Obesity, Type 1 Diabetes, and Psoriasis: An Autoimmune Triple Flip.

Obesity, type 1 diabetes, and psoriasis are wide-ranging health problems. Genetics, epigenetics, and environmental factors together with immune disturbances are involved in these diseases. The white adipose tissue is an active endocrine organ, secreting a wide variety of soluble mediators called adipokines that have a central role in the relationship between adipose tissue and immune system. Inflammatory cytokines, including the IL-23/IL-17 and IL-18 axes, and microRNAs are involved in many processes, including immunity and inflammation, thus having a major role in the onset of these three diseases. In this review, we present an overview of the roles of adipokines, cytokines, and microRNAs in the pathogenesis and the progression of these three diseases.

FOXP3, ICOS and ICOSL gene polymorphisms in systemic sclerosis: FOXP3 rs2294020 is associated with disease progression in a female Italian population.

Systemic sclerosis (SSc), an autoimmune disorder, is characterized by vasculopathy, inflammation, progressive perivascular and interstitial fibrosis. Its pathogenesis is largely unknown, however strong evidences suggest that genetic predisposition may contribute to SSc development. Several gene polymorphisms involved in regulatory T cell function have been identified in many autoimmune diseases, including SSc. Moreover, dysregulation of co-stimulatory and/or co-inhibitory signals, including ICOS signalling, can lead to autoimmunity. The aim of the present study was to investigate the association of the FOXP3 rs2294020, ICOS rs6726035 and ICOSL rs378299 SNPs with both the susceptibility and the progression to SSc in an Italian case-series of patients. SNP genotyping results were successfully obtained from a total of 350 subjects including 166 individuals with SSc and 184 healthy controls. Although analysis tests did not show any significant associations between the SNPs under study and susceptibility to SSc, the occurrence of FOXP3 rs2294020 in female patients was associated with decreased time to progression from early to definite SSc (allelic model: HR=1.43; CI=1.03-1.99; p=0.03; dominant model: HR=1.54; CI=1.04-2.28; p=0.03). The inclusion of presence of ACA autoantibodies in the model did not significantly change the estimates. No conclusions can be drawn for the susceptibility to the disease or the time to progression in men due to the low statistical power. This study provides evidence of the association of rs2294020 with SSc evolution in female patients, modulating the time of progression from the diagnosis of early SSc to the diagnosis of definite SSc, while no effect on SSc susceptibility per se was found. rs2294020 may be considered a disease-modifying gene-variant rather than a disease-susceptibility SNP in SSc.

Association between rs2294020 in X-linked CCDC22 and susceptibility to autoimmune diseases with focus on systemic lupus erythematosus.

Autoimmune diseases often share common susceptibility genes. Most genetic variants associated with susceptibility to systemic lupus erythematosus are also associated with other autoimmune diseases. The X-linked variant rs2294020 is positioned in exon 7 of the CCDC22 gene. The encoded protein functions in the regulation of NF-κB, a master regulator in immune response. The aim of this study is to investigate whether the rs2294020 polymorphism may be a general susceptibility factor for autoimmunity. We evaluated case-control association between the occurrence of rs2294020 and different autoimmune diseases, including new data for systemic lupus erythematosus and previous genome-wide association studies (GWAS) (though most did not analyse the X chromosome) of psoriasis, celiac disease, Crohn's disease, ulcerative colitis, multiple sclerosis, vitiligo, type-1 diabetes, rheumatoid arthritis, and ankylosing spondylitis. Cases from patients affected by amyotrophic lateral sclerosis and type-2 diabetes were also included in the study. We detected nominal significant associations of rs2294020 with systemic lupus erythematosus (additive model test: p=0.01), vitiligo (p=0.016), psoriasis (p=0.038), and in only one of two studies of multiple sclerosis (p=0.03). Our results suggest that rs2294020 is associated with the risk of several autoimmune diseases in European populations, specifically with diseases that present themselves, among else, in the skin.

Effects of adalimumab, etanercept and ustekinumab on the expression of psoriasin (S100A7) in psoriatic skin.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. It is characterized by immune cell activation and altered epidermal differentiation. S100A7 (psoriasin) is overexpressed in psoriasis, suggesting a determinant role of this protein in inflammation and keratinocyte differentiation. OBJECTIVE: The purpose of this study was to investigate the expression of S100A7 in the skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. METHODS: S100A7 expression and distribution were analyzed by immunohistochemistry. RESULTS: S100A7, overexpressed in epidermal keratinocytes of psoriatic lesions, was downregulated, under the biological therapy with adalimumab, etanercept or ustekinumab, only in patients achieving a PASI score<15. CONCLUSIONS: Dysregulation of S100A7 may represent a non-negligible player in the maintenance of psoriasis and the relative epidermal changes. Blockage of S100A7 may represent an additional therapeutic approach in the treatment of psoriasis.

Biological therapy induces expression changes in Notch pathway in psoriasis.

Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.