Alessandra Frezzolini

Eotaxins and CCR3 Receptor in Inflammatory and Allergic Skin Diseases: Therapeutical Implications

Cell migration is mediated by a group of chemotactic cytokines called chemokines: low molecular weight molecules that have been shown as important leukocyte chemical attractants to sites of inflammation and infection. Eotaxin-1, also called CCL11, was first described in 1994, as a highly specific eosinophils chemokine. Many cell types including lymphocytes, macrophages, bronchial smooth muscle cells, endothelial cells and eosinophils, are able to produce this chemokine, predominantly after cytokine stimulation, however little is known about its expression in human skin in vivo. Eotaxin-1 also regulates the chemiotaxis and, in some conditions, activation of basophils, mast cells and T lymphocytes. Chemokine receptors are named from their ligand families, thus the CC chemokine eotaxin-1 binds to the CCR3 receptor which is expressed on eosinophis, mast cells, Th2 type lymphocytes and even on keratinocytes. It seems that eotaxin-1 is one of the most important cytokines involved in tissue inflammation playing a central role in the pathogenesis of allergic airway diseases (asthma and rhinitis), in inflammatory bowel disease and gastrointestinal allergic hypersensitivity and recently it has been proposed as a therapeutical target for these conditions. Our group has studied the role of eotaxin-1 in the pathogenesis of two skin conditions: dermatitis herpetiformis and AIDS-associated eosinophilic folliculitis, demonstrating that this chemokine, together with Th2 type cytokines (IL-13 and IL-4) is important in cell recruitment, inflammation and tissue damage; moreover eotaxin has proven to paly an important role in other skin conditions such as, bullous pemphigoid, pemphigoid gestationis, atopic dermatitis and allergic drug reactions Recent advances in the understanding of eotaxin-1-mediated mechanisms of chemotaxis in allergic and inflammatory conditions may predict that therapeutic antagonism is achievable. This paper will focus on the role that eotaxin and its receptor play in the pathogenetical mechanism in a number of dermatologic diseases, some of which, like atopic dermatitis, may benefit from the introduction of novel and more selective therapeutic options.

The role of proopiomelanocortin-derived peptides in skin fibroblast and mast cell functions.

ABSTRACT: We have previously described proopiomelanocortin (POMC) gene‐expression in human normal cultured dermal fibroblasts, and its dose‐ and time‐dependent modulation by transforming growth factor‐β (TGF‐β) and tumor necrosis factor‐α (TNF‐α). The aim of the work described here was to investigate POMC‐derived peptide release in vitro by cultured fibroblasts following incubation with different concentrations of both TNF‐α and TGF‐β for 24 hours (1, 5, and 10 ng/ml). The effect of simultaneous addition of both TNF‐α and TGF‐β (10 ng/ml) was also evaluated. Culture supernatants of human skin fibroblasts were collected to detect adrenocorticotropin hormone (ACTH), α‐melanotropin (α‐MSH), and β‐endorphin (β‐EP) levels by specific immunoenzymatic assay. We investigated the in vitro histamine‐releasing activity of the POMC‐derived peptides, α‐MSH and β‐EP, on human foreskin mast cells. Detection of cleavage products in supernatants from cultured normal human dermal fibroblasts indicated intracellular processing by POMC protein. We were able to measure detectable levels of all peptides in basal conditions. TNF‐α addition resulted in an increase in β‐EP and ACTH levels. TGF‐β‐stimulated fibroblasts showed no alteration in β‐EP and α‐MSH levels, whereas ACTH release was significantly enhanced. Both α‐MSH and β‐EP induced histamine release from human foreskin mast cells in vitro with β‐EP‐induced histamine levels as high as those observed with the calcium ionophore, ionomycin. Our data document fibroblast POMC‐derived peptide release and modulation by cytokines, suggesting that they have a possible role in extracellular matrix deposit regulation and skin inflammation.

Interleukin-16 expression and release in bullous pemphigoid.

Cutaneous infiltration of activated CD4+ T cells and eosinophils is an early event in blister formation during bullous pemphigoid (BP), suggesting that the trafficking of circulating leucocytes through the sites of inflammation, their activation and cytokine release is crucial in the pathogenesis of the disease. IL‐16 is a major chemotactic factor able to recruit CD4+ cells in the skin during inflammation and to induce the expression of functional high‐affinity interleukin (IL)‐2 receptors, thus contributing to cellular activation and proliferation. We performed a study in order to evaluate the presence of IL‐16 in skin samples and sera and blister fluids of patients affected with BP in active phase of the disease (nu2003=u200339), compared with healthy donors studied as control group. Ten patients were also evaluated before and after steroid therapy. Our results demonstrated that IL‐16 was expressed strongly by keratinocytes and by dermal infiltrating CD4+ T lymphocytes in lesional skin of BP patients. High levels of IL‐16 were detected in sera and blisters of BP, significantly higher in respect to healthy donors. When patients were investigated for the presence of eosinophil cationic protein (ECP) and soluble CD30 (sCD30) to reveal signs of eosinophils and Th2‐cells activation, we found a positive correlation between IL‐16 serum levels and both ECP and sCD30, suggesting that IL‐16 is involved in Th2 lymphocytes and eosinophils recruitment during BP.

Pigmented purpura-like eruption as cutaneous sign of mycosis fungoides with autoimmune purpura☆☆☆★

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 patients condition, both the purpuric eruption and patchy cutaneous lesions, thus suggesting T-cell abnormalities may be responsible for the development of the disease.

Evaluation of inflammatory parameters in physical urticarias and effects of an anti‐inflammatory/antiallergic treatment

Background u2002Physical 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.

The pathogenic activity of anti-desmoglein autoantibodies parallels disease severity in rituximab-treated patients with pemphigus vulgaris.

BackgroundPemphigus vulgaris (PV) is an autoimmune blistering disease mediated by IgG autoantibodies targeting desmogleins (Dsgs). The anti-CD20 monoclonal antibody rituximab is increasingly used in corticosteroid-resistant PV patients. In a subset of rituximab-treated patients in remission, high ELISA index values have been reported; however, their significance remains so far unclear.ObjectiveTo address the discrepancy between anti-Dsg3 serum antibody titers and disease severity.Materials and Methods6 rituximab-treated PV patients were prospectively followed-up for two years and anti-Dsg3 autoantibodies levels and pathogenic activity were measured.ResultsAll patients achieved complete remission without any serious side effects. Both anti-Dsg3 autoantibodies (p = 0.031) and their pathogenic activity (p = 0.003) were significantly related to disease severity. However, in selected patients, the dissociation index was a more sensitive indicator for PV clinical activity than the ELISA index.ConclusionsOur findings have demonstrated the existence of non-pathogenic autoantibodies in PV patients in remission, establishing the basis for the design of a system able to precisely monitor the course of disease.

Usefulness of skin immunofluorescence for distinguishing SLE from SLE-like renal lesions: a pilot study

Lupus nephritis (LN) may represent a diagnostic problem, particularly in pediatric patients that present with typical histological lesions but do not fulfill the American Rheumatism Association (ARA) criteria for the diagnosis of systemic lupus erythematosus (SLE). Based on the well-described deposition of immunoglobulins (Ig) and complement at the dermoepithelial junction in SLE, we hypothesized that skin biopsies may help in the diagnosis of LN. To test this hypothesis, we carried out a pilot study, performing a skin biopsy in 22 patients with LN and 13 patients with lupus-like lesions, regardless of the time elapsed from onset of renal disease. The latter group of patients was further divided into a purely renal group, designated as isolated full-house nephropathy (FHN), and a dubious cases group, presenting with additional clinical and biological features consistent with SLE but insufficient for diagnosing SLE. None of the 6 isolated FHN patients had positive skin immunofluorescence. Conversely, 5/7 patients in the dubious cases group (pu2009<u20090.02) and 13/22 in the LN group (pu2009<u20090.002) had positive staining for C1q, and 5/7 patients in the dubious cases group (pu2009<u20090.02) and 16/22 patients in the LN group (pu2009<u20090.001) had positive staining for IgM. No correlation was observed with the time elapsed from the initial diagnosis. These data suggest that skin biopsies may help distinguishing LN from isolated FHN. In addition, they identify an intermediate group of patients with evidence of systemic involvement despite the absence of a sufficient number of ARA criteria to be labeled as SLE.