Gloria Vásquez

Regulatory B Cells and Mechanisms

Regulatory B cells have gained prominence in their role as modulators of the immune response against tumors, infectious diseases, and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, among others. The concept of regulatory B cells has been strongly associated with interleukin (IL)-10 production; however, there is growing evidence that supports the existence of other regulatory mechanisms, such as the production of transforming growth factor β (TGF-β), induced cell death of effector T cells, and the induction of CD4+CD25−Foxp3+ regulatory T cells. The regulatory function of B cells has been associated with the presence and activation of molecules such as CD40, CD19, CD1d, and BCR. Alterations in signaling by any of these pathways leads to a marked defect in regulatory B cells and to increased clinical symptoms and proinflammatory signs, both in murine models and in autoimmune diseases in humans. B cells mainly exert their regulatory effect through the inhibition of proliferation and production of proinflammatory mediators, such as TNF-α, IFN-γ, and IL-17 by CD4+ T cells. A better understanding of how regulatory B cells function will offer new perspectives with regard to the treatment of various human diseases.

Primary cardiac disease in systemic lupus erythematosus patients: protective and risk factors—data from a multi-ethnic Latin American cohort

OBJECTIVES The aim of this study was to assess the cumulative incidence, risk and protective factors and impact on mortality of primary cardiac disease in SLE patients (disease duration ≤2 years) from a multi-ethnic, international, longitudinal inception cohort (34 centres, 9 Latin American countries). METHODS Risk and protective factors of primary cardiac disease (pericarditis, myocarditis, endocarditis, arrhythmias and/or valvular abnormalities) were evaluated. RESULTS Of 1437 patients, 202 (14.1%) developed one or more manifestations: 164 pericarditis, 35 valvulopathy, 23 arrhythmias, 7 myocarditis and 1 endocarditis at follow-up; 77 of these patients also had an episode of primary cardiac disease at or before recruitment. In the multivariable parsimonious model, African/Latin American ethnicity [odds ratio (OR) 1.80, 95% CI 1.13, 2.86], primary cardiac disease at or before recruitment (OR 6.56, 95% CI 4.56, 9.43) and first SLICC/ACR Damage Index for SLE assessment (OR 1.31, 95% CI 1.14, 1.50) were risk factors for the subsequent occurrence of primary cardiac disease. CNS involvement (OR 0.44, 95% CI 0.25, 0.75) and antimalarial treatment (OR 0.62, 95% CI 0.44, 0.89) at or before recruitment were negatively associated with the occurrence of primary cardiac disease risk. Primary cardiac disease was not independently associated with mortality. CONCLUSION Primary cardiac disease occurred in 14.1% of SLE patients of the Grupo Latino Americano de Estudio de Lupus cohort and pericarditis was its most frequent manifestation. African origin and lupus damage were found to be risk factors, while CNS involvement at or before recruitment and antimalarial treatment were protective. Primary cardiac disease had no impact on mortality.

Microparticles That Form Immune Complexes as Modulatory Structures in Autoimmune Responses

Microparticles (MPs) are induced during apoptosis, cell activation, and even “spontaneous” release. Initially MPs were considered to be inert cellular products with no biological function. However, an extensive research and functional characterization have shown that the molecular composition and the effects of MPs depend upon the cellular background and the mechanism inducing them. They possess a wide spectrum of biological effects on intercellular communication by transferring different molecules able to modulate other cells. MPs interact with their target cells through different mechanisms: membrane fusion, macropinocytosis, and receptor-mediated endocytosis. However, when MPs remain in the extracellular milieu, they undergo modifications such as citrullination, glycosylation, and partial proteolysis, among others, becoming a source of neoantigens. In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), reports indicated elevated levels of MPs with different composition, content, and effects compared with those isolated from healthy individuals. MPs can also form immune complexes amplifying the proinflammatory response and tissue damage. Their early detection and characterization could facilitate an appropriate diagnosis optimizing the pharmacological strategies, in different diseases including cancer, infection, and autoimmunity. This review focuses on the current knowledge about MPs and their involvement in the immunopathogenesis of SLE and RA.

Review of Current Workforce for Rheumatology in the Countries of the Americas 2012-2015.

BackgroundWith the increases in and aging of the populations of the Americas, monitoring the number of rheumatologists is critical to address and focus on areas of greatest need. ObjectivesThe aim of this study was to gather data on the rheumatology workforce from 21 national societies in the Pan American League of Associations for Rheumatology (PANLAR). MethodsIn September and October 2012 and again in October and November 2015, the heads of the 21 rheumatology national societies were contacted in the 2012 survey; all national societies responded except Cuba. In the 2015 survey, all responded except Nicaragua, for which information was provided by national society presidents in adjacent countries. ResultsThe data from 21 societies contained in PANLAR consist of 10,166 adult and 678 pediatric rheumatologists serving 961 million people. The number of rheumatologists per 100,000 population varies greatly from 3.9 per 100,000 people (Uruguay) to 0.11 per 100,000 people (Nicaragua). The number of training programs also varies widely, with some countries having no indigenous programs. The distribution of rheumatologists is mainly in the large cities, particularly in the smaller countries. Pediatric rheumatologists have dramatically increased in number in 2012, but 96% reside in 6 countries. This remains an underserved area in most countries. ConclusionsThe rheumatology workforce in the Americas has improved between 2012 and 2015, especially in the number of pediatric rheumatologists. However, numerically and in the perception of the 21 member societies of PANLAR, the number is still inadequate to meet the increasing demands for rheumatologic care, especially in the care of children with rheumatic disease and in rural areas.

Endothelial Alterations in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Potential Effect of Monocyte Interaction

Patients with systemic autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are prone to develop atherosclerosis and cardiovascular diseases five times more often than the general population; this increase in frequency could be partially explained by an increase in the macrovasculature endothelial damage. In these autoimmune diseases, a microvascular endothelial injury has also been reported in different organs and tissues, especially in sites where ultrafiltration processes occur. Different components that are characteristic to the immunopathology of RA and SLE could be involved in the endothelial cell activation, permeability increase, functional alteration, and vascular injury. Circulating immune complexes (IC) detected in SLE and RA have been proposed to participate in the endothelial injury. In the vascular environment, IC can generate different responses that could be mediated by monocytes, because these cells have patrolling and monitoring functions on the endothelium. However, with certain stimuli such as TLR ligands, the monocytes are retained in the lumen, releasing proinflammatory mediators that participate in the endothelial damage. This paper aims to review some aspects about the endothelial activation and dysfunction in the context of SLE and RA, as well as the potential role that monocytes apparently play in this process.

Potential Involvement of Platelet-Derived Microparticles and Microparticles Forming Immune Complexes during Monocyte Activation in Patients with Systemic Lupus Erythematosus

Microparticles (MPs) are vesicles derived from the plasma membrane of different cells, are considered a source of circulating autoantigens, and can form immune complexes (MPs-ICs). The number of MPs and MPs-ICs increases in patients with systemic lupus erythematosus (SLE). MPs activate myeloid cells by inducing IL-6 and TNF-α in both SLE and other diseases. Therefore, we propose that the recognition of MPs-ICs by monocytes rather that MPs may define their phenotype and contribute to the inflammatory process in patients with SLE. Thus, the aims of this study were to evaluate the association among circulating MPs-ICs from different cell sources, alterations observed in monocyte subsets, and disease activity in patients with SLE and to establish whether monocytes bind and respond to MPs-ICs in vitro. Circulating MPs and monocyte subsets were characterized in 60 patients with SLE and 60 healthy controls (HCs) using multiparametric flow cytometry. Patients had higher MP counts and frequencies of MPs-CD41a + (platelet-derived) compared with HCs, regardless of disease activity. MPs from patients with SLE were C1q + and formed ICs with IgM and IgG. MPs-IgG + were positively correlated with active SLE (aSLE), whereas MPs-IgM + were negatively correlated. Most of the circulating total ICs-IgG + were located on MPs. The proportion and number of non-classical monocytes were significantly decreased in patients with SLE compared with HCs and in patients with aSLE compared with patients with the inactive disease. Non-classical monocytes obtained from patients with SLE exhibited increased levels of CD64 associated with MPs-IgG +, MPs-C1q +, total circulating ICs-IgG +, and disease activity. The direct effects of MPs and MPs-IgG + on monocytes were evaluated in cell culture. Monocytes from both HCs and patients bound to and internalized MPs and MPs-IgG + independent of CD64. These vesicles derived from platelets (PMPs), mainly PMPs-IgG +, activated monocytes in vitro and increased the expression of CD69, CD64, and pro-inflammatory cytokines such as IL-1β, TNF-α, and IFN-α. Therefore, MPs are one of the most representative sources of the total amount of circulating ICs-IgG + in patients with SLE. MPs-IgG + are associated with SLE activity, and PMPs-IgG + stimulate monocytes, changing their phenotype and promoting pro-inflammatory responses related to disease activity.

First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)–Pan-American League of Associations of Rheumatology (PANLAR)

Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an ‘overarching’ treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings.

Papel de la vía de señalización del TWEAK/Fn14 en la nefritis lúpica y otros escenarios clínicos

Knowledge of the signalling pathways involved in various diseases has enabled advances in the understanding of pathophysiological, diagnostic and therapeutic models of several inflammatory and autoimmune diseases. Systemic lupus erythematosus is a widely studied autoimmune disease that can affect multiple organs, with a major impact on morbidity and mortality when it involves the kidneys. Over the past 10 years, interest in the role of the TWEAK/Fn14 signalling pathway in lupus nephritis, as well as other clinical settings, has increased. By reviewing the literature, this article assesses the role of this pathway in lupus nephritis, underlines the importance of TWEAK in urine (uTWEAK) as a biomarker of the disease and stresses the favourable results published in the literature from the inhibition of the TWEAK/Fn14 pathway as a therapeutic target in experimental animal models, demonstrating its potential application in other settings. Results of ongoing clinical trials and future research will give us a better understanding of the real benefit of blocking this pathway in the clinical course of several conditions.

Therapeutic Guidelines for Latin American Lupus Patients: Methodology

Modem medicine is in a continuous state of flux given the relentless development of new evidence: thus, it is quite difficult for clinicians to abreast of all advances as they happen

A Retrospective Study of the Immunological and Non-Immunological Factors Associated with Kidney Allograft Rejection in Two Transplant Centres in Medellin, Columbia

Introduction Transplantation is the most clinically accepted therapy for the treatment of ESRD. Rejection diagnosis is complicated due to multiple factors involved in this process and in transplant failure; therefore, the main aim of our study was to identify immunological and non-immunological factors associated with rejection and kidney allograft loss in a cohort of 991 transplanted patients in Medellín, Colombia, between 2005 and 2015. Methods In this retrospective observational cohort study, the descriptive component was carried out by frequencies, and bivariate analysis by the Kaplan Meier method, in the Cox proportional hazards model was applied the Hosmer Lemeshow Criterion and the Cox Regression Method. Results In this cohort, the half of the follow-up time where 50% of the rejection occurred was 24 months. The overall incidence of rejection was 17.5% and 13.5% of kidney allograft loss. According to rejection by the Banff classification, the most frequent was T cell-mediated rejection (TCMR) with a frequency of 26%. Of the 173 patients diagnosed with rejection, 107 lost the graft. Statistically significant associations were found in the categories of the following variables: Age, <30 years HR7.398 (IC95%, 2.024-27.034) p=0.002, 31-40 years HR4.433 (IC95%, 1.111-17.072) p=0.03, 41-50 years 4.22 (IC95%, 1,102-16,165) p=0.036. Gender, female HR3,509 (IC95%, 1,431-8,606) P=0,006; Within these, women with more than 4 pregnancies HR4.11 (IC95% 1,535-11,056) p=0.005. Sensitization, HLA class I antibodies Class-I HR2.932 (IC95%, 1.352-6.359) p=0.006, with the persistent risk of allograft rejection during the entire time of the study. Finally, transplanted recipients from donors younger than 20 and from 21 to 30 years old, have a protective factor in order not to lose the kidney allograft (HR 0.33 (95% CI, 0.123-0.889) p=0.028 and HR 0.35 (IC95%, 0.13-0.952) p=0.04) respectively. Discussion and Conclusions This study becomes an important scientific evidence for the transplant centres in the city of Medellín and in all de country. The overall incidence of rejection of the study is higher than that previously reported in a cohort of receptors in the city, the type of rejection mediated by T cells is the most frequent throughout the follow-up, as well as during the first 36 months post-transplant, the interaction of patients under the age of 51 years, female and HLA class I antibodies are associated with an increased risk of allograft rejection. The understanding and the importance of these variables, during the different moments of the transplant in our population, become useful and important tools to increase the survival rates and decrease the incidence of rejection and loss of the renal allograft.