Skin IL-17A and IFN-γ Production Correlate with Disease Severity in Patients with Psoriasis and Streptococcal Infection.

Psoriasis is a multisystemic inflammatory disorder mainly involving the skin and joints, whose etiopathogenesis is still not completely understood. An association with streptococcal throat infection has been suggested. We aim to investigate a correlation between IL-17A and IFN-γ production by T cells infiltrating skin lesions and PASI in 313 patients with psoriasis, compared with that in 252 healthy controls. The phenotype of ß-hemolytic Streptococci-specific infiltrating T cells in skin lesions was evaluated and characterized for IFN-γ, IL-4, and IL-17A production. In addition, PBMCs were tested by ELISpot for IFN-γ and IL-17A after streptococcal antigen exposure. A total of 64 of 313 (20.4%) patients with psoriasis had throat streptococcal infection. Of the 3,868 skin-derived T-cell clones from psoriasis with streptococcal infection, 66% proliferated in response to ß-hemolytic Streptococci antigens. Most ß-hemolytic Streptococci-specific T cells displayed T helper 17 and T helper 1 phenotypes. The levels of IFN-γ and IL-17A secreted by skin-infiltrating T cells of patients with psoriasis significantly correlated with PASI score. In ß-hemolytic Streptococci-positive patients, IFN-γ and IL-17A production by peripheral blood T cells after stimulation with streptococcal antigens was quantified by ELISpot. The results obtained may suggest ELISpot as a useful diagnostic tool to identify patients with psoriasis that may deserve antibiotic treatment.

Multicentric Reticulohistiocytosis Associated with an Early Form of Systemic Lupus Erythematosus: A Case Report of a Rare Disease, with Mini Review of the Literature.

Multicentric reticulohistiocytosis (MRH) is the most frequently described form of reticulohistiocytosis (RH), and it is classified as a class IIb non-Langerhans cell histiocytosis. It has been designated as multicentric, being characterized by multisystemic involvement. In fact, although mainly involving the skin, along with the joints, it is a systemic inflammatory condition potentially involving every internal organ. As MRH-related skin findings can mimic rheumatoid nodules or Gottron papules, the histopathology of the cutaneous lesions is often necessary for the correct diagnosis. Approximately one-third of MRH patients have confirmed concomitant autoimmune disorders. A wide variety of autoimmune disorders associated with the disease have been reported in the literature, suggesting immune dysfunction as a factor in the pathophysiology of MRH. A case of MRH associated with autoimmune manifestation is reported in the context of a mini review of the literature, with a focus on clinical presentation, treatments, and treatment outcomes. Moreover, eight cases of MRH associated with autoimmune diseases are briefly discussed.

An update on the management of refractory cutaneous lupus erythematosus.

Management of cutaneous lupus erythematosus (CLE) involves a combination of preventive measures, topical and systemic drugs, fairly similar for the different subtypes. Although guidelines exist, to date, no specific drugs have been specifically licensed for CLE. Antimalarials remain the first-line systemic treatment, but many patients do not respond, making refractory lupus a challenge for clinicians. The choice of alternative medication should be based on effectiveness, safety and cost. Most of the available drugs for CLE have been adapted from systemic lupus erythematosus (SLE) treatment but the existing literature is limited to small studies and evidence often lacks. As knowledge of pathogenesis of both CLE and SLE is improving, promising new therapies are emerging. In this review, we discuss the available medications, focusing on the novelties under development for CLE.

Tuscan consensus on the use of UVBnb phototherapy in the treatment of psoriasis.

Psoriasis (PSO) is traditionally defined as an immune-mediated, inflammatory dermatological disease characterized by a chronic-relapsing course and associated with multifactorial inheritance (genetic predisposition and influence of various environmental factors). Considered until recently a dermatological disease only, today PSO is correctly known as a systemic one because of the involvement of multiple organs with important impact on social life and relationships. PSO is found in the 0.3-4.6% of the world's population, while its prevalence in the Italian population is estimated at 2.8%. Therefore, if we consider that in Tuscany more than 100,000 people out of 3,672,202 suffer of psoriasis, it is of paramount importance to focus on a shared clinical and therapeutic protocol to manage the disease. With the aim of ensuring diagnostic-therapeutic suitability, high levels of care and standardization of treatment, a unique clinical-therapeutic management model has been developed and validated in Tuscany, involving all accredited regional dermatological centers. Among the possible alternatives to be implemented in the treatment of patients with mild, moderate-severe psoriasis, UVBnb phototherapy is widely used alone or in association with other systemic and non-systemic devices. Despite this, there is still no universally shared therapeutic protocol. In this context the CO.FO.TO working group (Consensus Fototerapia Toscana) is born with the aim of defining and validating the main guidelines in the use of phototherapy with UVBnb in psoriasis; the guidelines are based both on the real-life experience of the different centers of reference in the region and on the revision of the recent literature.

Treatment of psoriasis with topical agents: Recommendations from a Tuscany Consensus.

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real-life-based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real-life setting.

Homocysteine serum levels are increased and correlate with disease severity in patients with lupus erythematosus.

OBJECTIVES: To determine homocysteine (Hcy) serum levels in patients with cutaneous lupus erythematosus (CLE) and a possible correlation with the disease activity. METHODS: Ninety-three patients with LE and 30 healthy controls were included in the study. For each patient, disease activity was calculated and plasma levels of Hcy was measured by enzymatic colorimetric assay. RESULTS: Forty-six patients had chronic cutaneous LE (CCLE), 14 had LE tumidus (LET), 17 had subacute CLE (SCLE) and 16 had SLE. Median values [25°-75° percentile] were 7[4-9] for CCLE, 3.5[2.3-4.8] for LET, and 8[7-10] for SCLE; for SLE the RCLASI score was 7.5[4.8-13] and the SELENA/SLEDAI score was 10.5[9-13.3]. HHcy was present in 73.9% of patients with CCLE, 35.7% with LET, 82.4% with SCLE, 81.2% with SLE, 20% of healthy controls. Overall, patients with LE showed a higher median serum Hcy level than the control group (15[13-18.2] vs. 11[8.8-12.2], p<0.001). There was a significant correlation between Hcy serum levels and disease activity, both in patients with CLE and SLE. CONCLUSIONS: We demonstrated that Hcy levels were higher in patients with different forms of CLE and correlated with disease activity calculated by CLASI. Therefore, HHcy could be related to LE pathogenesis and might be a triggering factor in predisposed individuals.

Oral Curcumin (Meriva) Is Effective as an Adjuvant Treatment and Is Able to Reduce IL-22 Serum Levels in Patients with Psoriasis Vulgaris.

Curcumin is a complementary therapy that may be helpful for the treatment of psoriasis due to its anti-inflammatory, antiangiogenic, antioxidant, and antiproliferative effects. In the present study we performed a randomized, double-blind, placebo-controlled clinical trial to assess the effectiveness of a bioavailable oral curcumin in the treatment of psoriasis. Sixty-three patients with mild-to-moderate psoriasis vulgaris (PASI < 10) were randomly divided into two groups treated with topical steroids and Meriva, a commercially available lecithin based delivery system of curcumin, at 2 g per day (arm 1), or with topical steroids alone (arm 2), both for 12 weeks. At the beginning (T0) and at the end of the therapy (T12), clinical assessment and immunoenzymatic analysis of the serum levels of IL-17 and IL-22 were performed. At T12, both groups achieved a significant reduction of PASI values that, however, was higher in patients treated with both topical steroids and oral curcumin than in patients treated only with topical steroids. Moreover, IL-22 serum levels were significantly reduced in patients treated with oral curcumin. In conclusion, curcumin was demonstrated to be effective as an adjuvant therapy for the treatment of psoriasis vulgaris and to significantly reduce serum levels of IL-22.

Regulatory T cells as well as IL-10 are reduced in the skin of patients with dermatitis herpetiformis.

BACKGROUND: Dermatitis herpetiformis (DH) and celiac disease (CD) are considered as autoimmune diseases that share a defined trigger (gluten) and a common genetic background (HLA-DQ2/DQ8). However, the pathogenesis of DH is not fully understood and no data are available about the immune regulation in such a disease. OBJECTIVE: The aim of this study was to assess if alterations in the pattern of the immune response and, in particular, impairments of regulatory T (Tregs) cells may contribute to the phenotypic differences between DH and CD. METHODS: We investigated the presence of Tregs cell markers, in the skin, the duodenum and the blood of patients with DH by immunohistochemistry, confocal microscopy and flow cytometry. As controls, we included patients with bullous pemphigoid, patients with CD without skin lesions, as well as healthy subjects (HS). RESULTS: In the skin of DH patient, we found a significantly lower proportion of FOXP3(+) Tregs and IL-10(+) cells than in HS (p < 0.001 for both cell populations). In duodenal samples, no differences where found in the proportion of Tregs between patients with DH and patients with CD without skin manifestations. Finally, the frequency of CD25(bright)FOXP3(+) cells within the CD4(+) subset was significantly reduced in CD patients either with or without DH with respect to HS (p = 0.029 and p = 0.017, respectively). CONCLUSIONS: Our findings suggested that a reduction of Tregs may play a major role in the skin, leading to a defective suppressive function and thus to the development of the lesions. By contrast, no differences could be detected about Tregs between patients with DH and patients with CD in the duodenum, suggesting that the mechanisms of the intestinal damage are similar in both diseases.

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.

Naturally occurring regulatory T cells in mucous membrane pemphigoid lesions.

BACKGROUND: A growing body of evidence suggests the involvement of naturally occurring CD4+ CD25+ regulatory (nTreg) T cells in autoimmune diseases. OBJECTIVE: To evaluate the expression of some nTreg markers in mucous membrane pemphigoid (MMP) lesions. METHODS: Lesional biopsies from six patients with untreated MMP were stained immunohistochemically with anti-CD25, -FoxP3, -CD103, and -CCR5. RESULTS: All of the stained cells, both in MMP lesions and controls, were observed in the interstitial lamina propria or dermis. Positive cell counts of all the markers studied were low or very low in all sections, and significantly higher in MMP specimens than in healthy controls. CONCLUSIONS: The expression of CCR5 and CD103, which mediate recruitment into peripheral tissues, indicates that CD25+ FoxP3+ nTreg cells may be present in MMP lesions according to a specific homing. nTreg cells may contribute to directing the MMP immunoinflammation towards chronicity, and thus favor the cicatricial evolution of lesions.

Immunopathogenesis of folliculitis decalvans: clues in early lesions.

Folliculitis decalvans (FD) is a rare variant of primary cicatricial alopecia, for which the etiopathogenesis remains unclear. Our purpose was to evaluate whether certain immunologic mechanisms might have a significant role in the pathogenesis of FD. Lesional scalp biopsy specimens from 7 patients with FD, 7 with lichen planopilaris, and 4 with alopecia areata were studied immunohistochemically by using monoclonal antibodies to CD1a, CD3, CD4, CD8, CD20, CD25, HLA-DR, interleukin (IL)-1beta, IL-4, IL-8, interferon gamma, tumor necrosis factor alpha, basic fibroblast growth factor (b-FGF), transforming growth factor (TGF)-beta, endothelial leukocyte adhesion molecule 1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule. We showed that early FD lesions are characterized by an infiltration of activated T-helper cells, featuring mixed TH1/TH2 polarization. IL-8 and ICAM-1 may contribute to the infiltration of neutrophils, whereas b-FGF and TGF-beta may represent important mediators of the fibrosis that characterizes late-phase FD.

The CD40/CD40 ligand system in the skin of patients with subacute cutaneous lupus erythematosus.

OBJECTIVE: To investigate whether CD40 and CD40 ligand (CD40L) is expressed in the skin of patients with subacute cutaneous lupus erythematosus (SCLE). METHODS: Six female patients with SCLE were studied. Skin biopsies were obtained from lesional and healthy sunprotected skin. Frozen sections were stained immunohistochemically using monoclonal antibodies to CD4, CD40, and CD40L. As controls we used 5 patients with discoid LE (DLE), 5 with dermatomyositis (DM), 3 with lichen planus (LP), and 2 with erythema multiforme (EM), as well as the normal-appearing skin of 5 healthy volunteers. RESULTS: The CD40 was intensely expressed in all SCLE, DLE, and DM lesions, and only focally in healthy sunprotected skin specimens. The number of CD40+ cells in SCLE dermis was lower than in DLE, similar to that in DM, LP and EM, and higher than in SCLE sunprotected skin. CD40L+ cells infiltrated the SCLE, DLE, DM, LP, and EM lesional dermis, and were more numerous in SCLE lesional skin than in SCLE healthy sunprotected skin. CONCLUSION: We showed that the CD40/CD40L system may represent an important pathway of induction of SCLE lesions. The expression of such costimulatory system in healthy sunprotected skin also may signify that its abnormal activation is constitutive in SCLE, as previously observed in systemic LE.

FoxP3-expressing T regulatory cells in atopic dermatitis lesions.

Recently, studies were conducted to evaluate the impact of T regulatory (T regs) cells in the pathophysiology of atopic dermatitis (AD). The aim of this study was to investigate whether natural T regs are present in AD skin lesions. We performed skin biopsies in 12 adult patients affected by moderate-to-severe AD and 4 healthy volunteers. The specimens were stained immunohistochemically with anti-human CD25 and forkhead/winged helix transcription factor (FoxP3). Double immunostaining for CD25 and FoxP3 was performed also. CD25+ cells strongly infiltrated the perivascular and papillar dermis of all lesional specimens, and FoxP3+ cells were distributed in the perivascular and interstitial AD dermis, and some cells also infiltrated the dermoepidermal junction and the basal and suprabasal epidermal layers. All healthy skin specimens showed weak CD25 and FoxP3 stainings. Double immunostaining showed that CD25+ FoxP3+ cells were distributed in the perivascular, interstitial, and periadnexal dermis, and healthy skin specimens featured few CD25+ FoxP3+ cells scattered throughout the dermis. The past and present data show that an impaired function of natural T regs may not play a primary role in the pathophysiology of AD lesions.

The CD40/CD40 ligand system is involved in the pathogenesis of pemphigus.

The CD40/CD40 ligand (CD40L) system has never been investigated in autoimmune bullous diseases belonging to the pemphigus group in humans. Skin biopsy specimens from 21 patients with pemphigus vulgaris, 10 with pemphigus foliaceous and healthy volunteers were studied by immunohistochemistry (for CD40 and CD40L) and reversal transcriptase polymerase-chain reaction (for CD40L), while sera were analyzed by enzyme-linked immunosorbent assay for soluble CD40L. In all pemphigus specimens, the basal and suprabasal layers of the epidermis and perivascular infiltrating cells were CD40+. CD40L+ cells moderately infiltrated the perivascular and interstitial dermis of pemphigus specimens. CD40L mRNA was strongly evident in all pemphigus samples while no signal was detected in the healthy controls. The expression of soluble CD40L was significantly greater in pemphigus sera than in controls. We showed here that the CD40/CD40L system is upregulated both in lesional skin and in serum of patients with pemphigus.

Serum levels of the Th1 promoter IL-12 and the Th2 chemokine TARC are elevated in erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis and correlate with soluble Fas ligand expression. An immunoenzymatic study from the Italian Group of Immunopathology.

BACKGROUND: No data exist as to Th2 chemokines in erythema multiforme (EM) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). OBJECTIVE: To evaluate thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and regulated upon activation, normal T-lymphocyte-expressed and secreted chemokine (RANTES) expression in EM and SJS/TEN and to correlate with the serum levels of the Th1 promoter interleukin (IL)-12 and soluble Fas ligand (sFasL). MATERIALS AND METHODS: IL-12, sFasL, TARC, MDC and RANTES expression were analyzed by ELISA techniques in 31 untreated EM (n = 24) or SJS/TEN (n = 7) patients and in 28 healthy donors (HD). RESULTS: EM and SJS/TEN exhibited significantly higher levels of TARC, IL-12 and sFasL with respect to HD. TARC upregulation paralleled both the IL-12 (p = 0.0225) and sFasL increase (p = 0.0194). CONCLUSIONS: Our results support a role of TARC in the pathophysiology of EM/SJS/TEN and confirm the coexistence of a Th2 response in addition to the predominant Th1 profile.

The effects of tacrolimus ointment on regulatory T lymphocytes in atopic dermatitis.

Only very recently studies were conducted in order to evaluate the impact of regulatory T (Treg) cells in the pathophysiology of atopic dermatitis (AD). Nine adult patients with moderate-to-severe AD in riacutization period of a chronic disease were given tacrolimus ointment, while seven hydrocortisone butyrate ointment, that served as controls. We performed lesional-skin biopsies before and after treatment, that were stained immunohistochemically with monoclonal antibodies to CD4, CD25, forkhead/winged helix transcription factor (FoxP3), interleukin (IL)-10 and transforming growth factor (TGF)-beta. CD4+ cells were significantly reduced in post-treatment series. Tacrolimus treatment achieved a significant reduction of CD25+ cells. FoxP3+ cells were present in untreated AD lesions. Both treatments did not significantly modify the number of FoxP3+ cells. The number of IL-10+ cells increased in post-treatment series. Tacrolimus enhanced the production of TGF-beta, while hydrocortisone did not. Restoration of TGF-beta-producing Treg cells may represent another important pharmacodynamic effect of tacrolimus on AD.