mostrado anticuerpos contra la glucosa-6-fosfato isomerasa en un modelo animal de artritis, ha reavivado el interés por el estudio sobre la contribución de las células B en la patogénesis de las artritis inflamatorias crónicas. Sin embargo, el RTX ha logrado sólo mejoras leves en los síntomas articulares en los pacientes con artritis psoriásica (APs). Esto, junto con otras evidencias, como la falta de autoanticuerpos detectables o la presencia inusual de agregados foliculares en la APs, sugiere que las células B no juegan el mismo papel en la patogénesis de la AR y la APs. Actualmente se le atribuye a la célula B un papel relevante en la patogénesis de la artritis. Tres posibles mecanismos de acción artritogénica han sido propuestos para las células B: 1) la producción de autoanticuerpos y formación de complejos inmunes; 2) la producción local de factores solubles proinflamatorios, incluyendo el factor de necrosis tumoral (TNF) -α o la interleucina (IL) -6, y de metaloproteasas (MMPs), importantes como efectores finales de la destrucción articular; y 3) la regulación de las funciones de las células T localmente en la sinovial para actuar de este modo como células presentadoras de antígeno (APCs). Aunque se desconoce el papel real y el orden de relevancia de estos potenciales mecanismos patogénicos, los datos experimentales sugieren que las células B deben migrar y acumularse en el microambiente sinovial para ejercer su acción en la inflamación articular. Los objetivos fundamentales de este proyecto son estudiar los mecanismos implicados en el proceso de transmigración y acumulación de los linfocitos B en los focos de inflamación, desde las moléculas implicadas en la interacción dinámica linfocito B-endotelio a los factores solubles como las quimioquinas que, presentes en la sinovial inflamada, son responsables del reclutamiento de células B en el tejido sinovial. En este trabajo también se estudiará la implicación de las células B en la presentación de antígeno y en los mecanismos de destrucción articular (producción de metaloproteasas). En resumen, los principales hallazgos de este trabajo se pueden resumir en: 1) las moléculas de adhesión VLA-4/VCAM-1 son las principales responsables de la interacción dinámica entre las células B y las células endoteliales durante la primera fase de la cascada de adhesión; 2) el BCA-1/CXCL3 y el MIP-3α/CCL20 parecen ser las quimioquinas responsables de la migración y acumulación de las células B en la sinovial inflamada de pacientes con artritis; 3) las células B del infiltrado sinovial de pacientes con AR sufren cambios en las moléculas implicadas en la presentación de antígeno y coestimulación (HLA-DR, CD40, CD86, IFIT-4) lo que indica que podrían estar actuando como APCs en el foco inflamatorio, y 4) las células B presentes en el microambiente sinovial de pacientes con artritis muestran un incremento en el contenido de MMP-1 y MMP-9 respecto de las de sangre periférica. Esperamos que este estudio permita profundizar en el conocimiento del papel que juegan las células B en la patogenia de la artritis y de esta forma contribuir al desarrollo de estrategias anti-células B que puedan ser utilizadas en el manejo de esta y otras enfermedades inflamatorias crónicas de base autoinmune

Pacientes con confección por VHC en el servicio de infecciones del HUC: pasado, presente... ¿No futuro?

Introducción: En mayo de 2016, la Asamblea de la Salud adoptó la primera estrategia mundial del sector de la salud contra las hepatitis víricas (2016-2021) cuyo objetivo final es eliminar esta enfermedad de la lista de problemas de salud pública antes de 2030. Con la introducción de los antivirales de acción directa se ha visto unas tasas de curación superiores al 95%, con tratamientos de corta duración y asociando una tolerancia excelente. Material y métodos: Estudio descriptivo retrospectivo de las características de los pacientes del servicio de infecciones del HUC vistos entre enero del año 2000 y diciembre de 2019 con diagnóstico de VHC (n= 346). Los datos se han obtenido de la historia clínica digital, principalmente del SITHepaC, de los pacientes de la muestra. Almacenando estos datos para su posterior análisis en el paquete estadístico SPSS 20.0. Resultados: Hemos recogido una muestra de 346 pacientes (79,5% varones y 20,5% mujeres), con una media muestral de 52,26 años. El genotipo 1a es el más prevalente en nuestros datos, presente en un 30,3% de los estudiados. Un 35% son pacientes coinfectados (VIH-VHC), estando más presente en el grupo de los hombres (91 pacientes). Conclusiones: El estudio epidemiológico de las hepatitis C en nuestro medio es de gran valor para comprender la magnitud de este problema de salud pública y qué medidas tomar para conseguir finalmente un objetivo común, su erradicación.Introduction: The first global strategy in the health sector against viral hepatitis (2016- 2021) was adopted by the Health Assembly in May 2016. The final objective was to eliminate this disease from the list of public health problems before 2030. The introduction of direct-acting antivirals has involved a cure rate of over 95% with shortterm treatments and associating excellent tolerance. 4 Material and methods: Retrospective descriptive study of the characteristics of patients seen between January 2000 and December 2019 with a diagnosis of HCV (n = 346) from the HUC’s infection service. The data has been obtained from the digital medical history of the patients in the sample, mainly from SITHepaC. These data were stored for later analysis in the SPSS 20.0 statistical package. Results: We have collected a sample of 346 patients (79.5% male and 20.5% female) with a sample mean of 52.26 years. The 1a genotype is the most prevalent in our data, it is presented in 30.3% of those studied. The 35% are coinfected patients (HIV-HCV), being the male group the highest affected (91 patients). Conclusions: The epidemiological study of hepatitis C virus in our environment is of great value to understand the magnitude of this public health problem and what measures to take accordingly to finally achieve a common goal, its eradication

Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis

Background: B cells exert their pathogenic action in rheumatoid arthritis (RA) locally in the synovium. This study was undertaken to elucidate the chemokines responsible for the recruitment of B cells in the inflamed synovium, taking into account that the rich chemokine milieu present in the synovial tissue can fine-tune modulate discrete chemokine receptors. Methods: Expression levels of chemokine receptors from the CC and CXC family, as well as CD27, were assessed by flow cytometry in CD20+ mononuclear cells isolated from the peripheral blood (PB) and synovial fluid (SF) of RA and psoriatic arthritis patients. Transwell experiments were used to study migration of B cells in response to a chemokine or in the presence of multiple chemokines. Results: B cells from the SF of arthritis patients showed a significant increase in the surface expression of CCR1, CCR2, CCR4, CCR5 and CXCR4 with respect to PB. Conversely, SF B cells expressed consistently lower amounts of CXCR5, CXCR7 and CCR6, independent of CD27 expression. Analysis of permeabilized B cells suggested internalization of CXCR5 and CCR6 in SF B cells. In Transwell experiments, CCL20 and CXCL13, ligands of CCR6 and CXCR5, respectively, caused a significantly higher migration of B cells from PB than of those from SF of RA patients. Together, these two chemokines synergistically increased B-cell migration from PB, but not from SF. Conclusions: These results suggest that CXCL13 and CCL20 might play major roles in RA pathogenesis by acting singly on their selective receptors and synergistically in the accumulation of B cells within the inflamed synovium

HDL cholesterol efflux capacity and lipid profile in patients with systemic sclerosis

Objective It is well established that patients with systemic sclerosis (SSc) have a disrupted lipid profile and an increased cardiovascular risk. Cholesterol efflux capacity (CEC), the ability of high-density lipoprotein (HDL)-cholesterol to accept cholesterol from macrophages, has been linked to cardiovascular events. The aim of this study was to establish whether CEC and lipid profile were impaired in SSc patients with respect to controls and whether these changes were associated with disease-related data. Methods Cross-sectional study encompassed 188 individuals: 73 SSc patients and 115 controls. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed in patients and controls. A multivariable analysis was performed to study the differences in CEC between patients and controls, and if SSc-related data could explain such differences. Results The multivariable analysis adjusted for demographic characteristics, cardiovascular risk factors, and lipid-related molecules showed that total cholesterol (beta coefficient: - 22 [95%CI - 37 to - 7], p = 0.004), triglycerides (beta coefficient: 24 [95%CI 2-47], p = 0.033), lipoprotein A (beta coefficient: 22 [95%CI 2-43], p = 0.033), and CEC (beta coefficient: - 6 [95%CI - 10 to - 2]%,p = 0.002) were significantly different between patients and controls. Skin thickness, as assessed by modified Rodnan skin score, was independently associated with a lower CEC (beta coefficient: - 0.21 [95%CI - 0.37 to - 0.05]%, p = 0.011) after multivariable adjustment. Conclusion SSc patients show an abnormal lipid profile with respect to controls including CEC. Skin thickness is independent and inversely associated with CEC in SSc patients.Spanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación (2013–2016)REUNINVES (Asociación para la Ayuda a la Investigación del Hospital Universitario de Canarias)5.606 Q1 JCR 20211.403 Q1 SJR 2021No data IDR 2021UE

Differences in Capacity of High-Density Lipoprotein Cholesterol Efflux Between Patients With Systemic Lupus Erythematosus and Rheumatoid Arthritis

Objective: Cholesterol efflux capacity (CEC) is the ability of high-density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages. Lipid profiles and CEC appear to be altered in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) due to disease activity and inflammation. CEC has been linked to cardiovascular events in the general population and to subclinical atherosclerosis in SLE and RA patients. The aim of this study was to establish whether CEC varies between patients with SLE and those with RA. Methods: The study encompassed 460 individuals (195 SLE patients and 265 patients with RA). CEC (using an in vitro assay) and concentrations of lipoprotein serum were assessed in both populations. A multivariable regression analysis was performed to study whether CEC differs between SLE patients and RA patients. Results: Comparison of lipid patterns revealed that patients with RA have lower HDL cholesterol and higher apolipoprotein B serum levels than SLE patients. CEC was downregulated in SLE patients compared to patients with RA (β -12 [95% confidence interval -13, -10], P < 0.001). It occurred independently of traditional cardiovascular risk factors, statin use, disease-related data, and other variations in the lipid profile related to the diseases. Conclusion: Patients with RA have a more proatherogenic lipid pattern compared to those with SLE. However, CEC seems to be more damaged in SLE patients than in RA patients.Sin financiación4.794 JCR (2020) Q2, 13/34 Rheumatology2.032 SJR (2020) Q1, 4/58 RheumatologyNo data IDR 2020UE

L-selectin expression is regulated by CXCL8-induced reactive oxygen species produced during human neutrophil rolling

Neutrophils destroy invading microorganisms by phagocytosis by bringing them into contact with bactericidal substances, among which ROS are the most important. However, ROS also function as important physiological regulators of cellular signaling pathways. Here, we addressed the involvement of oxygen derivatives in the regulation of human neutrophil rolling, an essential component of the inflammatory response. Flow experiments using dihydroethidium‐preloaded human neutrophils showed that these cells initiate an early production of intracellular ROS during the rolling phase of the adhesion cascade, a phenomenon that required cell rolling, and the interaction of the chemokine receptor CXCR2 with their ligand CXCL8. Flow cytometry experiments demonstrated that L‐selectin shedding in neutrophils is triggered by ROS through an autocrine–paracrine mechanism. Preincubation of neutrophils with the NADPH oxidase complex inhibitor diphenyleniodonium chloride significantly increased the number of rolling neutrophils on endothelial cells. Interestingly, the same effect was observed when CXCL8 signaling was interfered using either a blocking monoclonal antibody or an inhibitor of its receptor. These findings indicate that, in response to CXCL8, neutrophils initiate ROS production during the rolling phase of the inflammatory response. This very early ROS production might participate in the modulation of the inflammatory response by inducing L‐selectin shedding in neutrophils.This work was supported by grants from the Fondo de Investigaciones Sanitarias of Spain Grants PI12/02499 and PI15/01810 (to. F.D.‐G.), co‐funded by the European Regional Development Fund. This work was also supported by Asociación para la Ayuda a la Investigación en Reumatología del Hospital Universitario de Canarias (REUNINVES) and by the Spanish Society of Rheumatology

Impaired HDL cholesterol efflux capacity in systemic lupus erythematosus patients is related to subclinical carotid atherosclerosis

Objectives Lipid profiles appear to be altered in SLE patients due to disease activity and inflammation. Cholesterol efflux capacity (CEC) is the ability of high-density lipoprotein cholesterol to accept cholesterol from macrophages. CEC has been linked to cardiovascular events in the general population and is impaired in SLE patients. The aim of this study was to establish whether CEC is related to subclinical carotid atherosclerosis in SLE patients. Methods The present report is of a cross-sectional study that encompassed 418 individuals: 195 SLE patients and 223 controls. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed in patients and controls. Carotid intima-media thickness and carotid plaques were evaluated in SLE patients. A multivariable analysis was performed to study the relationship of CEC to SLE-related data, lipid profile and subclinical carotid atherosclerosis. Results CEC was downregulated in SLE patients [8.1  (4.2) % vs 16.9 (10.4) %, P = 0.004). This occurred independently of traditional cardiovascular risk factors, statin use or other variations in the lipid profile related to the disease. Traditional cardiovascular risk factors, both in patients and controls, and SLE-related data such as activity, severity or damage were not associated with CEC. After multivariable regression analysis including lipid profile–related molecules, CEC was inversely and independently associated with the presence of carotid plaques in SLE patients [odds ratio 0.87 (95% CI: 0.78, 0.97), P = 0.014]. Conclusion CEC is impaired in SLE patients independently of other inflammation-related lipid profile modifications that occur during the disease. CEC is associated with carotid plaques in SLE patients.Sin financiaciónSpanish Ministry of Health, Subdirección General de Evaluación y Fomento de la Investigación, Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016.Fondo Europeo de Desarrollo Regional—FEDER—(Fondo de Investigaciones Sanitarias, FIS, PI17/00083).7.580 JCR (2020) Q1, 5/34 Rheumatology1.957 SJR (2020) Q1, 14/253 Pharmacology (medical)No data IDR 2020UE

Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis

Abstract Background B cells exert their pathogenic action in rheumatoid arthritis (RA) locally in the synovium. This study was undertaken to elucidate the chemokines responsible for the recruitment of B cells in the inflamed synovium, taking into account that the rich chemokine milieu present in the synovial tissue can fine-tune modulate discrete chemokine receptors. Methods Expression levels of chemokine receptors from the CC and CXC family, as well as CD27, were assessed by flow cytometry in CD20+ mononuclear cells isolated from the peripheral blood (PB) and synovial fluid (SF) of RA and psoriatic arthritis patients. Transwell experiments were used to study migration of B cells in response to a chemokine or in the presence of multiple chemokines. Results B cells from the SF of arthritis patients showed a significant increase in the surface expression of CCR1, CCR2, CCR4, CCR5 and CXCR4 with respect to PB. Conversely, SF B cells expressed consistently lower amounts of CXCR5, CXCR7 and CCR6, independent of CD27 expression. Analysis of permeabilized B cells suggested internalization of CXCR5 and CCR6 in SF B cells. In Transwell experiments, CCL20 and CXCL13, ligands of CCR6 and CXCR5, respectively, caused a significantly higher migration of B cells from PB than of those from SF of RA patients. Together, these two chemokines synergistically increased B-cell migration from PB, but not from SF. Conclusions These results suggest that CXCL13 and CCL20 might play major roles in RA pathogenesis by acting singly on their selective receptors and synergistically in the accumulation of B cells within the inflamed synovium

Additional file 1: of Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis

Table S1. Mean fluorescence intensity and percentage of positive cells for each chemokine receptor on PB and SF from arthritis patients and healthy controls. (DOCX 16 kb