Warren Leonard (Bethesda, MD, USA) reviewed the evidence that IL-21 is critical to the development of certain autoimmune diseases, including type I diabetes and SLE, but may also have therapeutic utility for cancer treatment [33
]. IL-21 induces the expression of the Prdm1
gene by B cells and T cells, which encodes B-lymphocyte-induced maturation protein 1, a critical regulator of plasma cell differentiation. Most IL-21-regulated genes, including Prdm1
, are associated with combined STAT3- interferon regulatory factor 4 (IRF4) promoter sites, and IL-21-induced STAT3 binding is dramatically reduced in the absence of IRF4 [34
]. This suggests an important role for IRF4 alongside STAT3 in the regulation of TFH
differentiation, which was confirmed. These findings furthermore suggest that other cytokines and biological processes that depend on STAT3 may also utilise IRF4.
IL-22 is a member of the IL-10 family that promotes innate immunity, with overexpression associated with dermatitis and psoriasis. Carlo Chizzolini (Geneva, Switzerland) presented data showing that the production of IL-22 by human Th cells can occur either alongside or independently of IL- 17 and/or IFNγ. The emergence of IL-17-producing and IL-22-producing T cells is differentially regulated, with ligands of the aryl hydrocarbon receptor favouring IL-22 expression and with prostaglandin E2
acting synergistically with IL-23 to favour IL-17 expression [35
]. The results suggest that signalling through the aryl hydrocarbon receptor may be important in shifting the polarisation of T cells from an IL-17-producing phenotype to an IL-22-producing phenotype, with possible clinical consequences in terms of impaired immune defences and skin immunopathology (Figure ) [36
Figure 3 Effects of aryl hydrocarbon receptor ligands on human T-cell polarisation. Proposed model of the effects of aryl hydrocarbon receptor (AHR) ligands on human T-cell polarisation and their hypothetical clinical consequences. TCDD, group of dioxins; 2,3,7,8-tetrachlordibenzodioxin (more ...)
The potential for B-cell-based therapy in autoimmune disorders was considered by Simon Fillatreau (Berlin, Germany), who asked whether it might be possible to design an ideal therapeutic B cell combining the weak immunogenicity of resting B cells with the effective suppressive functions of activated B cells. Fillatreau reviewed studies showing that quiescent B cells can be reprogrammed to present antigen and secrete IL-10, and that transfer of these reprogrammed B cells protects against experimental autoimmune encephalomyelitis in mice by suppressing adaptive immunity and preventing immune-mediated tissue degradation.
Ina Kötter (Tübingen, Germany) summarised the results of studies investigating IFNα as a treatment for Behçet's disease, which is an inflammatory disorder associated with wide-ranging symptoms including mouth and genital ulcers as well as eye inflammation. A meta-analysis of trials conducted in 2004 indicated that IFNα2a
is an effective alternative for the treatment of Behçet's disease, particularly with regards to mucocutaneous lesions [38
], and subsequent studies have demonstrated consistent benefits [39
]. In a recent study, all except one of 53 patients (98%) with severe uveitis caused by Behçet's disease responded to IFNα2a
treatment, with treatment discontinued in remission for 89% of the patients. Fifty per cent of patients were still in remission nearly 4 years after cessation of a first course of IFNα2a
was shown to normalise pathologically elevated numbers of γδT cells, as well as decreased intracellular levels of IL-2. Serum IFNα levels were already increased in the patients before treatment, however, as were B-cell numbers, and both increased further under therapy. The mechanism of action of IFNα in Behçet's disease hence remains to be clarified, as some of its effects at first sight appear to be more immunostimulatory than immunosuppressive.