R. Di Caprio

Effects of adalimumab therapy in adult subjects with moderate-to-severe psoriasis on Th17 pathway

Until relatively recently, psoriasis has been considered to be a mainly T helper (Th)1‐driven inflammatory disease; however, several findings have now assessed a major role for Th17 cells in its pathogenesis. Adalimumab is a biological agent that inhibits TNF‐α, a pro‐inflammatory cytokine with a pivotal role in the mechanisms of the disease.

Mammalian target of rapamycin, insulin resistance and hidradenitis suppurativa: a possible metabolic loop

mosomal STS was detectable by fluorescent in situ hybridization analysis, suggesting no gross deletion of the STS locus. Suspecting the possible involvement of minor mutation(s), all the 10 exons of STS were sequenced, revealing that each patient had different single nucleotide substitutions in close proximity within exon 7. Patient 1 had a T>G substitution at nucleotide 1049, changing a valine to a glycine (c.1049T>G, p.V350G; Fig. 1e), whereas patient 2 had a G>A substitution at nucleotide 1075, changing a glycine to an arginine (c.1075G>A, p.G359R; Fig. 1f). The possibility of polymorphism was excluded using a world-wide SNPs database. To date, 20 point mutations of STS, including those reported here, have been identified in XLRI (Fig. 2b). Of these, 15 (75%) were missense mutations and the remaining 5 (25%) were nonsense mutations. The majority of these mutations (18/20, 90%) were localized exclusively within the downstream of exon 7, supporting the hypothesis that this region is essential for in vivo enzyme activity. More precisely, STS protein has 26 substrate binding and 10 catalytic sites that are highly homologous to those in other sulfatase family members, aryl sulfatase A and B. These characteristic amino acids are indispensable for maintenance of the tertiary structure, substrate binding/scaffolding and catalytic activity. Nevertheless, none of these functional amino acids, except two substrate binding sites (T165 and E349), relate to the 20 STS point mutations. Combining these assumptions with the considerably high incidence of complete STS deletion in XLRI, it is conceivable that STS point mutations sufficiently affect the baseline enzymatic activity to elicit the development of the disease. To look for mutation-specific conformational alterations, we aligned the secondary and tertiary structures of STS (Fig. 2c,d). It comprises tandem transmembrane domains across the cytoplasmic domain within exon 5, two post-translational glycosylation sites, five Ca binding sites and six disulphide bonds, thereby forming the ‘mushroom-like’ configuration embedded into the lumenal membrane of the endoplasmic reticulum. Interestingly, all mutations were clustered within the lumen side, but not within the transmembrane or cytoplasmic domains (Fig. 2d), indicating that the lumenal portion of STS is highly sensitive to the transversion of a single amino acid, albeit to a lesser extent with basic secondary structures (e.g. a-helices; Fig. 2b). Collectively, STS point mutations demonstrate restricted localization, causing efficient impairment of the corresponding enzyme activity, and are more unlikely to be responsible for the phenotypic heterogeneity in XLRI subjects.

Mammalian target of rapamycin in inflammatory skin conditions

The conserved serine/threonine kinase mammalian target of rapamycin (mTOR) is a major regulator of survival growth, proliferation and motility, in response to mitogens, energy and nutrient levels. Dysregulation of mTOR pathway has been observed in various inflammatory or neoplastic human diseases. To assess the potential involvement of mTOR in some of the most common inflammatory skin diseases, and its interaction with other inflammatory mediators, we investigated mTOR expression in psoriasis, allergic contact dermatitis (ACD) and atopic dermatitis (AD). mTOR gene expression was assessed in the following conditions: i) skin biopsies from 15 patients affected by psoriasis, 5 patients with ACD, 5 patients with AD and 3 patients with EGFR-inhibitor-induced skin rash; ii) in immortalized keratinocytes HaCaT, primary human keratinocytes (KCs) and full thickness skin organ cultures, incubated with tumor necrosis factor (TNF)-α, interleukin (IL) 17A or their combination; iii) in HaCaT cells stimulated with ultraviolet (UV)B; iv) in skin biopsies from 5 psoriatic patients before and after 16 weeks of anti-TNF-α therapy; mTOR expression was also evaluated through immunohistochemistry in lesional and non-lesional skin samples from 5 psoriatic patients. Moreover, mTOR major up-stream and down-stream regulator gene expression was assessed in skin biopsies from 15 patients affected by psoriasis, 5 patients with ACD, 5 patients with AD and 3 patients with EGFR-inhibitor-induced skin rash. All analyzed skin diseases showed an increase of mTOR gene expression whereas mTOR up-stream negative regulators were reduced or not enhanced in all of them. mTOR was strongly expressed in all epidermal layers of lesional and non-lesional psoriatic skin. Conversely, pro-inflammatory conditions, in vitro, were not able to increase mTOR levels, except for UVB. Similarly, anti-TNF-α therapy was not able to reduce mTOR gene expression in patients with psoriasis. Our study provides evidence that mTOR is involved in cutaneous inflammatory process, but through a signalling not directly dependent from Th1-Th17 pathway.

Understanding the role of haptoglobin in psoriasis: effects of ultraviolet B

Haptoglobin (Hp) is one of the acute phase proteins, whose main function is to bind free haemoglobin (Hb) and transport it to the liver for degradation and iron recycling. In addition to its role as an Hb scavenger, Hp has been shown to behave as an anti‐inflammatory, antioxidant and angiogenic factor. We previously investigated the role of Hp in the pathogenesis of psoriasis, and found that it displays some structural modifications that might be associated with protein function in the disease. Phototherapy is an efficacious treatment for psoriasis, although the biological mechanisms by which phototherapy improves psoriasis are still unclear.