Luís Inês

Frequency and functional activity of Th17, Tc17 and other T-cell subsets in Systemic Lupus Erythematosus

To compare frequency and functional activity of peripheral blood (PB) Th(c)17, Th(c)1 and Treg cells and the amount of type 2 cytokines mRNA we recruited SLE patients in active (n=15) and inactive disease (n=19) and healthy age- and gender-matched controls (n=15). The study of Th(c)17, Th(c)1 and Treg cells was done by flow cytometry and cytokine mRNA by real-time PCR. Compared to NC, SLE patients present an increased proportion of Th(c)17 cells, but with lower amounts of IL-17 per cell and also a decreased frequency of Treg, but with increased production of TGF-beta and FoxP3 mRNA. Iotan active compared to inactive SLE, there is a marked decreased in frequency of Th(c)1 cells, an increased production of type 2 cytokines mRNA and a distinct functional profile of Th(c)17 cells. Our findings suggest a functional disequilibrium of T-cell subsets in SLE which may contribute to the inflammatory process and disease pathogenesis.

Classification of Systemic Lupus Erythematosus: Systemic Lupus International Collaborating Clinics Versus American College of Rheumatology Criteria. A Comparative Study of 2,055 Patients From a Real-Life, International Systemic Lupus Erythematosus Cohort.

The new Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria aimed to improve the performance of systemic lupus erythematosus (SLE) classification over the American College of Rheumatology (ACR) 1997 criteria. However, the SLICC 2012 criteria need further external validation. Our objective was to compare the sensitivity for SLE classification between the ACR 1997 and the SLICC 2012 criteria sets in a real‐life, multicenter, international SLE population.

Functional characterization of peripheral blood dendritic cells and monocytes in systemic lupus erythematosus

With the purpose of contributing to a better knowledge of the APCs functional activity in SLE, we evaluated the distribution and functional ability to produce pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-12) of peripheral blood (PB) monocytes and DC (tDC), particularly myeloid (mDC) and CD14−/lowCD16+ DC subpopulations comparing them with those obtained from healthy individuals. The study was performed in 34 SLE patients with diverse disease activity scores (SLEDAI) and 13 healthy age- and sex-matched controls (NC). Our results show an overall decrease in absolute number and relative frequency of tDC in SLE patients with active disease when compared to those with inactive disease and NC, although this decrease did not seem to have an effect on the distribution of PB DC subsets. The monocytes number in SLE patients was similar to those found in NC, whereas a higher frequency of monocytes producing cytokines as well as the amount of each cytokine per cell found without stimulation was particularly observed in those patients with active disease. After stimulation, we observed a higher frequency of IL-12-producing monocytes in active SLE patients. On the other hand, we found among DCs higher frequencies of cytokine-producing CD14−/lowCD16+ DCs and a higher amount of cytokines produced per cell, particularly in active disease. These findings support an increased production of inflammatory cytokines by APCs in active SLE, mostly associated with alterations in CD14−/lowCD16+ DC subset homeostasis that might contribute to explain the dynamic role of these cells in disease pathogenesis.

Epidemiology of Systemic Lupus Erythematosus

Publisher Summary Epidemiology is the study of the distribution of illnesses and diseases and the factors affecting their incidence and clinical course in the population. Systemic lupus erythematosus (SLE), an autoimmune disease with a broad spectrum of clinical and immunological manifestations, is a major challenge to study epidemiologically, but research on SLE has been carried out in many parts of the world. These include descriptive studies of incidence and prevalence, observational studies of SLE prognosis, and the identification of potentially preventable causes of morbidity and mortality. Analytic and genetic epidemiologic studies suggest a multifactorial etiology of SLE. A better understanding of the epidemiology of SLE should help us understand its etiology, identify predictors of morbidity and mortality, and improve SLE care and outcomes. Epidemiologic clues for potential cause(s) remain elusive, not so much from lack of effort, but lack of strong signals. Even the most established risk factors, except for gender, explain the minority of cases. Overall, epidemiologic studies demonstrate a good and possibly improved prognosis since its first description, making SLE a chronic but potentially dangerous illness. Studies also indicate considerable variations in outcome and differences between ethnic groups and between industrial and preindustrial countries that are probably increasing, comprising a major research challenge and a possible public health opportunity to correct these inequalities. Long-term morbidity is appreciated but its study is only just beginning. Future studies will need to look at what is really modifiable and to test interventions rigorously.

Identification of clinical predictors of flare in systemic lupus erythematosus patients: a 24-month prospective cohort study

OBJECTIVE SLE has a relapsing-remitting course with disease activity flares over time. This study aims to identify clinical predictors of SLE flares. METHODS This prospective cohort study over 24 months included all SLE patients on follow-up at one academic lupus clinic. Flare was defined as an increase in SLEDAI-2K score ≥4 points. Baseline clinical and demographic parameters were compared using survival analysis for time-to-flare outcome with univariate log-rank tests. Variables with significant differences were further evaluated as predictors with multivariate Cox regression models adjusting for potential confounding or contributing factors and hazard ratio (HR) calculation. RESULTS A total of 202 SLE patients were included. Over the follow-up period, 1083 visits were documented and 16.8% of patients presented with flares. In multivariate analysis, the following parameters emerged as flare predictors: SLE diagnosis up to 25 years of age (HR = 2.14, P = 0.03), lupus nephritis previous to baseline visit (HR = 4.78, P < 0.0001) and immunosuppressor treatment for severe SLE (HR = 3.22, P < 0.001). Baseline disease activity, disease duration and treatment with prednisone or HCQ were not predictive factors. CONCLUSION Patients with an SLE diagnosis before age 25 years, lupus nephritis or immunosuppressor treatment for severe SLE present greater HRs for flares, suggesting the need for tighter clinical monitoring. Current immunosuppressive strategies seem to be inefficient in providing flare prevention.

Tolerogenic versus Inflammatory Activity of Peripheral Blood Monocytes and Dendritic Cells Subpopulations in Systemic Lupus Erythematosus

Abnormalities in monocytes and in peripheral blood dendritic cells (DC) subsets have been reported in systemic lupus erythematosus (SLE). We aim to clarify the tolerogenic or inflammatory role of these cells based on ICOSL or IFN-α and chemokine mRNA expression, respectively, after cell purification. The study included 18 SLE patients with active disease (ASLE), 25 with inactive disease (ISLE), and 30 healthy controls (HG). In purified plasmacytoid DC (pDC) was observed a lower ICOSL mRNA expression in ASLE and an increase in ISLE; similarly, a lower ICOSL mRNA expression in monocytes of ALSE patients was found. However, a higher ICOSL mRNA expression was observed in ASLE compared to HG in myeloid DCs. Interestingly, clinical parameters seem to be related with ICOSL mRNA expression. Regarding the inflammatory activity it was observed in purified monocytes and CD14−/low CD16+ DCs an increase of CCL2, CXCL9, and CXCL10 mRNA expression in ASLE compared to HG. In myeloid DC no differences were observed regarding chemokines, and IFN-α mRNA expression. In pDC, a higher IFN-α mRNA expression was observed in ASLE. Deviations in ICOSL, chemokine, and IFN-α mRNA expression in peripheral blood monocytes and dendritic cells subpopulations in SLE appear to be related to disease activity.

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n = 35) and PB from SLE patients (n = 34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p = 0.006 and p = 0.05) and lower amount of IL-17 per cell (p = 0.03 and p = 0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p < 0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group.

The weaker sex: Characterization of gender disparities in a nationwide lupus register (Reuma.pt/SLE)

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 24 avril 2015

A5.3 Alterations on Peripheral Blood B Cell Compartments in Systemic Lupus Erythematosus: Relevance For Monitoring Lupus Activity and Therapy

Background and Objectives Despite recent insights on abnormalities of blood B cell subsets in human systemic lupus erythematosus (SLE), a peripheral blood biomarker with useful clinical information about the occurrence of an active disease period hasn’t yet been achieved. Moreover, the clinical relevance of anti-dsDNA antibodies and their utility for monitoring an individual patient remains a matter of debate. In this sense, we attempt to determine whether the degree of abnormalities of circulating B cell subsets correlates with SLE disease activity and constitute an useful tool for SLE patients monitoring. Materials and Methods We analysed by flow cytometry the major circulating B cell subsets (immature, naïve, memory and plasmablast) and their expression profile of B cell related molecules (CD19, CD20, CD81 and BAFFR) in 43 SLE patients, 18 with active and 25 with inactive disease, according to the SLE Disease Activity Index 2000 (SLEDAI, 2k), as well as in 30 healthy individuals. Results The results pointed to the existence of significant alterations on B cell homeostasis that are significantly correlated with disease activity. An overall decrease in absolute numbers of all B cell subsets was observed in SLE patients, with the exception of IgGplasmablast that remained equal or even higher than in the control group, particularly in active disease. Additionally, a higher number of plasmablast expressing each Ig-heavy chain isotypes was found in patients with mucocutaneous involvement. Moreover, among memory B cells, an increased IgG and decreased IgM positive cellswas observed in both SLE groups. Furthermore, a decreased expression of CD19 observed in active disease and an increased BAFFR expression in inactive disease in the majority of B cell subsets, may contribute not only for breaking tolerance during B cell development, but also for enhancing plasmablast survival. Conclusions In conclusion, flow cytometric monitoring of circulating B cell subsets, particularly focused on relative and absolute numbers of IgG plasmablasts, could provide a useful tool for monitoring disease activity, but also the therapy efficacy in patients with SLE.