The role of etanercept on the expression of markers of T helper 17 cells and their precursors in skin lesions of patients with psoriasis vulgaris

Very recently, it has been demonstrated that CD161, retinoic acid-related orphan receptor gamma-t (RORgamma-t) and CC-chemokin receptor 6 (CCR6) can be considered good surface markers to detect T helper 17 cells and their precursors, T cell populations that are considered to play an important role in the pathogenesis of psoriasis. In the present study, we evaluate the clinical involvement by calculating the PASI score and the number of CD4+, CD161+, RORgammat+ and CCR6+ cells before and after a 12-week course with etanercept or acitretin in patients with moderate-to-severe, plaque-type psoriasis vulgaris. Ten patients were given etanercept 50 mg twice weekly and 10 patients acitretin 0.4 mg/kg per day, both for 12 weeks. At the baseline and at the end of the treatment PASI was calculated, and skin biopsies were taken to evaluate the expression of CD4, CD161, RORgammat and CCR6 by immunohistochemistry. As controls, 10 patients with atopic dermatitis (AD) were included in the study. After 12 weeks, PASI was significantly lower than at the baseline for both groups. However, etanercept-treated patients showed lower PASI than acitretin-treated ones. While CD4+ cell numbers were similar in both diseases, all the other markers, that are considered more specific for Th17 cells and their precursors, were more expressed in psoriasis than in AD. Furthermore, only etanercept, but not acitretin, was able to significantly reduce CD161+, RORgammat+ and CCR6+ cells in skin lesions of patients with psoriasis. Our study provides further evidence of the role of Th17 pathway in the pathogenesis of psoriasis. Furthermore, our findings suggest that etanercept is able to downregulate the expression of the recently recognized markers of Th17 cells and their precursors CD161, RORgammat and CCR6, while acitretin is not. This activity on the Th17 lineage may contribute to the efficacy of etanercept in the treatment of psoriasis.     

Automatic generation of glomerular capillary topological organization.

Glomerular structural changes are conventionally investigated by optical or electron microscopy on two-dimensional (2D) sections. To understand the relationship between functional and structural changes of glomerular capillary networks in more detail, three-dimensional (3D) investigation of the capillary tufts is required. Since confocal microscopy and scanning electron microscopy cannot completely show the 3D topological organization of the capillary tuft, we have developed an automatic method to obtain a 3D model of the glomerular capillary lumen structure and to derive its topological organization. Serial semithin sections of a glomerular tuft, from rat kidney tissue, were digitized at high resolution. Capillary lumens were digitally outlined and segmented images were automatically aligned. A 3D model of the capillary tuft was automatically generated using the Visualization Toolkit library and the Marching Cubes algorithm. We then developed an original algorithm for automatic 3D skeletonization of capillary lumen volume to identify capillary segments and bifurcations and to obtain the topological organization of the network and geometric parameters of capillary segments (length, radius, and spatial configuration). Capillary segment connectivity was graphically presented in a 2D layout with an automatic procedure, revealing the lobular organization of the network. This technique, successfully applied to serial sections of a glomerular capillary, can be used to study a population of glomerular capillaries to disclose the structural effects of pathological conditions. The methodology can be extended to other vascular structures, such as the microcirculation of neoplastic tissues.     

Expression of cytokines,chemokines and other effector molecules in two prototypic autoinflammatory skin diseases,pyoderma gangrenosum and Sweet's syndrome

Pyoderma gangrenosum (PG) and Sweet''s syndrome (SS) are two inflammatory skin diseases presenting with painful ulcers and erythematous plaques, respectively; both disorders have a debilitating clinical behaviour and PG is potentially life-threatening. Recently, PG and SS have been included among the autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. However, an autoinflammatory pattern clearly supporting this inclusion has never been demonstrated. We studied 16 patients with PG, six with SS and six controls, evaluating, using a sandwich-based protein antibody array method, the expression profile of inflammatory effector molecules in PG, SS and normal skin. The expressions of interleukin (IL)-1 beta and its receptor I were significantly higher in PG (P = 0·0001 for both) and SS (P = 0·004–0·040) than in controls. In PG, chemokines such as IL-8 (P = 0·0001), chemokine (C-X-C motif) ligand (CXCL) 1/2/3 (P = 0·002), CXCL 16 (P = 0·003) and regulated upon activation normal T cell expressed and secreted (RANTES) (P = 0·005) were over-expressed. In SS, IL-8 (P = 0·018), CXCL 1/2/3 (P = 0·006) and CXCL 16 (P = 0·036) but not RANTES were over-expressed, suggesting that chemokine-mediated signals are lower than in PG. Fas/Fas ligand and CD40/CD40 ligand systems were over-expressed in PG (P = 0·0001 for Fas, P = 0·009 for Fas ligand, P = 0·012 for CD40, P = 0·0001 for CD40 ligand), contributing to tissue damage and inflammation, while their role seems to be less significant in SS. Over-expression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that PG and SS are autoinflammatory diseases. The differences in expression profile of inflammatory effectors between these two disorders may explain the stronger local aggressiveness in PG than SS.     

The last word on the so-called 'Rowell's syndrome'?

To date, 71 patients having the so-called 'Rowell's syndrome' (RS) have been reported in the literature. However, most of them did not show all the clinical and serological features first described by Rowell and co-workers in 1963. Moreover, since then, subacute cutaneous lupus erythematosus (SCLE) has been identified and the diagnostic criteria as well as the clinical features of erythema multiforme (EM) defined. Accordingly several authors have questioned the existence of RS over the past years. In the present paper, the main clinical, histopathological and immunopathological features of both SCLE and EM are described and all of the cases of RS reported in the literature are also reviewed in depth. A real association between discoid LE and EM was present only in a minority of cases and could be considered a mere coincidence. As for other associations, e.g. those between CLE and lichen planus or psoriasis, the coexistence of CLE and EM does not justify the framing of a separate syndrome as suggested by Rowell et al.     

Etanercept Downregulates the Th17 Pathway and Decreases the IL-17+/IL-10+ Cell Ratio in Patients with Psoriasis Vulgaris

Purpose

To evaluate circulating and lesional CD4⁺ and CD8⁺ cells belonging to Th1, Th2, and Th17 patterns as well as IL-10⁺ cells before and after a 12-week lasting course with etanercept or acitretin in patients with psoriasis.

Methods

15 patients were given etanercept 50 mg twice weekly and 15 patients acitretin 0,4 mg/kg/day, both for 12 weeks. At the baseline and at the end of the treatment, blood and skin samples were taken to investigate IL-4, IL-8, IL-10, IL-17, and IFN-γ-producing CD4⁺ and CD8⁺ cells. As controls, 10 healthy controls (HC) and 6 atopic dermatitis (AD) patients were included into the study.

Results

Psoriasis patients showed augmented IL-17- and IL-8-producing CD4⁺ cells in the blood than HC and AD patients. In the skin lesions, IL-17⁺ cells were more represented in psoriasis than in AD, while the number of IL-4-producing cells was reduced in psoriasis patients than in AD ones. Etanercept was able to significantly reduce the number of IL-17- and IL-8-producing CD4⁺ and CD8⁺ cells both in skin and blood, as well as to augment the proportion of IL-10-producing CD4⁺ cells in the skin of psoriatic patients, while acitretin was not.

Conclusions

Our results confirmed the role of Th17 cells in the pathogenesis of psoriasis. Etanercept, but not acitretin, was able to downregulate the Th17 pathway and to increase the percentages of IL-10-producing cells in the skin.