HYPOXIA AND MODULATION OF IMMUNE RESPONSES

The pathogenesis of rheumatoid arthritis (RA) is hypothesised to involve inappropriate triggering of the MHC controlled immune surveillance, resulting in altered T and B cell profiles. Recently, the cytokine profile of T helper lymphocytes has been associated with the disease. The cytokine repertoire of inflamed synovia is categorised as that of a Th1 response. The characteristic Th1 response displays increased expression of select cytokines such as TGFβ, IFNγ, TNFα, IL1, and IL2. In contrast, Th2 responses exhibit increased IL4, IL5, IL10, and IL13 (predominantly anti-inflammatory cytokines). While the levels of TNFα and IL1 are high within RA synovium,1the level of IL2 is paradoxically low.2 This is atypical of a Th1 response, but may be accounted for by the overriding hypoxic condition of the RA synovium.

Hypoxia transcriptionally upregulates TNF and IL1 but downregulates IL2.3 4 The predominance of a given cytokine in the microenvironment of the responding Th cell influences Th1/Th2 differentiation.5 This phenomenon is believed to be regulated by phosphorylation of the relevant signal transducers and activators of transcription (STATs), after cytokine binding to their associated receptors. Based on the knowledge that hypoxia can modulate both cytokine expression and phosphorylation events, we propose that within inflamed synovial tissues, hypoxia underlies the functional polarisation of the Th1/Th2 lymphocytes and the apparent Th2 to Th1 switch in RA. The T cell cytokine profile of inflamed synovia may account for the development of an “unorganised” or abnormal inflammatory response. However, it does not convincingly explain the persistence of the existing inflammatory reaction, or more …