Overproduction of immunoglobulin E (IgE) and T helper cell type 2 (TH2) cytokines, including interleukin 4 (IL-4), IL-5 and IL-13, can result in allergic disorders. Although it is known that IL-4 is critical to the polarization of naïve CD4+ T cells to a TH2 phenotype, both in vitro and in many in vivo systems, other factors that regulate in vivo IL-4 production and TH2 commitment are poorly understood. IL-18, an IL-1-like cytokine that requires cleavage with caspase-1 to become active, was found to increase IgE production in a CD4+ T cells-, IL-4- and STAT6-dependent fashion. IL-18 and T cell receptor-mediated stimulation could induce naïve CD4+ T cells to develop into IL-4-producing cells in vitro. Thus, caspase-1 and IL-18 may be critical in regulation of IgE production in vivo, providing a potential therapeutic target for allergic disorders.

CD4+CD25+ T regulatory cells (Treg) are thought to be important in the peripheral tolerance. Recent evidence suggests that human peripheral blood CD4+CD25+ T cells are heterogeneous and contain both CD4+CD25high T cells with potent regulatory activity and many more CD4+CD25low/med nonregulatory T cells. In this study, we found that virtually all peripheral blood CD4+CD25highFoxp3+ Treg expressed high levels of the chemokine receptor CCR4. In addition, 80% of Treg expressed cutaneous lymphocyte Ag (CLA) and 73% expressed CCR6. These molecules were functional, as CLA+ Treg showed CD62E ligand activity and demonstrable chemotactic responses to the CCR4 ligands CCL22 and CCL17 and to the CCR6 ligand CCL20. The phenotype and chemotactic response of these Treg were significantly different from those of CD4+CD25med nonregulatory T cells. We further demonstrated that blood CLA+ Treg inhibited CD4+CD25− T cell proliferation induced by anti-CD3. Based on homing receptor profile, CLA+ Treg should enter normal skin. We next isolated CD4+CD25high T cells directly from normal human skin; these cells suppressed proliferation of skin CD4+CD25− T cells. Therefore, the majority of true circulating Treg express functional skin-homing receptors, and human Treg may regulate local immune responses in normal human skin.

Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T cells. A major feature of CTCL is profound immunosuppression, such that patients with advanced mycosis fungoides or Sé zary syndrome have been compared with patients with advanced HIV disease and are susceptible to opportunistic infection. The etiology of this immunosuppression is unclear. We analyzed peripheral blood T cells of patients with CTCL with stage I to IV disease, using a sensitive betavariable complementarity-determining region 3 spectratyping approach. Our data revealed a profound disruption of the complexity of the T-cell repertoire, which was universally observed in patients with advanced disease (stages III and IV), and present in up to 50% of patients with early-stage disease (stages I and II). In most patients, multiple monoclonal and oligoclonal complementarity-determining region 3 (CDR3) spectratype patterns in many different beta-variable families were seen. Equally striking was a reduction of normal T cells (as judged by absolute CD4 counts) across multiple beta-variable families. In general, CTCL spectratypes were reminiscent of advanced HIV spectratypes published elsewhere. Taken together, these data are most consistent with a global assault on the T-cell repertoire in patients with CTCL, a process that can be observed even in early-stage disease. (Blood. 2003;102:4059-4066)

To study the pathophysiological roles of overexpressed caspase-1 (CASP1), originally designated as IL-1β-converting enzyme, we generated transgenic mice in which human CASP1 is overexpressed in their keratinocytes. The transgenic mice spontaneously developed recalcitrant dermatitis and skin ulcers, characterized by the presence of massive keratinocyte apoptosis. The skin of the mice contained the active form of human CASP1 and expressed mRNA for caspase-activated DNase, an effector endonuclease responsible for DNA fragmentation. Their skin and sera showed elevated levels of mature IL-18 and IL-1β, but not of IFN-γ. The plasma from these animals induced IFN-γ production by IL-18-responsive NK cells. Administration of heat-killed Propionibacterium acnes, a potent in vivo type 1 cell inducer, caused IFN-γ-mediated lethal liver injury in the transgenic mice, which was completely inhibited by treatment with neutralizing anti-IL-18 Ab. These results indicated that in vivo overexpression of CASP1 caused spontaneous apoptotic tissue injury and rendered mice highly susceptible to exogenous type 1 cell-inducing condition in collaboration with endogenously accumulated proinflammatory cytokines.

Atopic dermatitis (AD) is the most common and relapsing allergic disease of the skin. AD is characterized by a predominant expression of Th2-type cytokines associated with increased cellular infiltration in the skin, elevated circulating levels of IgE and eosinophilia. These findings are positively correlated with interleukin (IL)-4 and IL-13 expression in CD4+ T cells. In AD patients, Th2 cells, eosinophils, mast cells and dendritic cells are markedly increased in the skin lesions. However, Th1 cells are also involved in the development of AD lesions. In fact, Th1 cytokine mRNA expressions including γ-interferon and IL-12 are elevated in the chronic lesions as well as elevated Th2 cytokines in the acute AD lesions. The discovery of Th17 lineage and regulatory T (T(reg)) cells shifted the simple Th1/Th2 balance concept into a 4-way balance system. Th17/22 cells, Foxp3+ T(reg) and IL-10-producing T cells (Tr1) are involved in the mechanism of a local and systemic immunological milieu. In addition, super Th1 cells arranged from Th1 cells in high IL-18 milieu are also involved in the development of mouse AD lesions. Correction of Th2 cytokine predominance by Th1 inducers shows effectiveness in experimental models. However, fine-tuning of the delicate 4-way balance among Th1, Th2, Th17/22 and T(reg) cells is required for the control of AD. Efficacy of some biological agents in AD has been reported. However, further investigations are required to make possible the therapeutic application of biologicals, antigen-specific immunotherapy, non-antigen-specific immunotherapy, antagonists and biological response modifiers in the clinic. These novel approaches may constitute a potential curative therapy for AD.

Increased release of IL-18 in the skin causes atopic dermatitis (AD)-like skin lesions, suggesting a role of IL-18 in the pathogenesis of AD. Caspase-1 is a well-known activator of IL-18, but caspase-1 knockout mice still have biologically active IL-18. Normal human keratinocyte constitutively produces pro-IL-18, but it is unable to activate it, suggesting the existence of an alternative pathway for IL-18 in the skin. Dermal accumulation of mast cells is commonly observed in AD patients and in experimental mouse models of AD. Connective tissue mast cells contain high amounts of chymase and tryptase in their cytoplasmic granules. In the present study, we demonstrated that activation of IL-18 is a novel function of human mast cell chymase. Human mast cell chymase rapidly cleaves recombinant pro-IL-18 at 56-phenylalanine and produces a biologically active IL-18 fragment that is smaller than any other reported IL-18-derived species. The human mast cell chymase and the novel IL-18-derived active peptide may be novel therapeutic targets in AD- and IL-18-associated diseases

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The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.