RESEARCH - Up-regulation of cytokines and chemokines predates the onset of RA

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Arthritis & Rheumatism

Volume 62, Issue 2, Pages 383-391

Published Online: 7 Jan 2010

Up-regulation of cytokines and chemokines predates the onset of

rheumatoid arthritis

Heidi Kokkonen 1, Ingegerd Söderström 1, Joacim Rocklöv 2, Göran

Hallmans 2, a Lejon 2, Solbritt Rantapää Dahlqvist 1 *

1Umeå University Hospital, Umeå, Sweden

2Umeå University, Umeå, Sweden

Funded by:

Swedish Research Council; Grant Number: K2007-52X-20307-01-3

King Gustaf V's 80-Year Fund

Swedish Rheumatism Association

University of Umeå

European Community Sixth Framework Programme (project AutoCure)

Abstract

Objective

To identify whether cytokines, cytokine-related factors, and

chemokines are up-regulated prior to the development of rheumatoid

arthritis (RA).

Methods

A nested case-control study was performed in 86 individuals who had

donated blood samples before experiencing any symptoms of disease

(pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of

the pre-patients, blood samples were also obtained at the time of the

diagnosis of RA. The plasma levels of 30 cytokines, related factors,

and chemokines were measured using a multiplex system.

Results

The levels of several of the cytokines, cytokine receptors, and

chemokines were significantly increased in individuals before disease

onset compared with the levels in control subjects; i.e., those

representing signs of general immune activation (interleukin-1 [iL-1],

IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor),

activation of Th1 cells (interferon-, IL-12), Th2 cells (IL-4,

eotaxin), Treg cells (IL-10), bone marrow-derived factors (IL-7,

granulocyte-macrophage colony-stimulating factor, and granulocyte

colony-stimulating factor), as well as chemokines (monocyte

chemotactic protein 1 and macrophage inflammatory protein 1). The

levels were particularly increased in anti-cyclic citrullinated

peptide antibody- and rheumatoid factor-positive individuals, and the

concentration of most of these increased further after disease onset.

The concentration of IL-17 in individuals before disease onset was

significantly higher than that in patients after disease onset.

Individuals in whom RA subsequently developed were discriminated from

control subjects mainly by the presence of Th1 cells, Th2 cells, and

Treg cell-related cytokines, while chemokines, stromal cell-derived

cytokines, and angiogenic-related markers separated patients after the

development of RA from individuals before the onset of RA.

Conclusion

Individuals in whom RA later developed had significantly increased

levels of several cytokines, cytokine-related factors, and chemokines

representing the adaptive immune system (Th1, Th2, and Treg

cell-related factors); after disease onset, the involvement and

activation of the immune system was more general and widespread.

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