Increased levels of circulating Th17 cells in quiescent versus active Crohn's disease.
OBJECTIVE
Th17 cells, a subset of CD4+ T cells that produce interleukin (IL)-17A, IL-17F, IL-21, IL-22, IL-26, and the chemokine CCL20 are critically involved in the mucosal inflammation observed in Crohn's disease (CD). However, their role as mediators of inflammation in CD has been questioned by a recent clinical trial in which anti-IL-17A (secukinumab) treatment was ineffective. Besides being pro-inflammatory, Th17-related cytokines mediate mucosal protective functions. We aimed to investigate the role of Th17 cells in CD inflammation.


METHODS
Blood samples from 26 patients with active CD and 10 healthy controls (HC) were analyzed for levels of IL-17A-, IL-21- and IL-22-producing CD45RO+CD4+ T cells using multicolor flow cytometry. Samples were analyzed before and during adalimumab treatment to compare intra-individual changes during active and quiescent disease.


RESULTS
CD patients had statistically significantly higher levels of IL-17-A-, IL-21- and IL-22-producing CD45RO+CD4+ T cells in both active and quiescent disease compared with HC. Baseline levels of IL-21 and IL-22 producing CD45RO+CD4+ T cells correlated inversely with mucosal inflammation estimated by fecal calprotectin. Patients who responded to adalimumab treatment demonstrated a 2- to 3-fold increase in levels of IL-17A- and IL-21-producing CD45RO+CD4+ T cells in quiescent disease compared with active disease.


CONCLUSIONS
Our data support the involvement of Th17 cells and IL-21- and IL-22-producing CD45RO+CD4+ T cells in CD. Because patients had higher levels in quiescent disease compared with active CD, we question whether Th17 cells are promoters of inflammation. Instead, Th17 cells may counterbalance inflammation and maintain gut homeostasis.
Gastro-Immuno Research Laboratory (GIRL), Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, DK-8000 Aarhus C, Denmark. andedige@rm.dk
Anders
A
Dige
Sidsel
S
Støy
Tue K
TK
Rasmussen
Jens
J
Kelsen
Christian L
CL
Hvas
Thomas D
TD
Sandahl
Jens F
JF
Dahlerup
Bent
B
Deleuran
Jørgen
J
Agnholt
D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020381:Interleukin-17 / Q000097:blood; D007378:Interleukins / Q000097:blood; D008297:Male; D008875:Middle Aged; D058504:Th17 Cells / Q000378:metabolism*; D000097043:Interleukin-22; D000098546:Interleukin-21
D000068879:Adalimumab; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22; D000098546:Interleukin-21; C508717:IL17A protein, human