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This paper reviews the pathogenesis of psoriasis, in particular, the immunological cascade in psoriasis. Psoriasis is an immune-mediated skin disease where the T cell plays a pivotal role in the pathogenesis of the disease. The critical steps involved in the pathogenesis include Langerhans cell activation and maturation by antigens in the skin, activation of the T cell by mature Langerhans cells, differentiation and expansion of T cells within the lymph nodes, trafficking of activated T cells from the lymph node to the skin and the subsequent release of cytokines. These cytokines are responsible for epidermal and vascular hyperproliferation and pro-inflammatory effects. Each of these steps provides an opportunity for biological agents designed to block the psoriatic immunological cascade. This paper reviews the immunopathogenesis of psoriasis. Biologic agents in psoriasis, to be published separately, reviews the new biologic therapies that aim to selectively block the immunological steps implicated in the pathogenesis of psoriasis outlined in this paper. [ABSTRACT FROM AUTHOR]

Background: Members of the interleukin (IL)‐36 family, IL‐36α, IL‐36β and IL‐36γ, are potent chemoattractive cytokines for neutrophils and eosinophils. IL‐36 receptor antagonist (IL‐36Ra) inhibits IL‐36α, IL‐36β and IL‐36γ activity. However, the immunohistological expression of IL‐36α, IL‐36β, IL‐36γ and IL‐36Ra has never been addressed in normal follicles, folliculitis or eosinophilic pustular folliculitis (EPF). Methods: We performed immunohistochemical staining for IL‐36α, IL‐36β, IL‐36γ and IL‐36Ra using 10 cases of EPF, nine of non‐specific folliculitis, 10 normal skin samples and 10 samples of normal follicles adjacent to a sebaceous naevus as a control. Two dermatologists, who were blind to the patient records, evaluated all of the slides. Results: The immunoreactive IL‐36α was hardly detected in the follicular epithelium and epidermis in the normal skin, folliculitis or EPF. The expression of IL‐36β, IL‐36γ and IL‐36Ra was augmented in both folliculitis and EPF compared with that in normal follicles. Negative correlations were detected between IL‐36β and IL‐36Ra and between IL‐36γ and IL‐36Ra in normal follicles; however, these were absent in folliculitis. In contrast to normal follicles and folliculitis, a significant positive correlation between IL‐36β/γ and IL‐36Ra was shown in EPF. Conclusions: The overexpression of IL‐36β, IL‐36γ and IL‐36Ra is an integral part of the inflammatory response of folliculitis and EPF. The coordinated expression of IL‐36γ and IL‐36Ra may be related to the pathomechanism of EPF. [ABSTRACT FROM AUTHOR]

Imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine and has a molecular formula of C14H16N4. It was discovered by researchers at 3M Pharmaceuticals (St Paul, MN, USA) and is the newest in a class of drugs known as immune response modifiers. Imiquimod 5% cream has been formulated for the treatment of external genital and perianal warts (condylomata acuminata) in male and female patients. Each gram of 5% cream contains 50mg of imiquimod. In preclinical studies, imiquimod induced the production of cytokines, the principal one for antiviral activity being interferon-α. Imiquimod does not induce direct antiviral activity, nor does it cause direct, non-specific cytolytic destruction. Preclinical studies suggest that its antiviral action results from in vivo cytokine-induced activation of the immune system. A double-blind, placebo-controlled study designed to evaluate this hypothesis has been previously presented. The results of the study showed that wart regression after treatment with imiquimod is strongly correlated with a decrease in virally infected cells and with increases in the expression of a spectrum of cytokines. This supports the hypothesis that stimulation of local cytokines by imiquimod leads to a reduction of human papilomavirus load and wart regression, without evidence of scarring. [ABSTRACT FROM AUTHOR]

Applied topically, imiquimod induces the production of interferon-α plus other cytokines. Because intralesional interferon is effective in the treatment of condylomata acuminata (genital warts), topical imiquimod has also been investigated as a potential therapy for this condition. The dosing regimen found to best balance efficacy, side-effects and practicality is 5% imiquimod cream applied overnight by the patient three times weekly until warts clear, for up to 16 weeks. The largest double-blind trial to examine this protocol involved 311 patients with external anogenital warts who were randomized to use imiquimod 5% cream, imiquimod 1% cream or vehicle cream. Evaluation of all patients given medication at any time showed that 50% of those who received 5% imiquimod experienced clearing of all baseline warts, as compared to 21% of those who used 1% imiquimod and 11% of those treated with vehicle. Overall, 5% imiquimod treatment was significantly more effective than vehicle (P< 0.0001). Excluding patients who discontinued medication for reasons unrelated to therapy (such as moving out of town or poor compliance), 56% of those who received 5% imiquimod experienced complete clearing of baseline warts. Clearing also occurred in 27% of those who received imiquimod 1%. Recurrence of baseline warts occurred in 13% of patients whose warts cleared with 5% imiquimod. When applied overnight at home three times each week, topical imiquimod 5% cream is an effective therapy with acceptable side-effects. The recurrence rate is low and further studies to specifically compare recurrence rates are warranted. [ABSTRACT FROM AUTHOR]

There is substantial evidence from experiments of nature that immune competence plays a major part in determining the outcome of anogenital human papillomavirus (HPV) infection. Cellular rather than humoral immunity would appear to be the key to the control and eradication of HPV-induced warts. It seems likely that the HPV early proteins, which are responsible for viral replication (E1 and E2) and for promoting tissue proliferation (E6 and E7) will be the target antigens recognized by antigen-specific T cells. Natural infection is slow to produce an appropriate therapeutic immune response to these proteins, probably because HPV has adopted a strategy to prevent the effective presentation of viral antigens to the host immune system. Human papilomavirus infection is non-lytic so there is little release of viral antigen to professional antigen-presenting cells. Additionally no local pro-inflammatory cytokine production and no local inflammation is induced by HPV infection. An optimal therapeutic strategy for anogenital HPV infection would be, therefore, to accelerate the induction of a strong virus-specific immune response by inducing local inflammation and the cytokines necessary to invoke HPV-specific immunity. [ABSTRACT FROM AUTHOR]