Amongst the heterogeneity of human immune responses T helper (Th) lymphocyte subsets have been shown to have an important role. (1) Of these different subsets, Th1 cells mediate cellular immunity, including cytotoxicity and delayed-type hypersensitivity responses through the specific production of interferon [gamma] (IFN[gamma]) and interleukin (IL) 2. Th2 cells, characterised by IL4, IL5, and IL13 production, favour humoral immunity and down regulate Th1 mediated cellular immunity. Th2 responses are associated with IL4/IL13 mediated IgE production and IL5 mediated eosinophilia. Th1 activity in its turn inhibits these responses and results in effective immune responses against several infectious agents such as bacteria and viruses. Also, in several autoimmune diseases Th1 cells contribute to the induction and persistence of inflammation and inflammation-induced tissue damage.
Numerous studies have shown that Th1-induced immunity is inhibited by suppressive Th cells other than [IL4.sup.+] Th2 cells. These suppressive ceils are also distinguished by their particular cytokine secretion and/or function: transforming growth factor 1 [beta] [(TGF[beta]).sup.+] Th3 cells, [IL10.sup.+] T regulatory 1 (Tr1) cells, and [CD4.sup.+][CD25.sup.+] anergic/suppressive cells. (2 3) Although all these subsets may contribute to suppression of Th1 activity, the balance between Th1 and Th2 cells has been shown to strongly influence many inflammatory responses. Owing to the mutually antagonising abilities of Th1 and Th2 cells in many experimental animal and human in vitro studies, the Th1/ Th2 balance in rheumatoid arthritis (RA) has been extensively studied.
"Balance between Th1 and Th2 cells strongly influences inflammatory responses"
Th1 predominance in RA and the impact of atopy-induced Th2 responses
In RA synovial tissue, synovial fluid, and serum, analysis of IFN[gamma] and IL4 production to indicate Th1 and Th2 activity, showed that Th1 activity was clearly predominant and Th2 activity was absent compared with control subjects (table 1). (4-6) The Th1/Th2 imbalance in RA joints is associated with high numbers of activated macrophages, leading to an aggressive form of arthritis with rapidly occurring joint destruction. (7) Based on the pivotal role of the Th1 predominance in RA it has been suggested that patients with RA will benefit from Th2 activity. Until now, treatments aimed at enhancing or mimicking Th2 activity--for example, through IL4 or IL10, have not provided evidence for this hypothesis. (8) However, the naturally occurring mutual antagonism of atopy and RA supports this hypothesis and indicates the role of Th1/Th2 balance in RA.
"RA is associated with a 40-50% reduction in atopic disorders"
The prevalence of RA, in which Th1 predominates, was found to have a favourable impact on several atopic disorders known to be associated with a clear Th2 predominance (table 2). In five European studies RA was associated on average with a 40-50% reduction in the prevalence of atopic disorders. (9-13) In one study which evaluated a limited number of patients with RA (n=40) atopy assessment by a health assessment questionnaire did not show a decreased prevalence. (10) However, when allergen skin prick tests were performed to confirm atopy, a decrease of 45% in patients with positive tests was found among patients with RA compared with healthy controls. (10) Similarly, in another study where hay fever was confirmed by this test, a 50% reduction in patients with RA compared with non-RA controls was seen. (12) Furthermore, this was associated with a reduction of serum IgE levels and eosinophilia, further, indicating suppressed Th2 responses.
In addition to the inhibition of Th2 mediated immunity by Th1 cells, in hay fever/patients with RA reduced Th1 activity (IFN[gamma] production) was seen compared with patients with RA with no hay fever …