Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA).

INTRODUCTION: The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA). METHODS: Peripheral blood from 42 GPA patients in remission and 29 age-matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (T(FH)), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL-21-receptor on B-cells was analyzed. RESULTS: Percentages of IL-21 producing Th-cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21-receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs. CONCLUSION: The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA-production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA

The Short-Term Effect of Weight Loss Surgery on Volumetric Breast Density and Fibroglandular Volume

Purpose: Obesity and breast density are both associated with an increased risk of breast cancer and are potentially modifiable. Weight loss surgery (WLS) causes a significant reduction in the amount of body fat and a decrease in breast cancer risk. The effect of WLS on breast density and its components has not been documented. Here, we analyze the impact of WLS on volumetric breast density (VBD) and on each of its components (fibroglandular volume and breast volume) by using three-dimensional methods. Materials and Methods: Fibroglandular volume, breast volume, and their ratio, the VBD, were calculated from mammograms before and after WLS by using Volpara™ automated software. Results: For the 80 women included, average body mass index decreased from 46.0 ± 7.22 to 33.7 ± 7.06 kg/m2. Mammograms were performed on average 11.6 ± 9.4 months before and 10.1 ± 7 months after WLS. There was a significant reduction in average breast volume (39.4 % decrease) and average fibroglandular volume (15.5 % decrease), and thus, the average VBD increased from 5.15 to 7.87 % (p < 1 × 10−9) after WLS. When stratified by menopausal status and diabetic status, VBD increased significantly in all groups but only perimenopausal and postmenopausal women and non-diabetics experienced a significant reduction in fibroglandular volume. Conclusions: Breast volume and fibroglandular volume decreased, and VBD increased following WLS, with the most significant change observed in postmenopausal women and non-diabetics. Further studies are warranted to determine how physical and biological alterations in breast density components after WLS may impact breast cancer risk.ECU Open Access Publishing Support Fun

T-CELL REACTIVITY TO PROTEINASE-3 AND MYELOPEROXIDASE IN PATIENTS WITH WEGENERS GRANULOMATOSIS (WG)

T cell-mediated immunity is hypothesized to play an important role in the pathogenesis of granulomatous inflammation and vasculitis as found in patients with WG. The antigenic specificities of those T cells remain, however, unknown. Anti-neutrophil cytoplasmic antibodies (ANCA) present in patients with WG are directed to proteinase 3 (PR3) and myeloperoxidase (MPO). In the present study we investigated the proliferative capacity of peripheral blood mononuclear cells (PBMC) from patients with WG and age- and sex-matched controls in response to the WG autoantigens PR3 and MPO. Possible mitogenic effects of active PR3 and toxic effects of active MPO were excluded by using heat-inactivated PR3 and MPO. Antigen-specific stimulation induced by these autoantigens was studied by using processed PR3 and MPO in the lymphocyte stimulation test (LST). Proliferation induced by processed antigen correlated with that by heat-inactivated free antigen. The general capacity to proliferate in response to mitogens and recall antigens did not differ between patients and controls. However, patients with WG who were or had been positive for PR3-ANCA (n = 17) responded more strongly to PR3 than to MPO and showed higher responses to PR3 compared with controls (n = 13). Within the PR3-ANCA group T cell proliferation did not correlate with ANCA titre. In a small group of patients with MPO-ANCA (n = 5) no differences were observed compared with controls for MPG-specific proliferation. The data presented demonstrate that autoreactive PR3-specific T cells are present in patients with WG. Their fine specificity and possible role in the pathogenesis of WG have to be defined in further studies

SERUM LEVELS OF SOLUBLE ADHESION MOLECULES INTERCELLULAR-ADHESION MOLECULE-1, VASCULAR CELL-ADHESION MOLECULE-1, AND E-SELECTIN IN PATIENTS WITH WEGENERS GRANULOMATOSIS - RELATIONSHIP TO DISEASE-ACTIVITY AND RELEVANCE DURING FOLLOW-UP

Objective. To assess the value of measuring serum levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble E-selectin for monitoring disease activity in Wegener's granulomatosis (WG). Methods. A sandwich enzyme-linked immunosorbent assay was used to measure levels of soluble adhesion molecules at the time of diagnosis in 22 consecutive patients with WG, in 12 WG patients studied serially prior to disease relapse, at the time of upper airways infection in 18 patients with inactive WG, and in 57 controls. Disease activity was assessed by disease activity score and C-reactive protein levels. Results. At diagnosis of WG, sICAM-1 and sVCAM-1 levels were significantly elevated and correlated with disease activity. At the time of relapse, a significant increase in all 3 soluble adhesion molecules was found compared with levels at 6 months prior to relapse, but only sVCAM-1 levels were significantly elevated compared with those in controls. Levels of soluble adhesion molecules at the time of relapse did not differ from those measured during an upper airways infection without disease activity. Conclusion. Elevated serum levels of sICAM-1 and sVCAM-1 can be found in active WG and correlate with disease activity. However, their clinical relevance for followup is limited due to lack of sensitivity and specificity for WG disease activity