A. Frezzolini

Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis

Background  Erythema multiforme (EM) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are caused by a dysregulation of cellular immunity.

The CD40/CD40 ligand system is expressed in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum.

Background  Erythema multiforme (EM) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are determined by a dysregulation of cellular immunity.

Circulating Interleukin 16 (IL‐16) in children with atopic/eczema dermatitis syndrome (AEDS): a novel serological marker of disease activity

Background: Chemokines play a central role in atopic eczema/dermatitis syndrome (AEDS). Interleukin 16 (IL‐16) has been described as a main cytokine involved in CD4+ cell recruitment during inflammation. Recently the influx of CD4+ lymphocytes has been related to the up‐regulation of IL‐16 in AEDS skin lesions. Circulating β‐chemokines (Eotaxin and RANTES) and IL‐16 were investigated in children with AEDS to correlate their presence with the severity of the disease. We also measured serum levels of soluble CD30 (sCD30), a marker of Th2 immune responses related to AEDS disease activity.

Serum-induced basophil CD63 expression by means of a tricolour flow cytometric method for the in vitro diagnosis of chronic urticaria.

Background:  Functional autoantibodies against the α‐chain of the high‐affinity IgE receptor (FcɛRIα) identify a subset of patients with chronic urticaria (CU) due to autoreactivity, as assessed by an in vivo positive response to autologous serum skin test (ASST). We performed a study to standardize the serum‐induced basophil activation assay by flow cytometry (FCM) using a new tricolour method, assessing the diagnostic performance of this test in discriminating between ASST+ and ASST− CU patients.

Psoriasis: comparison of immunological markers in patients with acute and remission phase

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.

T-helper 2 involvement in the pathogenesis of bullous pemphigoid: role of soluble CD30 (sCD30)

Abstract Bullous pemphigoid (BP) is an autoimmune blistering skin disease in which autoantibodies are directed against hemidesmosomal proteins of basal keratinocytes. The presence of activated T helper cells in lesions and peripheral blood of BP patients, the eosinophilia, the high levels of serum IgE, eosinophil cationic protein and soluble immune products such as IL-2, sIL-2R, IL-5, soluble CD23 (sCD23) strongly suggest the involvement of a cell-mediated immune reaction in which Th2 lymphocytes could play a pivotal role. To seek evidence to support this hypothesis we evaluated serum levels of IL-4 and sCD30, a specific activation marker of cells able to produce Th2-like cytokines, in 25 patients affected with BP. Serum from both healthy donors and pemphigus vulgaris (PV) patients were used as controls. Our results demonstrated significantly higher levels of IL-4 and sCD30 in patients with BP in relation to both normal individuals (16.6 ± 7.9 vs 4.5 ± 2.2 pg/ml, P < 0.0001; 30.3 ± 10 vs 10.5 ± 4 U/ml, P < 0.0001) and PV patients (6.2 ± 4 pg/ml, P < 0.0001; 16 ± 8.5 U/ml, P < 0.0001). Furthermore, a positive correlation between IL-4 and sCD30 was found ( R = 0.85, P < 0.0001). In a subset of seven patients observed after systemic immunosuppressive therapy, we detected a significant reduction in sCD30 serum levels (36.9 ± 7.3 vs 16.3 ± 6.8 U/ml, P = 0.002), with a parallel improvement in their clinical condition. These results seem to be consistent with the systemic involvement of Th2 lymphocytes in the pathogenesis of BP and suggest a role for sCD30 as a serological marker of disease activity.

Serum levels of the Th1 promoter IL-12 and the Th2 chemokine TARC are elevated in erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis and correlate with soluble Fas ligand expression. An immunoenzymatic study from the Italian Group of Immunopathology.

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.

The role of T lymphocytes and cytokines in the pathogenesis of pemphigoid gestationis

Summary Background Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare autoantibody‐mediated bullous disease, usually associated with pregnancy and the postpartum period. However, infiltrating cells have recently been suggested to also contribute to the pathogenesis of cutaneous lesions.

Immunohistochemical expression of apoptotic markers in drug-induced erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered to be severity variants of the same disease, which is almost always associated with drug intake. In contrast, erythema multiforme (EM) is a disorder regarded as only rarely caused by drugs. Keratinocyte apoptosis has been shown to play an important part in the pathogenesis of SJS and TEN, whilst its role in EM remains controversial. To determine the expression of apoptosis-associated molecules Fas, Fas ligand (FasL), Bcl-2 and Bax in the above disorders, an immunohistochemical analysis was performed. We studied both lesional skin from thirty patients having drug-induced EM and 5 cases classified within the SJS/TEN spectrum and normal skin samples. We found a keratinocyte overexpression of Fas antigen, an important molecule mediating apoptosis, not only in SJS and TEN but also in EM. Another noteworthy finding was the strong expression of Bcl-2, a protein known as blocking apoptosis, along the basal layer and in the dermal infiltrate both in SJS/TEN and in EM. Taken together, these findings suggest that Fas-dependent keratinocyte apoptosis may play a part in the pathogenesis of both SJS/TEN and EM. Fas-mediated cell death may be partially suppressed by the Bcl-2 protein.

Cyclosporin A (CyA) reduces sCD30 serum levels in atopic dermatitis: a possible new immune intervention

Atopic dermatitis (AD) is a chronic inflammatory skin disease frequently associated with asthma, rhinitis, and food allergy. Lymphocytes producing Th2‐type cytokines (such as interleukin [IL]‐3, IL‐4, and IL‐5) have been thought to have a key role in the pathogenesis of the disease. We have recently demonstrated that elevated serum levels of the soluble form of CD30 (sCD30), an activation marker of Th2‐cell clones, correlates with disease activity in pediatric patients suffering from AD. Clinical trials have demonstrated that cyclosporin A (CyA) treatment resulted in significant improvement of clinical symptoms in patients affected with AD. In this study, we evaluated the role of CyA in modulating sCD30 release in a group of adult patients affected by severe AD treated with CyA at the dosage of 3.5 mg/kg body weight for 12 weeks. Our results demonstrated, in parallel with an improvement of clinical symptoms, a significant reduction of serum levels of both IL‐4 and sCD30, thus suggesting that CyA can prevent the activation of Th2 cells observed in AD.