Keratinocytes contribute to cutaneous immune responses through the expression of cytokines. We investigated whether human keratinocytes can express IL-23, a newly defined IFN-γ-inducing cytokine composed of a unique p19 subunit and a p40 subunit shared with IL-12. Cultured keratinocytes from normal and lesional psoriatic skin were found to express constitutively mRNA for both subunits of IL-23. Low but significant levels of the heterodimeric IL-23 protein could be detected in cell lysates and supernatants from stimulated keratinocytes by immunoblotting and ELISA. Functional analysis showed that these low levels of keratinocyte-derived IL-23 were sufficient to enhance the IFN-γ production by memory T cells. Immunostaining of skin sections confirmed expression of both subunits of IL-23 by keratinocytes in situ and also revealed expression of this cytokine in the dermal compartment. IL-23 expression was significantly higher in psoriatic lesional skin, compared with normal and psoriatic nonlesional skin. The immunostained preparations of cultured cells and IL-23 levels in culture supernatants did not show any difference between normal and psoriatic keratinocytes indicating no intrinsic aberration of IL-23 expression in keratinocytes from psoriatic skin. Double staining of cytospin preparations demonstrated that IL-23 p19 is also expressed by epidermal Langerhans cells, dermal dendritic cells, and macrophages. Psoriasis is a chronic inflammatory skin disease mediated by IFN-γ-expressing type 1 memory T cells. As IL-23 is important to activate memory T cells to produce IFN-γ, its augmented expression of IL-23 by keratinocytes and cutaneous APC may contribute to the perpetuation of the inflammation process in this disease.

BackgroundAlthough recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ.Methodology/Principal FindingsBy spectral imaging analysis of double-stained skin sections we demonstrated that IL-17 was mainly expressed by mast cells and neutrophils and IL-22 by macrophages and dendritic cells. Only an occasional IL-17pos, but no IL-22pos T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin. However, examination of in vitro-activated T cells by flow cytometry revealed that substantial percentages of skin-derived CD4 and CD8 T cells were able to produce IL-17A alone or together with IL-22 (i.e. Th17 and Tc17, respectively) or to produce IL-22 in absence of IL-17A and IFN-γ (i.e. Th22 and Tc22, respectively). Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin. Interestingly, we found IL-22 single-producers in many skin-derived IL-17Apos CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17Apos T cells as well.Conclusions/SignificanceThe increased presence of Tc17 and Tc22 cells in lesional psoriatic skin suggests that these types of CD8 T cells play a significant role in the pathogenesis of psoriasis. As part of the skin-derived IL-17Apos CD4 and CD8 T clones developed into IL-22 single-producers, this demonstrates plasticity in their cytokine production profile and suggests a developmental relationship between Th17 and Th22 cells and between Tc17 and Tc22 cells.

The current understanding of the function of natural killer (NK) T cells in innate immunity and their potential to control acquired specific immunity, as well as the remarkable efficacy of antitumour necrosis factor-alpha biological treatments in psoriasis, forces us to refine the current T-cell hypothesis of psoriasis pathogenesis, and to give credit to the role of innate immunity. Psoriasis might be envisioned to be a genetically determined triggered state of otherwise dormant innate immunity. This aggravated state of innate immunity is represented by the activity of NK T cells, dendritic cells, neutrophils and keratinocytes, leading to the recruitment and activation of preferentially type 1 T cells, possibly in an antigen-independent way. Keratinocytes in psoriasis then are sensitive to the effects of T-cell activation and cytokine production, interferon (IFN)-gamma, by responding with psoriasiform hyperplasia. The chronic inflammation of psoriatic lesions suggests that this might be due to a deficiency in downregulation processes (e.g. a defect in the regulatory T-cell repertoire) and/or the persistence of an unknown trigger resulting in an exaggerated innate immune response.

UVB irradiation can cause considerable changes in the composition of cells in the skin and in cutaneous cytokine levels. We found that a single exposure of normal human skin to UVB induced an infiltration of numerous IL-4+ cells. This recruitment was detectable in the papillary dermis already 5 h after irradiation, reaching a peak at 24 h and declining gradually thereafter. The IL-4+ cells appeared in the epidermis at 24 h postradiation and reached a plateau at days 2 and 3. The number of IL-4+ cells was markedly decreased in both dermis and epidermis at day 4, and at later time points, the IL-4 expression was absent. The IL-4+ cells did not coexpress CD3 (T cells), tryptase (mast cells), CD56 (NK cells), and CD36 (macrophages). They did coexpress CD15 and CD11b, showed a clear association with elastase, and had a multilobed nucleus, indicating that UVB-induced infiltrating IL-4+ cells are neutrophils. Blister fluid from irradiated skin, but not from control skin, contained IL-4 protein as well as increased levels of IL-6, IL-8, and TNF-α. In contrast to control cultures derived from nonirradiated skin, a predominant type 2 T cell response was detected in T cells present in primary dermal cell cultures derived from UVB-exposed skin. This type 2 shift was abolished when CD15+ cells (i.e., neutrophils) were depleted from the dermal cell suspension before culturing, suggesting that neutrophils favor type 2 T cell responses in UVB-exposed skin.

Infliximab (Remicade; Schering-Plough, Kenilworth, NJ, U.S.A.) is a chimeric monoclonal antibody that acts as a tumour necrosis factor-alpha inhibitor. Infliximab is registered for the treatment of rheumatoid arthritis, psoriatic arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis and plaque-type psoriasis. Like other foreign protein-derived agents, infliximab may lead to infusion reactions during and after infusion. Infusion reactions occur in 3-22% of patients with psoriasis treated with infliximab. Most of these reactions are mild or moderate and only few are severe. Nevertheless, they may lead to discontinuation of treatment. As infliximab for psoriasis is prescribed as a last resort and is in most cases very effective, discontinuation of treatment is undesirable. With proper care and prevention of the infusion reactions the need to discontinue treatment with infliximab can be diminished. The objective of this article is to present a guideline for the management of infliximab-related infusion reactions, based on the best available evidence. This guideline can be used in patients with psoriasis as well as in dermatology patients receiving infliximab for off-label indications such as hidradenitis suppurativa or pyoderma gangrenosum.

Type-1 cytokine-producing T cells are important in the pathogenesis of psoriasis vulgaris, for which efficient therapy is provided by means of narrow-band ultraviolet-B (NB-UVB). The expression of the type-1 cytokine interferon-gamma (IFN-gamma) is regulated by interleukin-12 (IL-12), IL-15, IL-18 and IL-23; however, not much is known about the effect of this therapy on the levels of these cytokines in lesional psoriatic skin in situ. In this study, we investigated the effects of NB-UVB therapy on the expression of IFN-gamma-inducing cytokines. Ten patients with chronic plaque-type psoriasis selected to be treated with NB-UVB therapy were recruited for these experiments and the expression of cytokines IL-12, IL-15, IL-18, IL-23 and IFN-gamma in lesional psoriatic skin before, during and after therapy was determined with the help of immunohistochemistry. Double staining was performed in order to determine the cell types expressing these cytokines. The decrease in the psoriasis area and severity index was accompanied by a significant decrease in the expression of IFN-gamma, and concomitantly, significant reduction of IFN-gamma inducers -- IL-12, IL-18 and IL-23. Thus, we concluded that the decrease of IFN-gamma expression in psoriasis lesions after NB-UVB therapy could be a result of diminished expression of IL-12, IL-18 and IL-23 in lesional skin. Therapies targeting these three cytokines should, therefore, be considered in the treatment of psoriasis.

Exposure to an erythemal dose of ultraviolet B (UVB) is known to induce interleukin (IL-10) expression in human skin. It is generally believed that this IL-10 is predominantly expressed by CD11b+ HLA-DR+ macrophages that infiltrate the UVB-exposed skin. This cytokine is presumed to contribute to the immunosuppressive effects of UVB by inhibiting cell-mediated immune responses. We recently demonstrated that neutrophils, which also invade UVB-irradiated skin, express CD11b and HLA-DR as well. In addition, we showed that the presence of these neutrophils affects T-cell responses in primary T-cell cultures derived from UVB-exposed skin. Since neutrophils invade UVB-exposed skin and, like macrophages, express CD11b and HLA-DR, we sought to determine whether neutrophils represent another source of IL-10. Skin biopsies were obtained from four healthy volunteers before and 2 days after exposure to four minimal erythema doses of UVB. A series of immunohistochemical double-staining procedures using the following markers was performed: IL-10, CD11b, HLA-DR, CD36, neutrophil elastase, and CD66b. As expected IL-10 could be detected in CD11b+ HLA-DR+ CD36+ macrophages in the epidermis and dermis of UVB-exposed skin. Surprisingly, the majority of the abundant IL-10 expression was found in CD11b+ HLA-DR+ elastase+ CD66b+ neutrophils. Cytospin preparations from dermal cell suspensions confirmed the IL-10 expression by neutrophils displaying characteristic multilobular nuclei. Thus, neutrophils in UVB-exposed skin express IL-10 and should be recognized as active coplayers in the creation of the UVB-induced immunosuppressive microenvironment.

The type 1 T cell-derived cytokine interferon gamma (IFN-gamma) is overexpressed in psoriatic lesional skin. Recently, we have shown that a single high erythemal dose of broad-band ultraviolet B (UVB) irradiation reduces type 1 and favors type 2, i.e. interleukin-4 (IL-4), cytokine expression in normal and psoriatic skin. In this study, we wanted to see whether conventional narrow-band UVB (NB-UVB) therapy (i.e. repeated exposure to nonerythemal doses) also affects type 1/type 2 cytokine expression of T cells present in chronic plaque type psoriatic lesions. Staining of cryostat sections showed decreased expression of both IFN-gamma and IL-4 in situ after NB-UVB therapy. CD4(+) dermal T cell lines, derived from psoriatic lesional skin, displayed significantly decreased intracellular IFN-gamma expression during and after NB-UVB therapy as compared to pretreatment values. Intracellular IL-4 expression was increased in most patients after therapy. Analysis of the supernatants of these stimulated dermal T cells revealed that IFN-gamma production decreased significantly following NB-UVB therapy, whereas IL-4 expression increased in the T cell supernatants from most patients, confirming the intracellular determinations. In addition, IL-10 and transforming growth factor-beta levels in the supernatants appeared to be increased in the majority of patients following UVB therapy. Apart from the well-known killing effect of UVB on T cells, our results show that the improvement in psoriatic skin following NB-UVB therapy is also due to a reduced capacity of the surviving dermal T cells to express the proinflammatory cytokine IFN-gamma.