The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin-induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.

No abstract

Background Pemphigus encompasses a group of life‐threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first‐line treatment for moderate and severe pemphigus vulgaris in Europe and the United States. Objectives The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. Results The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.

Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12–dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1α in response to lipopolysaccharide/interferon γ or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1α mRNA accumulation in lymph nodes of L. major–infected BALB/c mice was ∼3-fold lower than that in C57BL/6 mice. Local injections of IL-1α during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major–infected BALB/c mice, IL-1α administration resulted in increased Th1- and strikingly decreased Th2-cytokine production. IL-1α and IL-12 treatments were similarly effective, and IL-1α efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1α acts in conjunction with IL-12 to influence Th-development in cutaneous leishmaniasis and prevents disease progression in susceptible BALB/c mice, perhaps by enhancing DC-induced Th1-education. Differential production of IL-1 by C57BL/6 and BALB/c mice may provide a partial explanation for the disparate outcomes of infection in these mouse strains.

IntroductionThe steroid hormone 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ) is known for its important role in regulating calcium homeostasis and bone mineralization. 1 1␣,25(OH) 2 D 3 acts through a nuclear receptor, the vitamin D receptor (Vdr), which is a member of the steroid and thyroid hormone receptor superfamily. More recently, evidence has accumulated that the hormone can have important functions in the immune system. Expression of Vdr was found in different immune effector cells of the myeloid and lymphoid lineage under resting and activating conditions. 2,3 These findings contributed to the hypothesis that locally produced 1␣,25(OH) 2 D 3 may perform regulatory functions on those cells. Indeed, over the past few years it has been demonstrated that 1␣,25(OH) 2 D 3 can act as an important immunosuppressive modulator. 1␣,25(OH) 2 D 3 has been shown to suppress T-cell proliferation 4 and to decrease the production of the T helper type 1 (Th1) cytokines interleukin 2, interferon ␥ (IFN-␥), and tumor necrosis factor ␣ (TNF-␣), leading to the inhibition of Th1 cell development. 5 Besides its direct effects on T cells, 1␣,25(OH) 2 D 3 and its analogs are potent inhibitors of dendritic cell (DC) differentiation and maturation and can impair the capacity of DCs to induce alloreactive T-cell activation. 6,7 In line with this, Vdr-deficient mice have been shown to have an increased frequency of mature DCs in lymph nodes. 8 Additional support for the immunomodulatory role of 1␣,25(OH) 2 D 3 in vivo came from studies of autoimmune diseases in several different animal models. It has been demonstrated that 1␣,25(OH) 2 D 3 can prevent or suppress experimental autoimmune encephalomyelitis, 9 rheumatoid arthritis, 10 systemic lupus erythematosus, 11 type 1 diabetes, 12 and inflammatory bowel disease, 13,14 further supporting its potent suppressive effects on the immune system.In contrast to its well-characterized effects on adaptive immune responses, much less is known about the effects of 1␣,25(OH) 2 D 3 on effectors of innate immunity, especially on macrophages. It has been shown that 1␣,25(OH) 2 D 3 can induce the differentiation of myeloid progenitors into macrophages. 15,16 However, the effects of 1␣,25(OH) 2 D 3 on mature and activated macrophages that are involved in inflammatory reactions have not been characterized yet. Such possible effects might be of especial importance since it was demonstrated that macrophages can release biologically active 1␣,25(OH) 2 D 3 on activation with IFN-␥. 17,18 The production of 1␣,25(OH) 2 D 3 by activated macrophages is regulated by the IFN-␥-mediated induction of 1␣-hydroxylase expression, the enzyme controlling the last step of 1␣,25(OH) 2 D 3 synthesis. 17,18 In Supported by the National German Genome Network (NGFN; 01GR0439), EU FP5 project EUMORPHIIA (QLG2- CT-2002-00930), and Volkswagenstiftung.L.H. performed research and wrote the paper; J.B., J.E., and S.S. performed research; T.F. contributed reagents and analytical tools; R.G. and M.P.K analyzed data; R.B. initiate...