Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Enhanced IL-17A and IL-22 Production by Peripheral Blood Mononuclear Cells Distinguish Systemic Sclerosis from Healthy Individuals.
Brembilla1, Nicolò C., Truchetet2, Marie-Elise, Montanari1, Elisa, Allanore3, Yannick, Chizzolini1, Carlo
In systemic sclerosis (SSc) inappropriate T cell responses are thought to participate in initiating events ultimately leading to excessive extracellular matrix deposition and fibrosis. The pattern of cytokine produced distinguish T cell subsets with distinct functional capabilities and the pattern of chemokine receptor expressed at the surface of T cells participate to the code used for homing in peripheral tissues, including the skin. Aim of the present work was to assess whether T cells present in the peripheral blood (PB) of SSc patients could be distinguished from those of healthy controls in terms of cytokine production and whether the chemokine receptor expression on T cells could further predict their functional subset and homing capability.
PB mononuclear cells and clinical characteristics were obtained from 19 immunosuppressant agents naive SSc and 18 healthy controls (Ctrl) upon informed consent and approval by the ethical committee. Multiparameter cytofluorimetric analysis was performed to assess the surface expression of CD4, CD45RA, CCR4, CCR6, CCR10, CXCR3, and CD161 as well the intracellular accumulation of IL-17A, IL-22, IFN-gamma, and IL-4 upon activation by CD3/CD28 crosslinking in PB mononuclear cells at time 0 and after 7 days of culture. The results were stratified according to the presence of SSc, limited (lSSc) or diffuse disease (dSSc). The results of the various patient populations were compared using the Mann Whitney U test and correlations between variables computed using the Spearman r test.
SSc individuals had higher frequencies of CD4+ T cells and higher frequencies of IL-17A and IL-22 producing CD4+ T cells both at time 0 and upon 7 days of culture when compared to Ctrl. A significant increase in IL-4 production was observed only in the dSSc subset. The intracellular levels of IL-17A and IL-22 with the exclusion of IFN-gamma were tightly correlated indicating co-production by the same CD4+ T cell in SSc and not in Ctrl. When the expression level of various chemokine receptors on CD4+ T cells was taken into account, the production level of IL-17A was positively correlated with the lack of CXCR3 expression (p = 0.0009) and particularly so in the CXCR3-CCR6+ subset (p = 0.0006). Furthermore, the frequency of CD161+ CD4+ T cells was higher in SSc than in Ctrl.
Our results for the first time show that increased IL-17A is accompanied by IL-22 but not IFN-gamma production in SSc CD4+ T cells, thus stressing a preferential Th17 cell expansion in SSc. Furthermore, the production of these cytokines correlates with the expression levels of chemokine receptors important for skin homing, strongly indicating that they may participate to dysregulated matrix deposition at least in this target organ. These results provide a rationale for targeting IL-17 and the Th17 differentiation pathway as novel approaches to harness the clinical course of SSc.
To cite this abstract, please use the following information:
Brembilla, Nicolò C., Truchetet, Marie-Elise, Montanari, Elisa, Allanore, Yannick, Chizzolini, Carlo; Enhanced IL-17A and IL-22 Production by Peripheral Blood Mononuclear Cells Distinguish Systemic Sclerosis from Healthy Individuals. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1992