Rheumatoid arthritis (RA) exact pathogenesis remains uncertain, although autoimmune processes appear to play a role, and RA is often referred to as a Th1-driven disease. However, it is well known that RA patients have a reduced capacity to produce IL-2 and interferon gamma (IFN-γ). IL-7 is an important cytokine during early events leading naïve T cells towards Th1 polarisation. We have associated low levels of circulating IL-7 with reduced thymyc T-cell development and T-cell functions in the periphery. The origin of IL-7 in the circulation is not clear and stromal cells in the bone marrow, liver, gut and lymph nodes are potential production sources. The only cytokines known to regulate the expression of IL-7 in different tissues are IFN-γ (bone marrow), transforming growth factor beta (TGF-β) (skin) and both IL-1 and tumour necrosis factor alpha (TNF-α) (synovium). We therefore investigated the relationship between levels of circulating IL-7, a Th1 (IFN-γ) and a Th2 (TGF-β) cytokine, a proinflammatory cytokine (TNF-α) and two transcription factors essential for T-cell polarisation (T-bet and GATA3).
Patients 'in remission' were defined as having controlled disease, with no change of activity for at least 6 months, C-reactive protein below 15, no swollen or tender joints and on stable treatment (with or without therapy). A cohort of these patients was selected on the basis of their high and low levels of circulating IL-7. RA patients with active, early, disease-modifying anti-rheumatic drug (DMARD) naive disease were also recruited. Circulating levels of cytokines were measured by ELISA and the expression of T-bet and GATA3 by real-time PCR on mRNA extracted from peripheral blood mononuclear cells.
We selected 10 patients with either low or high levels of circulating IL-7. Levels of IFN-γ, TGF-β and TNF-α were measured. High levels of IL-7 were significantly associated with higher levels of IFN-γ (P = 0.04) and a tendency for lower levels of TGF-β but no difference was found for TNF-α. Furthermore, there was a direct correlation between levels of IL-7 and IFN-γ (R = 0.650, P = 0.005). It is established that a high ratio of expression between T-bet and GATA3 defined a tendency towards Th1 polarisation. T-bet levels of expression were significantly higher in patients with high IL-7 (P < 0.0001) and we found a positive correlation between the two (R = 0.600, P = 0.011). Similar results and correlation were found using the ratio of T-bet to GATA3 expression (P < 0.0001 and R = 0.700, P = 0.002). These results were confirmed in a cohort of 10 patients with active, early, DMARD naïve disease.
These results confirm that Th1 polarisation is impaired in RA. In addition, they suggest that either the Th1 cytokines regulate the levels of circulating IL-7 or that the transcription factors regulating Th1 polarisation also regulate the expression of IL-7. Further studies on the mode of regulation for IL-7 expression in the circulation are necessary to understand how this cytokine may participate to the pathogenesis of RA.