Th17 cells and Crohn's disease

[Guest guest]

Inflamm. Bowel Dis. Nov 16 [Epub ahead of print] (2007)

Linking genetic susceptibility to Crohn's disease with Th17 cell

function: IL-22 serum levels are increased in Crohn's disease and

correlate with disease activity and IL23R genotype status.

Silke Schmechel, BS 1, Astrid Konrad, MD 1, Diegelmann, BS 1,

Jurgen Glas, MD 1 2, Wetzke, MD 1 3, Ekaterini Paschos, DMD 4,

Lohse, MD 5, Burkhard Goke, MD 1, Stephan Brand, MD 1 *

1Department of Medicine II, Grosshadern, University of Munich, Germany

2Clinic for Preventive Dentistry and Periodontology, University of

Munich, Germany

3Department of Pediatrics, Hannover Medical School, Germany

4Department of Orthodontics, University of Munich, Germany

5Institute of Clinical Chemistry, Grosshadern, University of Munich,

Germany

email: Stephan Brand (stephan.brand@...)

*Correspondence to Stephan Brand, Department of Medicine II,

University Hospital Munich, Grosshadern, University of Munich, D-

81377 Munich, Germany

Keywords

IL-22 • IL-23R • IL-17A • IL-17F • Th17 cells • TNF-a • IL-6 •

Crohn's disease • ulcerative colitis • inflammatory bowel disease •

genetics • polymorphism • CARD15 • NOD2

Abstract

Background: We analyzed the influence of Crohn's disease (CD)-

associated IL23R gene variants on IL-22 that is expressed in IL-23R+

Th17 cells.

Methods: IL-22 serum levels were measured in 242 CD patients and in

31 healthy controls. Subanalyses included serum levels of IL-6, TNF-

a, IL-17A, IL-17F, C-reactive protein (CRP), and leukocyte count. In

all patients, genotyping for 10 CD-associated IL23R single nucleotide

polymorphisms (SNPs) and the 3 main CD-associated CARD15 variants was

performed.

Results: There was a highly significant increase in IL-22 serum

expression in CD patients compared to healthy controls (P = 2.53 × 10-

9). IL-22 serum levels correlated with disease activity: IL-22 levels

in patients with a Crohn's disease activity index (CDAI) >150 were

significantly higher than in patients with a CDAI <150 (P = 0.001),

while TNF-a and IL-6 were not significantly different between these 2

groups. Analyzing the effect of 10 IL23R variants on IL-22 serum

levels, we demonstrated that the quotients of mean IL-22 serum levels

of carriers of the minor allele to the mean serum IL-22 in wildtype

carriers correlated highly with the corresponding CD susceptibility

risk for each gene variant (r = 0.807). The IL-22 levels in carriers

of CD risk-increasing IL23R variants were significantly higher than

in carriers of CD risk-decreasing IL23R variants (P = 0.008).

Conclusions: The Th17 cytokine IL-22 is expressed at high levels in

CD and correlates with disease activity, offering a better separation

between active and inactive CD than IL-6 and TNF-a. IL23R genotypes

influence IL-22 serum expression, linking genetic CD susceptibility

to Th17 cell function for the first time.

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Th17 cells are pro-inflammatory T helper cells that are implicated in

a number of animal models of autoimmune diseases. Because these cells

express IL23R on their surface, and IL23R has been found to be a

susceptibility gene in human inflammatory bowel disease, psoriasis

and ankylosing spondilitis, it is encouraging to see that these Th17

cells are now being examined in human IBD.

It is interesting to me that the IL-22 cytokine described in the

above paper, may actually have a PROTECTIVE effect on the hepatocytes

of the liver:

___________________

Immunity. 2007 Oct;27(4):647-59.

Interleukin-22 but not interleukin-17 provides protection to

hepatocytes during acute liver inflammation.

Zenewicz LA, Yancopoulos GD, Valenzuela DM, AJ, Karow M,

Flavell RA

Department of Immunobiology, Yale University School of Medicine, New

Haven, CT 06520, USA.

The cytokine interleukin-22 (IL-22) is primarily expressed by T

helper 17 (Th17) CD4(+) T cells and is highly upregulated during

chronic inflammatory diseases. IL-22 receptor expression is absent on

immune cells, but is instead restricted to the tissues, providing

signaling directionality from the immune system to the tissues.

However, the role of IL-22 in inflammatory responses has been

confounded by data suggesting both pro- and anti-inflammatory

functions. Herein, we provide evidence that during inflammation, IL-

22 played a protective role in preventing tissue injury. Hepatocytes

from mice deficient in IL-22 were highly sensitive to the detrimental

immune response associated with hepatitis. Additionally, IL-22-

expressing Th17 cells provided protection during hepatitis in IL-22-

deficient mice. On the other hand, interleukin-17 (IL-17), which is

coexpressed with IL-22 and can induce similar cellular responses, had

no observable role in liver inflammation. Our data suggest that IL-22

serves as a protective molecule to counteract the destructive nature

of the immune response to limit tissue damage. PMID: 17919941.

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It will be interesting to see if Th17 cells are involved in

ulcerative colitis, and specifically if in the ulcerative colitis

associated with PSC this protective effect of IL-22 on the liver is

impaired in some way?

Dave R.