Modulation of Toll-like receptors in psoriatic patients during therapy with adalimumab

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

Reduction of T Lymphoma Cells and Immunological Invigoration in a Patient Concurrently Affected by Melanoma and Sezary Syndrome Treated With Nivolumab

Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients' response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients' response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (NCT03385226, NCT04118868)

Modulation of Toll-like Receptors in Psoriatic Patients during Therapy with Adalimumab

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

Squamous cell carcinoma-related antigen (SCCr-Ag), sICAM-1 and β2- microglobulin are useful markers of disease activity in psoriasis

The development of squamous cell carcinomas is the main cause of death of patients with Dystrophic epidermolysis bullosa. We think it is of interest to know their clinical characteristics and the treatment difficulties they cause.We followed the clinical evolutions and carried out histopathological studies of eight primary cutaneous squamous cell carcinomas on three males and one female with recessive dystrophic epidermolysis bullosa. Patient ages ranged from 16 to 34 years (mean 27).Two patients had two tumours and one three, all were in characteristically scarred skin; four on upper limbs; four on lower. Maximum tumour dimensions ranged from 2 to 28 cm (mean 13), and represented 6 or more months of evolution. In three cases the affected limb must be amputated. Five tumours were well differentiated, three were moderately differentiated.The patients consulted too late and their large lesions needed aggressive treatment. Appropriate information and regular examination of patients with RDEB helps early diagnosis of tumours and may avoid disabling operations

Expression of matrix metalloproteinases 2, 9 and 11 in erythema multiforme: immunohistochemical comparison with Stevens-Johnson syndrome/toxic epidermal necrolysis

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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

Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines

Background: Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders. Keratinocytes actively participate in cutaneous inflammatory responses by elaborating various chemokines. Objective: We investigated the capacity of IL-4, IFN-gamma, and TNF-a to modulate the expression of CCL and CXCL chemokines in cultured keratinocytes from patients and healthy individuals, as well as chemokine expression in situ. Methods: Keratinocyte cultures were established from normal-looking skin of adult patients with AD or psoriasis vulgaris and from healthy subjects. Monocyte chemoattractant protein 1 (MCP-1)/CCL2, RANTES/CCL5, IL-8/CXCL8, and IFN-gamma -induced protein of 10 kd (IP-10)/CXCL10 production was evaluated at the mRNA and protein levels by using RNase protection assay and ELISA, respectively. The expression of the same chemokines was studied in chronic Lesional skin by means of immunohistochemistry or in situ hybridization. Results: Only IL-8 mRNA was detected in unstimulated keratinocyte cultures. MCP-1 and IP-10 were potently induced by IFN-gamma, whereas IL-8 and RANTES were preferentially upregulated by TNF-a and, to a lesser extent, by IFN-gamma. IL-4 weakly induced IP-10, RANTES, and IL-8 but not MCP-I. Keratinocytes of patients with AD invariably responded with significantly earlier and higher RANTES expression. By contrast, keratinocytes of patients with psoriasis displayed much higher Levels of both constitutive and induced IL-8 and a stronger induction of MCP-1 and IP-10. RANTES and MCP-I mRNA(+) keratinocytes were detected in the basal layer of lesions of patients with AD and psoriasis. IP-10 and IL-8 were consistently upregulated in the epidermis of patients with psoriasis but not in lesions of patients with AD. Conclusions: Keratinocytes of patients with AD and psoriasis show an intrinsically abnormal and different chemokine production profile and may thus favor the recruitment of distinct leukocyte subsets into the skin