Expansion of intestinal CD4+CD25(high) Treg cells in patients with ankylosing spondylitis: a putative role for interleukin-10 in preventing intestinal Th17 response.
OBJECTIVE
Subclinical gut inflammation has been demonstrated in patients with ankylosing spondylitis (AS). This study was undertaken to determine the frequency of regulatory CD4+CD25(high) T cells (Treg cells) and to evaluate Treg cell-related cytokines (interleukin-2 [IL-2], transforming growth factor β [TGFβ], and IL-10) and transcription factors (FoxP3 and STAT-5) in the ileum of patients with AS.


METHODS
Quantitative gene expression analysis, by reverse transcriptase-polymerase chain reaction, of Treg-related cytokines (IL-2, TGFβ, and IL-10) and transcription factors (STAT-5 and FoxP3) was performed on ileal biopsy specimens from 18 patients with AS, 15 patients with active Crohn's disease (CD), and 15 healthy subjects. Tissue and circulating Treg cells were also analyzed by flow cytometry.


RESULTS
A significant up-regulation of IL-2, TGFβ, FoxP3, STAT-5, and IL-10 transcripts in the terminal ileum of AS patients displaying chronic ileal inflammation was observed. Flow cytometric analysis of Treg cells showed significant peripheral expansion in both patients with AS and chronic inflammation and patients with CD (mean ± SD 1.08 ± 0.4% and 1.05 ± 0.3%, respectively) as compared with healthy subjects (0.25 ± 0.12%) (P < 0.05). Interestingly, a 5-fold increase in the proportion of Treg cells was observed in the gut of patients with AS (5 ± 3%) as compared with healthy subjects (1.2 ± 0.4%) (P < 0.001), with 70-80% of these cells also producing IL-10. In vitro studies showed that blocking IL-10 was sufficient to induce Th17 polarization on lamina propria mononuclear cells isolated from AS patients.


CONCLUSIONS
Our findings provide the first evidence that an active Treg cell response, mainly dominated by IL-10 production, occurs in the gut of AS patients and is probably responsible for the absence of a clear Th17 polarization in the ileum of AS patients.
Ciccia
Francesco
F
University of Palermo, Palermo, Italy.
Accardo-Palumbo
Antonina
A
Giardina
Annarita
A
Di Maggio
Piera
P
Principato
Alfonso
A
Bombardieri
Michele
M
Rizzo
Aroldo
A
Alessandro
Riccardo
R
Ferrante
Angelo
A
Principe
Simona
S
Peralta
Sergio
S
Conte
Francesco
F
Drago
Sandro
S
Craxì
Antonio
A
De Leo
Giacomo
G
Triolo
Giovanni
G
D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology*; D016753:Interleukin-10 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000378:metabolism / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology*; D058504:Th17 Cells / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053759:Interleukin-23; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D016212:Transforming Growth Factor beta; D016753:Interleukin-10