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The KALRN gene (encoding kalirin) has been implicated in several neuropsychiatric and neurodegenerative disorders. However, genetic evidence supporting this implication is limited and targeted epigenetic analyses are lacking. Here, we tested associations between epigenetic variation in KALRN and interindividual variation in depressive symptoms (PHQ9) and cognitive (MoCA) performance, in an Italian population cohort (N = 2409; mean (SD) age: 67 (9) years; 55% women). First, we analyzed the candidate region chr3:124584826–124584886 (hg38), within the KALRN promoter, through pyrosequencing of 1385 samples. Then, we widened the investigated region by analyzing 137 CpGs annotated to the whole gene, rescued from epigenome-wide (Illumina EPIC) data from 1024 independent samples from the same cohort. These were tested through stepwise regression models adjusted for age, sex, circulating leukocytes fractions, education, prevalent health conditions and lifestyles. We observed no statistically significant associations with methylation levels in the three CpGs tested through pyrosequencing, or in the gene-wide association analysis with MoCA score. However, we observed a statistically significant association between PHQ9 and cg13549966 (chr3:124106738; β (Standard Error) = 0.28 (0.08), Bonferroni-corrected p = 0.025), located close to the transcription start site of the gene. This association was driven by a polychoric factor tagging somatic depressive symptoms (β (SE) = 0.127 (0.064), p = 0.048). This evidence underscores the importance of studying epigenetic variation within the KALRN gene and the role that it may play in brain diseases, particularly in atypical depression, which is often characterized by somatic symptoms. [ABSTRACT FROM AUTHOR]

SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3- derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo. [ABSTRACT FROM AUTHOR]

The aim of the study was to assess whether the level of physical activity in daily life in previously sedentary adults had been sustained 7 years beyond a 1-year supervised walking program. One hundred ten participants (63 females, 57.5 ± 8.4 years; 47 males, 66.4 ± 7.9 years) were recalled and assessed for physical activity in daily life, weight, body mass index, blood pressure, and walking speed. Fifty-nine percentage of the participants measured met and exceeded the World Health Organization physical activity guidelines (Group 1), while 41% did not (Group 2). In both groups, we observed a significant decrease of weight (72.0 ± 14.0 kg vs. 69.7 ± 14.0 kg in Group 1; 77.4 ± 19.5 kg vs. 75.4 ± 18.6 kg in Group 2) and body mass index (25.9 ± 3.7 vs. 25.1 ± 3.9 in Group 1; 27.9 ± 5.6 vs. 27.2 ± 5.4 in Group 2). Group 1 showed a significant increase in walking speed (5.8 ± 0.7 km/hr vs. 6.2 ± 0.8 km/hr), while systolic pressure did not change from the baseline. In Group 2, systolic pressure significantly increased (131.3 ± 13.5 mmHg vs. 138.0 ± 15.5 mmHg), while walking speed did not change. A guided walking program seems to have been effective in educating sedentary people to remain physically active over time. [ABSTRACT FROM AUTHOR]

Immunomodulation with anti‐TNF‐α is highly effective in the treatment of various immune‐mediated inflammatory diseases, including hidradenitis suppurativa (HS). However, this may be responsible for unexpected paradoxical psoriasiform reactions. The pathogenic mechanisms underlying the induction of these events are not clear, even though the involvement of innate immune responses driven by plasmacytoid dendritic cells (pDC) has been described. In addition, the genetic predisposition to psoriasis of patients could be determinant. In this study, we investigated the immunological and genetic profiles of three HS patients without psoriasis who developed paradoxical psoriasiform reactions following anti‐TNF‐α therapy with adalimumab. We found that paradoxical psoriasiform skin reactions show immunological features common to the early phases of psoriasis development, characterized by cellular players of innate immunity, such as pDC, neutrophils, mast cells, macrophages, and monocytes. In addition, IFN‐β and IFN‐α2a, two type I IFNs typical of early psoriasis, were highly expressed in paradoxical skin reactions. Concomitantly, other innate immunity molecules, such as the catheledicin LL37 and lymphotoxin (LT)‐α and LT‐β were overproduced. Interestingly, these innate immunity molecules were abundantly expressed by keratinocytes, in addition to the inflammatory infiltrate. In contrast to classical psoriasis, psoriasiform lesions of HS patients showed a reduced number of IFN‐γ and TNF‐α‐releasing T lymphocytes. On the contrary, IL‐22 immunoreactivity was significantly augmented together with the IL‐36γ staining in leukocytes infiltrating the dermis. Finally, we found that all HS patients with paradoxical reactions carried allelic variants in genes predisposing to psoriasis. Among them, SNPs in ERAP1, NFKBIZ, and TNFAIP genes and in the HLA‐C genomic region were found. [ABSTRACT FROM AUTHOR]

Objective : Our pharmacogenomic study evaluated the influence of the presence/absence of genetic variants of psoriasis-risk loci on the clinical response to secukinumab. Differences in the single-nucleotide polymorphism (SNP) pattern characterizing HLA-Cw6 + or HLA-Cw6 - patient subpopulations, showing high or low responses to secukinumab, were also analyzed. Methods : 417 SNPs were analyzed by Next-Generation Sequencing technology, in a cohort of 62 psoriatic patients and undergone secukinumab treatment. Univariate regression analysis was employed to examine the association between SNP and clinical response to secukinumab. Multivariate analysis was also performed to assess multivariate differences in SNP pattern of HLA-Cw6 + or HLA-Cw6 - patients showing high or low responses to secukinumab. Results : Eight SNPs in HLA-C and upstream region (rs13207315, rs6900444, rs12189871, rs12191877, rs4406273, and rs10484554), including HLA-Cw6 classical allele (rs1131118), and three in MICB-DT (rs9267325), DDX58 (rs34085293) and TYK2 (rs2304255) genes, associating with excellent response to secukinumab were identified. Importantly, rs34085293 or r s2304255 SNP status defined a subgroup of super-responder patients. We also found that HLA-Cw6 + and HLA-Cw6 - patients carried out specific patterns of SNPs associating with different responses to secukinumab. Conclusion : Assessment of HLA-Cw6 , together with other allelic variants of genes, could be helpful to define patients which better benefit from anti-IL-17 therapy. Abbreviations: PASI: Psoriasis Area and Severity Index; SNP: Single-Nucleotide Polymorphism Rs: Reference SNP; PASI75: 75% reduction in Psoriasis Area and Severity Index; PASI90: 90% reduction in Psoriasis Area and Severity Index; PASI100: 100% reduction in Psoriasis Area and Severity Index; NGS: Next-Generation Sequencing; OR: Odds Ratio; CAP: Canonical Analysis of Principal coordinates; BMI: Body Mass Index; LD: Linkage Disequilibrium.

Immunomodulation with anti-TNFα biologics is highly effective in the treatment of various immune-mediated inflammatory diseases, even though 2-5% of patients treated can develop paradoxical psoriasiform skin lesions. We recently analyzed three patients affected by severe hidradenite suppurativa (HS), and who developed paradoxical psoriasiform reactions following treatment with the TNF-α blockers. Psoriasiform skin reactions showed immunological and immunohistochemical features common to acute psoriasis, characterized by cellular players of innate immunity, such as plasmacytoid dendritic cells (pDC), neutrophils, mast cells, macrophages, and monocytes. In addition, IFN-β and IFN-α2a, two type I IFNs typical of early psoriasis, were highly expressed in paradoxical skin reactions. Concomitantly, the lymphotoxin (LT)-α and LT-β were overproduced. Detection of innate immunity cells was carried out on skin sections from HS patients, by immunohistochemistry (IHC) by using antibodies (Abs) against markers identifying specific leukocyte subpopulations. Anti-BDCA2, anti-CD15, anti-CD117, anti-CD68, anti-CD11c, and anti-CD3 Abs were employed to detect pDC, neutrophils, mast cells, macrophages, monocytes/dendritic cells, and T lymphocytes, respectively. In parallel, skin expression of the innate immunity soluble mediators IL-36γ, IFN-β, IFN-κ, LT-α and LT-β was also evaluated by IHC by using specific Abs. In this chapter, we describe the methods and protocols to detect the in situ expression and localization of innate immunity molecules and leukocyte subpopulations in skin lesions where inflammatory and psoriasiform reactions are evoked by anti-TNF- α biological therapy.