Th17 expansion in granulomatosis with polyangiitis (Wegener's): the role of disease activity, immune regulation and therapy.
BACKGROUND
In autoimmune diseases, IL-17 producing T-cells (Th17), a pro-inflammatory subset of T-cells, are pathophysiologically involved. There is little knowledge on the role of Th17 cells in granulomatosis with polyangiitis (GPA). In the present study, we investigated Th17 cells, Tregs and subsets of circulating Th17 cells in GPA and related results to disease activity.


METHODS
42 GPA patients in remission, 18 with active disease and 14 healthy controls (HC) were enrolled. Th17 cells, their subsets and regulatory T-cells were determined by intracellular fluorescence activated cell sorter (FACS). Data are given as mean percentage ±SD of total T-helper-cells.


RESULTS
Th17 cells are expanded in active and quiescent GPA as compared to HC (1.7±1.4% vs. 0.7 ±0.3%, P = 0.006 and 1.9 ±1.5% vs. 0.7 ±0.3%, P<0.0001). Th17 expansion is stable over time and does not decline when remission is achieved. However, a negative association of Th17 cells and steroid dosage is observed (r=-0.46, P = 0.002). The Th17 expansion was not balanced by Tregs as indicated by skewed Th17/Treg ratios in active and quiescent GPA. Th17 subsets co-producing IFNγ or IL-10 are significantly increased in GPA. GPA patients in remission not receiving maintenance therapy have significantly more IL-10/IL-17A double positive T-cells than HC (0.0501 ±0.031% vs. 0.0282 ±0.016%, P = 0.007).


CONCLUSIONS
We provide evidence for a persistent, unbalanced expansion of Th17 cells and Th17 subsets which seems to be independent of disease activity. Maintenance therapy reduces -but does not normalize- Th17 expansion.
Benjamin
B
Wilde
Marielle
M
Thewissen
Jan
J
Damoiseaux
Marc
M
Hilhorst
Pieter
P
van Paassen
Oliver
O
Witzke
Jan Willem
JW
Cohen Tervaert
D000328:Adult; D000368:Aged; D000954:Antigens, Surface / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D014890:Granulomatosis with Polyangiitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008875:Middle Aged; D012720:Severity of Illness Index; D013256:Steroids / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology*
D000954:Antigens, Surface; D020381:Interleukin-17; D013256:Steroids; D016753:Interleukin-10; D007371:Interferon-gamma