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Background: It has been proposed that the innate immune system plays a central role in driving the autoimmune T-cell cascade leading to psoriasis; however, there is no direct evidence for this. Observations:We observed aggravation and spreading of a psoriatic plaque when treated topically with the toll-like receptor (TLR) 7 agonist imiquimod. The exacerbation of psoriasis was accompanied by a massive induction of lesional type I interferon activity, detected by MxA expression after imiquimod therapy. Since imiquimod induces large amounts of type I interferon production from TLR7-expressing plasmacytoid dendritic cell precursors (PDCs), the natural interferon-producing cells of the peripheral blood, we asked whether PDCs are pres-ent in psoriatic skin. We identified high numbers of PDCs in psoriatic skin lesions (up to 16% of the total dermal infiltrate) based on their coexpression of BDCA2 and CD123. By contrast, PDCs were present at very low levels in atopic dermatitis and not detected in normal human skin. Conclusions:This study shows that psoriasis can be driven by the innate immune system through TLR ligation. Furthermore, our finding that large numbers of PDCs infiltrate psoriatic skin suggests a role of lesional PDCs as type I interferon-producing targets for the TLR7 agonist imiquimod.
Background: It has been proposed that the innate immune system plays a central role in driving the autoimmune T-cell cascade leading to psoriasis; however, there is no direct evidence for this. Observations:We observed aggravation and spreading of a psoriatic plaque when treated topically with the toll-like receptor (TLR) 7 agonist imiquimod. The exacerbation of psoriasis was accompanied by a massive induction of lesional type I interferon activity, detected by MxA expression after imiquimod therapy. Since imiquimod induces large amounts of type I interferon production from TLR7-expressing plasmacytoid dendritic cell precursors (PDCs), the natural interferon-producing cells of the peripheral blood, we asked whether PDCs are pres-ent in psoriatic skin. We identified high numbers of PDCs in psoriatic skin lesions (up to 16% of the total dermal infiltrate) based on their coexpression of BDCA2 and CD123. By contrast, PDCs were present at very low levels in atopic dermatitis and not detected in normal human skin. Conclusions:This study shows that psoriasis can be driven by the innate immune system through TLR ligation. Furthermore, our finding that large numbers of PDCs infiltrate psoriatic skin suggests a role of lesional PDCs as type I interferon-producing targets for the TLR7 agonist imiquimod.
Alpha interferon is available worldwide as at least six difAlpha interferons have been used widely to treat chronic hepatitis C virus infection. These include recombinant inter-ferent products made by as many pharmaceutical companies.It is approved for human use in the European Union and the ferons, purified natural leukocyte, and lymphoblastoid interferons. Alpha interferon is administered by subcutaneous or United States for several medical conditions, including hairy cell leukemia, chronic myelogenous leukemia, Kaposi's sarintramuscular injection either daily or three times weekly for a period of 6 to as long as 24 months. A wide array of adverse coma, condylomata acuminata, multiple myeloma, nonHodgkin's lymphoma, cutaneous T-cell lymphoma, basal cell effects of alpha interferon have been described. Several side effects such as fever, headache fatigue, arthralgias, and myal-carcinoma, chronic hepatitis B, and chronic hepatitis C. Both recombinant as well as lymphoblastoid and natural leukocyte gias are common, especially with the initial injections. These early side effects of interferon are predictable and are encoun-alpha interferons have been used to treat chronic hepatitis C virus infection. tered in the majority of patients. These may not require dose modification, but can be problematic for a significant propor-PHARMACOKINETIC DATA tion of patients. Other adverse events effects may require dose modification or even discontinuation of therapy in 2% to 10%Alpha interferon is usually administered by subcutaneous of patients. Neuropsychiatric side effects such as depression or intramuscular injection. Maximum serum levels occur 3 and irritability can be most troublesome; their mechanisms to 12 hours after injection, and serum levels are usually are not well understood. Granulocytes, platelets, and red below the limit of detection by 16 hours. 1 The elimination blood cell counts decrease during treatment, but the decreases half-life of interferon after both subcutaneous and intramusare usually mild, although they can be dose limiting if cell cular injections is 2 to 3 hours, and clearance from the syscounts are low initially. Interferon has important immuno-temic circulation is primarily by renal catabolism. After intramodulatory properties, and treatment can induce autoimmune venous administration, serum levels of interferon are phenomena, the most frequent being autoimmune thyroiditis maximal at the end of the infusion, becoming undetectable with either hypothyroidism or hyperthyroidism, especially within 4 hours of the infusion. The elimination half-life is in predisposed patients. Other autoimmune disease can be approximately 2 hours. Measurement of serum concentraaggravated by interferon therapy. Severe and even life-threat-tions of different preparations of alpha interferon is problemening side effects of interferon occur in 0.1% to 1% of patients; atical because the levels achieved are low after injection of these include thyroid, visual, auditory, renal, and cardiac im-typical doses of 3 to 10 milli...
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