This complexity raises the important question of whether it may be possible to target the mechanisms by which TNF contributes to disease selectively without suppressing its physiological actions. For example, transgenic mice engineered with an uncleavable TNF protein are protected against bacterial infection, but transmembrane TNF alone is not sufficient to support disease development in the TNF-dependent tristetraprolin knockout model of inflammatory arthritis [5]. Selective blockade of soluble TNF may therefore be a safer alternative to total TNF blockade for the treatment of chronic inflammation and autoimmunity.

Georg Kollias reviewed studies indicating that pathogenic TNF/TNF receptor 1 (TNFR1) signalling in inflammatory diseases of both the joints and intestine may be mediated specifically by mesenchymal cells such as synovial fibroblasts and intestinal myofibroblasts. Selective mesenchymal expression of the TNFR1 allele has been shown to be sufficient for development of a full arthritic and intestinal phenotype in a murine model of spondyloarthritic disease [6]. This may account for the commonly observed synovial-gut axis in human disease and identifies selective targeting of the TNFR1 pathway in mesenchymal cells as a promising therapeutic strategy.

Vijay Kuchroo (Harvard, Boston, MA, USA) reviewed recent advances in the understanding of the role of Th17 cells in the induction and regulation of tissue inflammation. Th17 cells have a protective role against certain extracellular pathogens but, when dysregulated, can induce severe inflammation and autoimmunity. They are effective in providing B-cell help: IL-17 specifically induces antibody class switching to IgG_2b and IgG₃. Differentiation of Th 17 cells in the mouse is induced by transforming growth factor beta together with either IL-6 or IL-21, followed by self-amplification involving IL-21 and then stabilisation by IL-23. Of note, transforming growth factor beta in the absence of IL-6 and IL-21 promotes the generation of T-regulatory (T_reg) cells, resulting in a reciprocal relationship between Th17 and T_reg cells that may present novel targets for treatment of inflammatory disorders [9].

IL-33 and IL-35 are novel additions to the expanding orchestra of cytokines, and Eddy Y Liew (Glasgow, UK) considered their functions in health and autoimmunity. In mouse models, IL-33 confers resistance to intestinal nematode infection and has cardioprotective activity. IL-33 has been shown, however, to exacerbate asthma, collagen-induced arthritis and Theiler's virus-induced encephalitis, and to induce allergic anaphylaxis, as well as being associated with Alzheimer's disease. In a recent study, IL-33 was shown to attenuate sepsis by preventing the downregulation of CXCR2 expression and chemotaxis, so enhancing neutrophil influx into the infection site [10]. IL-35 is an immunosuppressive cytokine that expands T_reg cells, suppresses Th17 cell development and enhances Th1 differentiation. Protection against collagen-induced arthritis in mice suggests a possible role for IL-35 in the treatment of inflammatory diseases [11].

IL-6 signals are transmitted via glycoprotein 130, classically as a result of IL-6 binding to the membrane-bound IL-6R. However, IL-6 can also activate glycoprotein 130 through binding to a soluble form of the IL-6R, a phenomenon termed IL-6 trans-signalling. Stefan Rose-John (Kiel, Germany) presented evidence that ADAM17, the disintegrin metalloproteinase responsible for membrane shedding of the IL-6R, may act as a molecular switch between the proinflammatory and antiinflammatory activities of IL-6 by affecting the balance of signalling between the membrane-bound and soluble forms of the IL-6R. Given that IL-6 trans-signalling appears to be the predominant mode of IL-6 signalling in inflammatory arthritis [16], Professor Rose-John concluded that selective inhibition of IL-6 trans-signalling (for example, with recombinant variants of soluble glycoprotein 130) may have advantages over global IL-6 blockade.

Jens Brüning (Cologne, Germany) then considered the role of IL-6 in metabolism and obesity-associated insulin resistance. In the acute physiological setting, the actions of IL-6 are antidiabetic, promoting glucose metabolism and muscle glucose uptake in a manner similar to insulin [17]. IL-6 expression in hepatocytes is promoted by neuronal insulin action, and hepatic IL-6 signalling may be important for glucose homeostasis. Knockout mice lacking hepatocyte IL-6Rs exhibit skeletal muscle insulin resistance but hepatic glucose production is unaltered. TNF neutralisation or Kupffer cell ablation can restore glucose sensitivity in the knockout mice, suggesting that IL-6 signalling in hepatocytes may promote glucose disposal by skeletal muscle by limiting Kupffer cell activation and the development of systemic inflammation.

Kurt Redlich (Vienna, Austria) discussed chemokine control of bone metabolism based on studies of C-C chemokine receptor 2 knockout mice. CCR2^-/- mice have increased bone mass and strength because of a reduction in the number, size and function of osteoclasts, and are protected from osteoporosis [20]. The results indicate a new pathway in the regulation of bone homeostasis in which binding of chemokines to C-C chemokine receptor 2 induces signalling via NFκB and extracellular signal-regulated kinase 1/2, leading to increased receptor activator of NFκB (RANK) expression by osteoclast progenitor cells, making them more susceptible to RANK ligand-induced osteoclastogenesis. Cytokine regulation of osteoclastogenesis was considered further by Jochen Zwerina (Erlangen, Germany), with specific reference to TNF, IL-1, IL- 17 and IL-6. IL-1 is an essential mediator of TNF-induced osteoclastogenesis while IL-17A blockade has been shown to reduce the production of TNF-induced synovial osteoclasts, although this did not result in improvements in disease severity in the hTNFtg murine model of RA. Recently, IL-6 blockade was shown to potently inhibit osteoclast formation and bone erosion in hTNFtg mice without suppressing joint inflammation, suggesting that IL-6 blockade may have beneficial effects on bone structure in the treatment for arthritis [21].

SLE is associated with the production of short-lived plasmablasts with a definite IFNα signature. Recent studies reviewed by Falk Hiepe (Berlin, Germany) have identified a specific plasmablast subset that expresses HLA-DR very strongly, and have shown that this HLA-DR^high cell fraction (but not the HLA- DR^low fraction) correlates closely with SLE disease activity and anti-DNA autoantibody titre [25]. This suggests that plasmablasts may make a distinct contribution to the pathogenesis of SLE, and may also be susceptible to immunosuppressive therapy where more differentiated, long-living plasma cells are resistant.

Martin Schiller (Heidelberg, Germany) considered the evidence that accumulation of apoptotic cell-derived membrane microparticles as a result of increased apoptosis or defective phagocytosis may contribute to the autoimmune response in SLE. These microparticles represent a source of nuclear autoantigens and have been shown to induce the maturation of dendritic cells. Further, they stimulated plasmacytoid dendritic cells to produce IFNα.

Gerd-Rüdiger Burmester (Berlin, Germany) considered the clinical value of blocking signalling via the granulocyte/macrophage colony-stimulating factor (GM-CSF) pathway. GM-CSF is elevated in synovial fluid from patients with RA, and targeting the GM-CSF pathway in animal models of RA reduced disease activity. Recently, the results from the first study in humans of a monoclonal antibody (CAM-3001) targeting the GM-CSF pathway were reported [29]. CAM-3001 had an acceptable safety profile in the phase I study and presented nonlinear pharmacokinetics, presumably because of an antigen-sink effect, with a half-life of 11 to 21 days. Although the study was not designed to assess efficacy, improvements in disease activity, reductions in C-reactive protein and normalisation of the erythrocyte sedimentation rate were seen with CAM-3001 and suggest potential clinical benefits of GM-CSF blockade in the treatment of RA.

Hendrik Schulze-Koops (Munich, Germany) presented recent data showing increased IL-17 levels and Th17 cell frequencies in the peripheral circulation of patients with very early psoriatic arthritis or RA, but not osteoarthritis. Inflammatory arthritis is associated with increased expression of Th17 cells that are resistant to the inhibitory effects of IL-4 and IFNγ, an observation that correlates with disease activity.

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 ​(Figure3)3) [36,37].

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.