June 30, 2009 Up-regulation of certain cytokines and chemokines (signaling molecules involved in the functioning of the immune system) can predict the development of rheumatoid arthritis (RA) three years before the onset of symptoms, according to the results of a new study presented at EULAR 2009, the Annual Congress of the European League Against Rheumatism in Copenhagen, Denmark.
The results of the study showed that up-regulation of certain cytokines (specifically Th1, Th2 and Treg) involved in the growth and proliferation of various cells integral to the immune system, predicted which individuals go on to develop RA. Interestingly, post-disease onset, chemokines, stromal cell and angiogenic-related markers were important in differentiating up-regulation in those who had developed RA compared to findings in the same individual before symptoms of RA.
Cytokines and chemokines are small signalling molecules which are integral to the immune system, as they mediate and regulate immunity, inflammation, and the development of blood cells (haematopoiesis). In this study, several of these molecules, as well as some cytokine receptors, showed significantly increased levels before disease onset compared with controls (median 3.3 years before symptoms), indicating general immune activation (p<0.05-0.001)* and therefore a progression of disease activity.
The levels were seen to be particularly elevated in individuals identified as being ACPA- (anti-citrullinated peptide antibody) and RF- (rheumatoid factor) positive (both known risk factors for RA), and most of the concentrations increased further after disease onset. Notably, the concentration of interleukin 17 (IL-17, a cytokine which acts as a regulator of multiple immune functions) was found to be significantly higher before onset compared with post-diagnosis (p>0.01).
Prof Solbritt Rantapää Dahlqvist, of the University Hospital Umeå, Sweden, who led the study said: "Our findings add another important piece to the complex puzzle of pathophysiological processes responsible for the occurrence of RA. Understanding more about what happens in the body, to precipitate the onset of RA, could potentially contribute to the development of new strategies for the treatment and even prevention of this debilitating disease."
This nested case-control study (whereby new case controls were applied into a cohort that was defined before the study began, at a rate of 1 case:3 controls) was performed in individuals (n=86, 65 females, 21 males) who had donated blood to the Medical Biobank of Northern Sweden (median 3.3 years) before onset of disease; and matched controls (n=256, 191 females, 61 males) from the same Biobank. At the time of RA diagnosis (using American College of Rheumatology (ACR) criteria), 69 (52 females and 17 males) individuals donated blood samples.
30 cytokines, cytokine receptors and chemokines** were measured in plasma samples using multiplex detection kits from Bio-Rad analysed by a Bio-Plex Array Reader (Luminex200, Labmap™ system).
*The cytokines, cytokine receptors and chemokines that were increased prior to disease onset included: IL-1, IL-2, IL-6, IL-7, IL-1RA, TNF-VEGF, Th1 (IFN-, IL-12), Th2 (IL-4, Eotaxin), Treg (IL-10) and chemokines MCP-1 and MIP-1.
**The 30 cytokines, cytokine receptors and chemokines that were investigated in total for links to onset of RA included: IL-1ß, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, basic FGF, G-CSF, GM-CSF, IFN-, IP-10, MCP-1, MIP-1, MIP-1, PDGF-BB, RANTES, TNF-, VEGF, MIG, MIF and IL-2R.
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