Effect of Rituximab on the circulating levels of cytokines produced or not produced by B lymphocytes in patients with rheumatoid arthritis

Rheumatoid Arthritis (RA) is a common autoimmune disease characterized by chronic inflammation in the joints that can progress to bone destruction. Although the pathophysiology of RA is unclear, T cells and B cells are though to be involved. Rituximab (RTX), a drug that eliminates CD20 + B cells, has helped to clarify and highlight the role of B cells in RA. B cells can contribute to autoimmunity by mechanisms dependent on the production of antibodies and independent of this production. The latter may depend on the role of B cells as antigen-presenting cells for T cells and their capacity to produce cytokines and chemokines. To contribute to our understanding of this mechanism, studies that evaluated levels of circulating cytokines and chemokines in patients with RA after treatment with RTX were reviewed. Most cytokines studied decreased their levels in circulation after treatment with RTX. IL-10 and IL-6 consistently were decreased in patients responding to treatment and maybe markers of Rituximab treatment

Effects of rituximab therapy on circulating cytokines and chemokines in patients with rheumatoid arthritis

La Artritis Reumatoide (AR) es una de las enfermedades autoinmunes más frecuentes caracterizada por provocar inflamación crónica en las articulaciones que puede progresar a la destrucción ósea. Pese a que fisiopatología de la AR aún no es clara, la evidencia disponible ha demostrado la implicación de las células T y las células B en el desarrollo, establecimiento y perpetuación de la enfermedad. Singularmente, el rituximab (RTX), un fármaco que actúa por medio de la depleción de las células B CD20+, ha contribuido a esclarecer la participación de las células B en la AR, suscitando un interés especial sobre las mismas. Las células B pueden contribuir a la autoinmunidad de manera dependiente de la producción de los anticuerpos, ya que se ha mostrado que luego de la terapia con RTX se puede mejorar el curso de la AR al reducir los niveles de autoanticuerpos patógenos, sin embargo, se demostró que la reducción de los autoanticuerpos no siempre se correlaciona con la eficacia del tratamiento con RTX, lo que implica que la mejora de la enfermedad después de la terapia de depleción de células B (TDCB) supone además la eliminación de funciones patogénicas independientes de anticuerpos de las células B. Tales funciones pueden tratarse de su actuación como células presentadoras de antígeno (CPA) eficaces para las células T y células productoras de citocinas y quimiocinas. En esta monografía se analizó este último mecanismo con base a la evidencia reportada en la literatura científica de los efectos de la terapia con RTX sobre la citocinas y quimiocinas circulantes en pacientes con artritis reumatoide. Adicionalmente, se discutieron las posibles citocinas y quimiocinas candidatas a ser marcadores predictivos de la respuesta al rituximab o marcadores de actividad de la enfermedad tras el tratamiento Los artículos científicos evaluados mostraron que la mayoría de las citocinas proinflamatorias y con funciones duales, es decir, con funciones tanto pro como anti-inflamatorias, disminuyeron sus niveles en circulación luego de la terapia con RTX, a excepción de la IL-8, CCL19, MCP-1 y EGF, cuyas concentraciones no cambiaron o fueron contradictorias a lo largo de los estudios revisados. Curiosamente, la IL-10, una citocina clásicamente descrita como antiinflamatoria, también disminuyó. De esta forma se realizó un acercamiento a entender la contribución de las células B productoras de citocinas y quimiocinas en la fisiopatología de la enfermedad. La IL-10 y la IL-6 presentaron resultados consistentes y pueden posiblemente ser considerados a futuro como potenciales marcadores predictivos del tratamiento con rituximab.Rheumatoid Arthritis (RA) is one of the most common autoimmune diseases characterized by causing chronic inflammation in the joints that can progress to bone destruction. Although the pathophysiology of RA is still unclear, the available evidence has shown the involvement of T cells and B cells in the development, establishment, and perpetuation of the disease. Uniquely, rituximab (RTX), a drug that acts by depleting CD20 + B cells, has contributed to shedding light on the involvement of B cells in RA, generating special interest in them. B cells can contribute to autoimmunity in a way that is dependent on the production of antibodies, since it has been shown that after RTX therapy the course of RA can be improved by reducing the levels of pathogenic autoantibodies, however, showed that the reduction in autoantibodies does not always correlate with the efficacy of RTX treatment, implying that the improvement of the disease after B-cell depletion therapy (TDCB) also supposes the elimination of antibody-independent pathogenic functions of B cells. Such functions may be about their acting as efficient antigen presenting cells (APCs) for T cells and cytokine and chemokine producing cells. In this monograph, the latter mechanism was analyzed based on the evidence reported in the scientific literature of the effects of RTX therapy on circulating cytokines and chemokines in patients with rheumatoid arthritis. Additionally, possible cytokines and chemokines candidates to be predictive markers of the response to rituximab or markers of disease activity after treatment were discussed. The evaluated scientific articles showed that the majority of pro-inflammatory cytokines with dual functions, that is, with both pro and anti-inflammatory functions, their circulating levels decreased after RTX therapy, with the exception of IL-8, CCL19, MCP-1 and EGF, whose concentrations did not change or were contradictory throughout the studies reviewed. Interestingly, IL-10, a cytokine classically described as anti-inflammatory, also decreased. In this way, an approach was made to understand the contribution of cytokine and chemokine producing B cells in the pathophysiology of the disease. IL-10 and IL-6 presented consistent results and may possibly be considered in the future as potential predictive markers of rituximab treatment.Bacteriólogo (a)Pregrad

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease