Julia Doveikis

Severity of Psoriasis Associates With Aortic Vascular Inflammation Detected by FDG PET/CT and Neutrophil Activation in a Prospective Observational Study

Objective—To understand whether directly measured psoriasis severity is associated with vascular inflammation assessed by 18F-fluorodeoxyglucose positron emission tomography computed tomography. Approach—In-depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index. Vascular inflammation was measured using average aortic target-to-background ratio using 18F-fluorodeoxyglucose positron emission tomography computed tomography. Results—Both the psoriasis patients (28 men and 32 women, mean age 47 years) and controls (13 men and 7 women, mean age 41 years) were young with low cardiovascular risk. Psoriasis area severity index scores (median 5.4; interquartile range 2.8–8.3) were consistent with mild-to-moderate skin disease severity. Increasing psoriasis area severity index score was associated with an increase in aortic target-to-background ratio (&bgr;=0.41, P=0.001), an association that changed little after adjustment for age, sex, and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis, 3.7±1.2 versus 2.9±1.2; P=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 versus 195.4±157.8 ng/mL; P<0.01) and neutrophil elastase-1 (43.0±2.4 versus 30.8±6.7 ng/mL; P<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein was related to both psoriasis skin disease severity (&bgr;=0.53; P=0.02) and vascular inflammation (&bgr;=0.48; P=0.02). Conclusions—Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 was related to both skin disease severity and vascular inflammation.

Psoriasis is associated with decreased plasma adiponectin levels independently of cardiometabolic risk factors

Psoriasis is an inflammatory skin disease that may be associated with an adverse cardiometabolic profile including modulated plasma adiponectin and leptin levels. Whether these levels are independent of cardiometabolic risk factors, which are also prevalent in psoriasis, is not known.

IL-17A Production in Human Psoriatic Blood and Lesions by CD146+ T Cells

To the Editor: CD146, also called melanoma cell adhesion molecule (MCAM), is a cell surface adhesion molecule on endothelial cells involved in homotypic and heterotypic cell interactions (Bardin et al, 2001). CD146 binding in endothelial cells (ECs) leads to a change in cellular permeability, actin distribution and redistribution of NF-kappa B p50 to the nucleus. CD146 has been shown to be present on 1–3% of circulating peripheral blood T cells in healthy humans (Elshal et al, 2005). CD146+ T cells have an effector memory phenotype, demonstrate up-regulation of a cluster of genes involved with adhesion, migration, homing, and inflammation, and have enhanced binding to endothelial monolayers in vitro (Elshal et al, 2007). These features of the CD146+ T cells in the peripheral circulation have led to speculation that these represent a small pool of cells primed for extravasation and/or homing of activated T cells (Elshal et al, 2007, Guezguez et al, 2007) in response to inflammatory stimuli. Circulating CD146+ T cells are elevated in several inflammatory autoimmune diseases such as sarcoidosis, inflammatory bowel disease, multiple sclerosis, connective tissue disease, and Behcets disease and produce IL-17 (Dagur et al, 2011, Dagur et al, 2010, LaRochelle et al, 2012). Whether these cells play a role at the site of active inflammation in these diseases remains unknown. Psoriasis, which is associated with increased vascular inflammation (Mehta et al, 2009) and access to both peripheral blood and the disease target tissue (e.g. skin), is ideal to study CD146+ T cell phenotype and function in an inflammatory condition. Here we present findings from a well-characterized patient population with psoriasis using peripheral blood samples and skin biopsies from psoriatic lesions and uninvolved skin. Forty-seven patients with psoriasis and sixty-seven healthy controls were included in this study. Diagnosis of psoriasis was confirmed by a dermatologist and severity was measured by percentage of body surface area (BSA) involved and the validated Psoriasis Area and Severity Index (PASI). Donor demographics and characteristics are presented in Supplemental Table 1. Skin biopsies were isolated from a representative psoriatic target lesion (6 mm) and are identified as lesional psoriatic skin. Non-lesional skin biopsies were obtained from a similar body area at least 10cm away from the nearest psoriasis skin lesion. Frozen sections were obtained from skin lesions for immunofluorescence studies and all patients provided written consent in as part of an IRB-approved study (NCT01778569). Venous blood was collected in sodium heparin vacutainers (Becton Dickinson (BD), San Jose, CA). Cells were stained and flow cytometric analysis was performed as previously described (6). Skin biopsies were digested in Collagenase IV (GIBCO BRL # 17104-019) at 5 mg/ml in RPMI 1640 for 45 min, stained, and then sorted in the same manner as peripheral blood. The following antibodies used for staining were obtained from BD: CD3, CD4, CD8, CD33, CD14, CD19, CD45, CD45-RO, CD146 (Clone P1H12). Anti-IL-17A (clone ebio64DEC17) was purchased from eBiosciences. Immunophenotyping results are expressed as means and standard errors of the mean. RNA was isolated from sorted CD146+ or CD146- T cell subpopulations using RNAquos Micro kits (Ambion) and real time PCR (QRTPCR) was performed using a 7900-sequence detector (PE-Applied Biosystems, Norwalk, CT). Data from a single specimen were considered one experiment (n). A p-value <0.05 was considered statistically significant. Statistical analysis was performed using STATA version 12.0 (StataCorp, College Station, TX, USA). To determine whether CD146+ T cells are prevalent in patients with a Th17 disorder, immunophenotyping was performed on fresh peripheral blood from patients with psoriasis. Psoriasis patients showed a significant elevation of circulating CD3+CD146+ T cells compared to healthy adults (3.91 ± 0.37% vs 2.96 ± 0.19% respectively, p =0.03) (Figure 1A). Increased CD146 expression reached statistical significance with the circulating CD4+ T cells (5.50 +/- 0.413% in PSO vs 3.55 +/− 0.213% respectively, p <0.0001), (Figure 1B), but not the CD3+CD8+CD146+ T cells (2.75 +/− 0.373% in PSO vs 2.30 +/− 0.216% respectively) (Figure 1C). CD146+ T cells were abundant within lesional skin biopsies, representing roughly 1/3 of the total CD4+ T and CD8+ T cell populations (Figures 1B, 1C). Immunofluorescence of frozen sections confirmed CD146+ T cells in lesional skin biopsies (Figure 1D). Lymphocytes, including CD146+ T cells, were rare in biopsies of non-lesional, unaffected skin from psoriasis patients. Figure 1 CD146+ T cells are significantly elevated in patients with psoriasis in the circulation and at the site of inflammation. Comparative frequencies (Mean +/− SEM) of: To determine IL-17A production from CD146- and CD146+ subsets of psoriatic T cells, cell suspensions from peripheral blood and lesional skin were stimulated for 3 hours with PMA and ionomycin, stained for cell surface markers, and then for intracellular IL-17A. CD146+ cells were the primary producers of IL-17A in lesional skin for both CD4+ (67.8± 9.5% p<0.005) and CD8+ (70.8± 11.4%, p<0.004) T cells (Figure 2A). In contrast, CD146+ cells accounted for ~20% of IL-17A producers in peripheral blood from both healthy adults and psoriatics. mRNA levels of IL-17A, RORc2, and CD146 were increased among unstimulated CD146+ T cells compared to CD146- cells, in both the blood and lesional skin, with a greater elevation in the lesions (Figure 2B). Figure 2 Figure 2A. Percentages of IL-17A -producing T cells which are CD146 positive. The T cells and T cell subsets secreting IL-17A were gated first and then the proportion of these cells expressing CD146 were determined. While previous studies have demonstrated increased circulating Th17 cells in psoriasis (Kagami et al, 2010), in this study we demonstrate that CD146+ T cells produce the majority of IL-17A at the active site of inflammation in psoriasis. Our study confirms previous reports of IL-17A production by CD146+ T cells in both healthy individuals and in patients with various autoimmune disorders and adds to those results by: 1) extending these findings to psoriasis; and 2) demonstrating that CD146+ T cells are important mediators of inflammation at the active site of disease. These findings suggest that CD146+ T cells in the circulation may represent a pool of cells with both the means to extravasate to the site of inflammation (via CD146 expression), and to mediate inflammation at a specific site. Limitations include analyzing patients with a variety of topical and systemic therapy and only studying patients with mild to moderate psoriasis. Previous studies examining this cell type in autoimmune diseases have been limited by not examining cells at the active site of inflammation – a hindrance overcome in the current work.

VASCULAR INFLAMMATION IN THE AORTA IS RELATED TO CORONARY PLAQUE BURDEN IN PSORIASIS

Background: Psoriasis, a chronic inflammatory skin disease, is associated with increased vascular inflammation (VI) by [18]-fluorodeoxyglucose (FDG) PET/CT. Psoriasis also increases the risk of myocardial infarction, which may be due to inflammatory, lipidrich coronary plaque. Whether VI in the aorta is related to coronary plaque burden is not known and is a critical step in understanding local effects of vascular inflammation. Therefore, we examined the relationship between VI by FDG PET/CT and coronary plaque burden by quantitative CT angiography in a well-phenotyped psoriasis cohort.