A pathogenic IFNα, BLyS and IL-17 axis in Systemic Lupus Erythematosus patients - PubMed (original) (raw)
A pathogenic IFNα, BLyS and IL-17 axis in Systemic Lupus Erythematosus patients
Patricia López et al. Sci Rep. 2016.
Abstract
This study aims to analyze in depth the role of IFNα in the upregulation of BLyS in different leukocyte populations and the possible relationship of these molecules with IL-17 and other pathogenic cytokines in SLE. Thus, IFNAR1 and membrane BLyS (mBLyS) expression was upregulated on various blood cell types from patients and closely correlated in all individuals. Moreover, BLyS serum levels associated positively with IFNα and IL-17A amounts, as well as with mBLyS on B cells and neutrophils. Interestingly, mBLyS on neutrophils was also correlated with IL-17A levels. Additionally, intracellular IL-17A expression was increased in both CD4(+) lymphocytes and neutrophils from patients, and IL-17(+)CD4(+) T cell frequency was associated with serum IFNα and IFNRA1 expression on B cells. Finally, in vitro assays support an IFNα role in the activation of Th17 cells in SLE. In conclusion, these data suggest that IFNα, BLyS and IL-17 could form a pathological axis in SLE, involving T and B lymphocytes, monocytes, DCs and neutrophils, which act in a vicious circle that encourage the preexisting inflammation and propagate the disease process.
Figures
Figure 1. Expression levels of IFNAR1 and membrane BLyS on blood leukocytes from SLE patients and healthy controls.
Membrane BLyS (mBLyS) and IFNAR1 levels were quantified by flow cytometry on fresh B cells, neutrophils, monocytes, pDCs and mDCs from 67 patients (SLE) and 29 healthy controls (HC). (A) Scatter plots represent MFI levels of BLyS and IFNAR1 in several blood subpopulations and horizontal bars show the median. Statistical significance was assessed by Mann-Whitney U test. (B) Graphs show the correlation between mBLyS and IFNRA1 expression (MFI) in each leukocyte population from SLE patients (circles) and healthy controls (squares). Correlation analyses were evaluated by Spearman test.
Figure 2. IL-17 producing cells are increased and associated with IFNα in SLE patients.
(A) IL-17 and IFNγ expression was analyzed intracellularly by flow cytometry in fresh peripheral blood neutrophils and CD4+ lymphocytes from SLE patients and HC. Representative dot-plots show positive cells for IL-17 or IFNγ expression, as determined by the fluorescence of cells labelled with the corresponding isotype -matched conjugated monoclonal antibody as a negative control. (B) Scatter-plots represent the percentage of IL-17+ or IFNγ+ cells among CD4+ lymphocytes or neutrophils in SLE patients and HC. Horizontal bars show the median. Statistical differences among groups were evaluated by Mann-Whitney U test. (C) Relationship between IL-17 producing CD4+ T cells and both IFNRA1 and IFNα in SLE patients. Graphs show the proportion of IL-17+ CD4+ cells related to the IFNRA1 expression on B cells (MFI) and the IFNα serum levels. Statistical significance was evaluated by the Spearman’s rank correlation test. (D) IL-17 levels in the culture supernatants of SLE and healthy PBMCs after IFNα treatment. Healthy and SLE PBMCs were treated with IFNα and the release of IL-17 was quantified after 2, 4 or 6 hours of culture. Bars represent median (interquartile range) of the percentage of change in the IL-17 levels in the presence of IFNα compared to unstimulated cultures. Independent experiments were performed with 10 healthy controls and 12 SLE patients. Statistical differences between IFNα-treated and untreated cells at each time of culture were evaluated by the Wilcoxon test for paired data. n.s.: not statically significant differences.
Figure 3. Proposed IFNα, BLyS and IL-17 pathogenic axis in SLE.
The high IFNα levels present in most SLE patients could promote the activation and induction of BLyS in B cells, monocytes, mDCs and neutrophils, including the low-density granulocyte (LDG) subset. Thus, the co-stimulation provided by these activated antigen-presenting cells - such as B cells, monocytes or mDCs-, to the Th17 subset enhanced in SLE patients can induce the release of IL-17. Moreover, IL-23 secretion by IFNα-activated mDCs may amplify Th17 differentiation. Also, IFNα-activated neutrophils under the inflammatory conditions presented in SLE are able to secrete IL-17. Then, this vicious circle is closed by the combined effect of IL-17 and BLyS. First, they promoted B cell survival and differentiation, which lead to autoantibody production and further generation of the immune complexes able to induce IFNα secretion by pDCs. In addition, both cytokines can activate neutrophils, thus sustaining the preexisting SLE inflammation. Finally, IFNα secretion by neutrophils, and especially by the LDG subset, propagates the disease process.
References
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