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Toll-like receptors (TLRs) are a key part of the innate immune system that detect pathogen-associated molecular patterns (PAMPs) of microorganisms and their stimulation results in the activation of signaling pathways leading to the modulation of inflammatory and immune responses. Since psoriasis is a complex, inflammatory and immune skin disease, characterized by an abnormal immune response and increased proliferation of keratinocytes, with an increased production of proinflammatory cytokines, TLRs could play an important role in the pathogenesis of the disease. We propose to assess the modulation of TLR expression on psoriatic skin of patients treated with Adalimumab and systemic conventional therapies. We therefore recruited fifteen patients: ten were treated with adalimumab and five with systemic conventional therapies; their clinical conditions were analyzed by PASI index and skin biopsies were evaluated for TLR1 and TLR2 expression by immunohistochemistry assays. Our data suggest adalimumab is not only able to improve the clinical condition of psoriatic patients, but also to modulate TLR1 and TLR2 expression involved in psoriasis, as in healthy skin. Adalimumab is a most promising biological drug able to orchestrate immune and inflammatory responses in psoriatic lesions, recovering TLR expression on basal keratinocytes and improving clinical conditions of psoriatic patients, with no evident side effects.

Summary Background. The basophil activation test (BAT) has been recently described as a useful in vitro tool for diagnosis of allergy to Anisakis species in patients with acute urticaria. Aim. To evaluate the relationship between sensitization to Anisakis simplex and chronic urticaria (CU), using flow cytometry analysis of in vitro BAT. Methods. A. simplex sensitization was evaluated in patients with CU (n = 57) and in atopic (n = 22) and healthy controls (n = 20) by means of skin prick test (SPT), specific IgE and Anisakis-induced BAT using a triple-labelled strategy with anti-CD123, anti-human leucocyte antigen DR and anti-CD63 antibodies. During a follow-up period of 6 months in 10 patients with CU who accepted a fish-free dietary regimen, the diagnostic performance of the in vivo and in vitro methods was calculated, and changes in specific IgE and BAT were evaluated with respect to clinical response. Results. A significant association between CU and A. simplex sensitization was found, with an overall prevalence of 75.4% in patients with CU (43/57) compared with 18% (4/22) and 10% (2/20) of the atopic and healthy controls, respectively (P 13%) had the highest sensitivity and specificity, with significantly better ability than specific IgE testing for the identification of A. simplex sensitization in patients with CU. During the 6-month follow-up, clinical improvement was seen in all patients, and specific IgE and BAT results decreased to normal values in 6/10 (60%) and 10/10 (100%) patients, respectively. Conclusions. BAT can be considered a reliable new in vitro method to evaluate A. simplex hypersensitivity in patients with CU, supplementing standardized procedures in both diagnosis and follow-up.

Background: No data exist as to Th2 chemokines in erythema multiforme (EM) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Objective: To evaluate thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and regulated upon activation, normal T-lymphocyte-expressed and secreted chemokine (RANTES) expression in EM and SJS/TEN and to correlate with the serum levels of the Th1 promoter interleukin (IL)-12 and soluble Fas ligand (sFasL). Materials and Methods: IL-12, sFasL, TARC, MDC and RANTES expression were analyzed by ELISA techniques in 31 untreated EM (n = 24) or SJS/TEN (n = 7) patients and in 28 healthy donors (HD). Results: EM and SJS/TEN exhibited significantly higher levels of TARC, IL-12 and sFasL with respect to HD. TARC upregulation paralleled both the IL-12 (p = 0.0225) and sFasL increase (p = 0.0194). Conclusions: Our results support a role of TARC in the pathophysiology of EM/SJS/TEN and confirm the coexistence of a Th2 response in addition to the predominant Th1 profile.

Summary Background Erythema multiforme (EM) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are caused by a dysregulation of cellular immunity. Objectives To evaluate further the potential role of certain cytokines and chemokine receptors in cutaneous lesions of patients affected by EM and SJS/TEN and to establish whether such diseases are polarized preferentially towards a T-helper (Th) 1 or Th2 pattern. Methods Biopsy specimens from eight patients with EM, six with SJS/TEN and three healthy controls were stained for immunohistochemical examination using the alkaline phosphatase–antialkaline phosphatase method. The monoclonal antibodies used included those to tumour necrosis factor (TNF)-a, interferon (IFN)-c, interleukin (IL)-2, IL-5, IL-13, receptor 3 for C-C chemokines (CCR3), receptor 3 for C-x-C chemokines (CXCR3) and CXCR4. Results The SJS/TEN specimens showed significantly higher expression of all the cytokines and chemokine receptors (except CXCR3) tested than the EM specimens. Both lesional series showed significantly higher expression of all the receptors tested than the healthy control specimens, with the sole exception of a lower expression of CCR3 in EM specimens. Comparison between molecules associated with a Th1 or Th2 response revealed a predominance of Th1 response in EM and no significant imbalance between Th1 and Th2 in SJS/TEN. Conclusions We have provided further evidence that TNF-a is strongly expressed in SJS/TEN lesions and therefore it may be involved in the epidermal necrosis featured in such diseases. IFN-c may play an important role both in EM and SJS/ TEN. IL-2, IL-5 and IL-13 may contribute to the cutaneous immunoinflammation in these diseases. Chemokine receptors may be involved strongly in the recruitment of inflammatory cells in lesional skin. In our cases we found a sharp polarization towards a Th1 pattern in EM, while the SJS/TEN lesions showed a mixed Th1/Th2 pattern.

Summary Background Erythema multiforme (EM) and Stevens–Johnson syndrome (SJS) ⁄toxic epidermal necrolysis (TEN) are determined by a dysregulation of cellular immunity. Objectives To evaluate the effector role of cellular immunity and the involvement of the CD40 ⁄CD40 ligand (CD40L) system in the pathogenesis of EM and SJS ⁄ TEN. Methods Biopsy specimens from eight patients with EM and six with SJS ⁄ TEN were stained for immunohistochemical examination using the alkaline phosphatase ⁄antialkaline phosphatase method. The monoclonal antibodies used included those to CD1a, CD4, CD8, CD40, CD40L, CD68, Fas, Fas ligand (FasL) and myeloperoxidase. Results The cellular infiltrate in both EM and SJS ⁄ TEN lesions was composed mainly of T lymphocytes and CD68+ macrophages. We also detected large amounts of neutrophils. Fas and FasL were very highly expressed in SJS and TEN, but weakly in EM. CD40 staining was strong in all tissue sections; there were numerous CD40L+ cells in SJS ⁄ TEN but much fewer in EM. Conclusions Activated T lymphocytes and macrophages, but also neutrophils, are presumably the main triggers of mucocutaneous damage in the SJS ⁄ TEN disease spectrum. The Fas ⁄ FasL system is significantly expressed in SJS ⁄ TEN lesions, but not in EM, where this apoptotic pathway presumably does not play a pivotal role in the epidermal damage. We suggest that the CD40 ⁄CD40L system may represent an important pathway of induction of SJS ⁄ TEN lesions, while in EM it would contribute to the immunoinflammation only as a second-line mechanism.

BACKGROUND Physical urticaria (PU) includes a heterogeneous group of urticarias whose etiopathogenic aspects are still obscure and whose therapeutical management is often difficult. We have previously demonstrated the efficacy of a sequential treatment with nimesulide, a unique nonsteroidal anti-inflammatory drug, and ketotifen in various forms of PU. METHODS The expression of some inflammatory parameters was evaluated in 10 patients affected with some forms of PU. In particular, serum levels of interleukin (IL)-4, IL-1beta, tumor necrosis factor (TNF)-alpha, adhesion molecules (sELAM, sICAM-1 and sVCAM), soluble receptors (sIL-2R, sCD30, sCD23) and IgE were assessed. Moreover, the cutaneous expression of IL-1beta, TNF-alpha and ICAM-1 was studied on biopsy specimens taken from nonlesional skin of patients. The same parameters were further evaluated in both skin and serum following treatment with nimesulide and ketotifen, in order to better understand the possible effects of these agents on the inflammatory network of PU. RESULTS Before therapy we could detect significantly higher serum levels of IL-1beta and TNF-alpha (P < 0.001) and of circulating adhesion molecules in comparison with controls (sELAM, sICAM: P < 0.001; sVCAM: P < 0.02); after treatment, a significant reduction of each was observed (P < 0.05). Simultaneously, a high expression of IL-1beta, TNF-alpha and ICAM-1 was detected in all skin specimens at the baseline, with a relevant decrease following therapy. CONCLUSIONS These results confirm the therapeutical value of treatment with nimesulide and ketotifen in PU and suggest that these agents are able to reduce the release and the expression of some inflammatory molecules that are up-regulated in PU.

Several published studies suggest the involvement of immune and inflammatory factors in psoriasis. We recently demonstrated that the number of circulating ICAM-1 + lymphocytes and the levels beta 2-microglobulin are useful parameters in monitoring the activity of the disease. In this study we investigated serum levels of SCCr-Ag in 24 patients with psoriasis in order to determine whether this antigen is a marker of disease activity. Our results demonstrated high serum levels of SCCr-Ag, IL-2, sIL-2R, sCD4, sCD8, sICAM-1 and beta 2-microglobulin in the acute phase of psoriasis. Furthermore, we found a positive correlation of SCC with TBSA, PASI score, sICAM-1 and beta 2-microglobulin. These data demonstrate that serum levels of SCCr-Ag depend on the severity of the disease and correlate with both immunological and inflammatory markers of disease activity. We suggest that expression of SCCr-Ag may be induced by cytokines in the microenvironment of psoriatic lesions, suggesting that SCC-Ag may play a role in the inflammatory process.

Background Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab—to our knowledge the largest series of patients so far—and review the existing literature on the topic. Observation The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m 2 once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed. Conclusions Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.

The immune system involvement in psoriasis has been documented by the presence of activated T-cells both in peripheral blood and in psoriatic skin lesions and by the intervention of cytokines in the inflammatory process. On this basis, we have undertaken a study in order to examine, in addition to activation markers such as CD25 and CD54 (ICAM-1) on peripheral blood mononuclear cells (PBMNCs) surface, serum levels of soluble interleukin (IL)-2 receptor (sIL-2R), soluble ICAM-1 (sICAM-1), soluble CD4 (sCD4), soluble CD8 (sCD8), beta 2-microglobulin and fibronectin (FN) in psoriatic patients analyzed both in acute and remission phase obtained by topical therapy alone. Our results show that PBMNCs expressing IL-2 receptor (CD25) were increased both in percentage and absolute number in respect to controls, and were not modified after remission. On the contrary, the significantly higher number of CD54+ lymphocytes evaluated in acute psoriasis, showed a reduction during the remission phase, even if the values persisted higher than controls. Serum levels of sIL-2R, sICAM-1, sCD4, sCD8 and beta 2-microglobulin were significantly higher than controls both in acute and remission phase; only FN levels were found to be lower, in patients evaluated both in acute psoriasis and after therapy, in respect to normal donors. On the whole, these results seem to indicate the persistence of both cellular and soluble activation markers even in psoriasis remission phase; in this light, we can suppose that topical therapy alone is not able to efficiently down-regulate activation mechanisms involved in the pathogenesis of the disease.

We describe the clinical and laboratory findings of a young man with mycosis fungoides. The disease was associated, since the early stages, with autoimmune purpura. Interferon alfa (IFN-alpha) administration improved this patient's condition, both the purpuric eruption and patchy cutaneous lesions, thus suggesting T-cell abnormalities may be responsible for the development of the disease.

To assess the role of platelets and lymphocyte-related immunological mechanisms in livedo vasculopathy (LV) and cutaneous small vessel vasculitis (CSVV). Livedo vasculopathy is thought to be related to the thrombotic occlusion of small and medium-sized dermal vessels. Cutaneous small vessel vasculitis comprises a heterogeneous group of disorders in which the main pathogenetic events could be modulated by circulating cytokines.Case series study of 2 groups of patients affected respectively with LV and CSVV.A large clinical and research institute for the study and treatment of cutaneous diseases.Consecutive patients with clinically and histologically proved idiopathic LV (n = 8) and CSVV (n = 20) were studied and compared with healthy donors (n = 20). Patients with potentially correlated systemic diseases were excluded.Surface expression of platelet P-selectin and circulating level of interleukin (IL) 1beta, tumor necrosis factor alpha (TNF-alpha), IL-8, IL-2, and soluble IL-2 receptor.The IL-2 and soluble IL-2 receptor levels were significantly higher in serum samples from patients with both LV (1.24 +/- 0.46 IU/mL [mean +/- SD] vs 0.46 +/- 0.24 IU/mL, P.001; 899 +/- 368 IU/mL vs 628 +/- 132 IU/mL, P.02) and CSVV (0.91 +/- 0.57 IU/mL, P.02; 1087 +/- 451 IU/mL, P.001) than in those from the healthy controls. The serum levels of IL-1beta, TNF-alpha, and IL-8 were higher in patients with CSVV than in controls (7.53 +/- 6.7 pg/mL vs 4.58 +/- 2.72 pg/mL; 23.7 +/- 12.6 pg/mL vs 10.82 +/- 2.46 pg/mL, P.001; 37.8 +/- 46 pg/mL vs 8.25 +/- 3.53 pg/mL, P.02, respectively). No significant difference in the serum levels of IL-1beta (7.2 +/- 4.9 pg/mL), TNF-alpha (12.9 +/- 3.47 pg/mL), and IL-8 (5.9 +/- 4.13 pg/mL) was observed in patients with LV compared with controls. An increased expression of platelet P-selectin was also detected in patients with LV in comparison with controls and patients with CSVV. The mean +/- SD percentage of positive cells for P-selectin was 43% +/- 5% in the patients with LV, 5.1% +/- 2% in the controls (P.001), and 5.3% +/- 2% in the patients with CSVV (P.001).Taken together, these data demonstrate that different pathogenetic mechanisms are operative in LV and CSVV. In fact, platelet and lymphocyte activation is present in LV, whereas the levels of inflammatory mediators are in a normal range. In CSVV, the high serum levels of proinflammatory cytokines suggest that they are actively involved in the pathogenesis of cutaneous vasculitis.