Delphine Staumont-Sallé

Peroxisome proliferator-activated receptor α regulates skin inflammation and humoral response in atopic dermatitis

BACKGROUND The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. In addition to their regulatory role on lipid and glucose metabolism, they exert anti-inflammatory properties. In skin both PPAR-alpha and PPAR-beta/delta regulate keratinocyte proliferation/differentiation and contribute to wound healing. The 3 PPAR isoforms are expressed by several cell types recruited into the dermis during inflammation. OBJECTIVE We have investigated the role of PPAR-alpha in the regulation of atopic dermatitis (AD), a common skin inflammatory disease. METHODS We chose a mouse model of inflammatory dermatosis with immunologic features of AD and used epicutaneous sensitization with ovalbumin in the absence of adjuvant, which mimics the human pathology. RESULTS On antigen sensitization, PPAR-alpha-deficient mice display increased epidermal thickening, dermal recruitment of inflammatory cells, lung inflammation, airway hyperresponsiveness, and IgE and IgG2a production compared with their wild-type counterparts. Increased inflammation was correlated to an enhancement of TH2 and, to a greater extent, TH1 responses and to increased skin expression of nuclear factor kappaB. Interestingly, PPAR-alpha expression was decreased in eczematous skin from patients with AD compared with skin from nonatopic donors, suggesting that defective PPAR-alpha expression might contribute to the pathology. Topical application of WY14643, a specific PPAR-alpha agonist, significantly decreased antigen-induced skin inflammation in the AD model. CONCLUSION PPAR-alpha acts as a negative regulator of skin inflammation in AD.

Eosinophil-derived IFN-γ induces airway hyperresponsiveness and lung inflammation in the absence of lymphocytes

BACKGROUND Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. After IL-5- and eotaxin-mediated tissue recruitment, they release several cytotoxic and inflammatory mediators. However, their exact contribution to asthma remains controversial. Indeed, in human subjects anti-IL-5 treatment inhibits eosinophilia but not antigen-induced airway hyperresponsiveness (AHR). Likewise, lung fibrosis is abrogated in 2 strains of eosinophil-deficient mice, whereas AHR is inhibited in only one of them. Finally, eosinophils have been shown to attract T(H)2 lymphocytes at the inflammatory site. OBJECTIVE The ability of eosinophils to promote AHR and lung inflammation independently of lymphocytes was investigated. METHODS Adoptive transfers of resting or activated eosinophils from IL-5 transgenic mice were performed into naive BALB/c mice, mice with severe combined immunodeficiency, and IFN-gamma-deficient BALB/c recipients. RESULTS Adoptively transferred eosinophils induced lung inflammation, fibrosis, collagen deposition, and AHR not only in BALB/c mice but also in recipient mice with severe combined immunodeficiency. Surprisingly, IFN-gamma expression was increased in lungs from eosinophil-transferred animals. Furthermore, IFN-gamma neutralization in recipients partially inhibited eosinophil-induced AHR. Moreover, IFN-gamma-deficient eosinophils or eosinophils treated with a blocking anti-IFN-gamma receptor antibody failed to induce AHR in IFN-gamma-deficient recipients. Finally, in vitro and at low concentrations, IFN-gamma increased eosinophil peroxidase release, potentiated chemotaxis, and prolonged survival, suggesting the existence of an autocrine mechanism. CONCLUSIONS These results support the important and previously unsuspected contribution of eosinophils to lung inflammation independently of lymphocytes through production of IFN-gamma, the prototypical T(H)1 cytokine.

CD3 bright signals on γδ T cells identify IL-17A-producing Vγ6Vδ1 + T cells

Interleukin‐17A (IL‐17A) is a pro‐inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto‐immunity. γδ T cells are recognized as IL‐17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3bright γδ T‐cell subset with an effector memory phenotype to rapidly produce IL‐17A, but not interferon‐γ. CD3bright γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1+ T‐cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor‐related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL‐23 and NOD‐like receptor family, pyrin domain containing 3 (NLRP3)‐inflammasome‐dependent IL‐1β. Finally, we demonstrated that IL‐17‐producing CD3bright γδ T cells responded promptly and strongly to pneumococcal infection and during skin inflammation. Here, we propose a new way to specifically analyze IL‐17‐producing Vγ6/Vδ1+ T cells based on the level of CD3 signals. Using this gating strategy, our data reinforce the crucial role of this γδ T‐cell subset in respiratory and skin disorders.

The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3-CD4+ aberrant T-cell phenotype.

AbstractThe CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5–75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35 G/L (range, 0.01–28.3), with a clonal TCR&ggr;&dgr; rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 ± 5.1 years. All patients treated with oral corticosteroids (CS) (n = 18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up.In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.

Eosinophils and urticaria

Previously believed to have an exclusive role in the release of cytotoxic mediators in the defense against helminthic infections, eosinophils are now considered key players in inflammatory reaction and regulation of immune response. Through activation of a large variety of membrane receptors and production of various pharmacologically active mediators, eosinophils may exert a detrimental role in tissues in which they have been recruited and may contribute to the perennization of inflammatory processes. The crucial role of eosinophils has been documented in several eosinophilic skin diseases, such as hypereosinophilic syndrome and bullous pemphigoid, and the literature provides strong evidence for their role in urticaria. The aim of this article is to discuss the mechanisms of specific tissue recruitment of eosinophils, the factors of eosinophil activation, and the contribution of these cells to inflammation and immunoregulation in urticaria. Recent advances in the knowledge of eosinophils will certainly help toward developing new strategies for the management of antihistamines resistant to urticaria.

FcεRI and FcγRIII/CD16 Differentially Regulate Atopic Dermatitis in Mice

The high-affinity IgE receptor FcεRI and, in some models, the low-affinity IgG receptor FcγRIII/CD16 play an essential role in allergic diseases. In human skin, they are present on APCs and effector cells recruited into the inflamed dermis. FcRγ is a subunit shared, among other FcRs, by FcεRI and CD16 and is essential to their assembly and signal transduction. Using an experimental model reproducing some features of human atopic dermatitis and specific FcR-deficient mice, we have herein delineated the respective contribution of FcεRI and FcγRIII/CD16 to the pathology. We demonstrate that symptoms of atopic dermatitis are completely absent in FcRγ-deficient animals but only partially inhibited in either FcεRI- or FcγRIII/CD16-deficient animals. Absence or attenuation of the pathology is correlated to increased skin expression of regulatory IL-10 and Foxp3. While FcεRI controls both Th1 and Th2 skin response, mast cell recruitment into draining lymph nodes and IgE production, CD16 regulates only Th2 skin response, as well as T cell proliferation and IgG1 production. This isotype-specific regulation by the cognate FcR is associated to a differential regulation of IL-4 and IL-21 expression in the draining lymph nodes. FcεRI and CD16 thus contribute to atopic dermatitis but differentially regulate immune responses associated with the disease. Targeting both IgE/FcεRI and IgG/CD16 interactions might represent an efficient therapeutic strategy for allergic diseases.

Traitement du lupus érythémateux chronique par sulfasalazine (18 cas)

OBJECTIVE To evaluate the efficacy and the tolerance of sulfasalazine in the treatment of chronic lupus erythematosus (CLE). PATIENTS AND METHODS We prescribed sulfasalazine (2 g/d) for 18 patients with severe CLE, all of whom had contraindications for or treatment failure with antimalarial drugs and thalidomide. This study analyses their response to treatment, duration of therapy, reasons for stopping, adverse effects, and the influence of the N-acetyltransferase 2 (NAT2) phenotype. RESULTS We observed 10 complete and 3 partial responses, and 4 patients maintained complete response for at least 7 years. Eight patients experienced adverse effects, and 2 needed to stop treatment (because of photosensitization and development of antinuclear antibodies). All side effects occurred in the first 3 months of treatment. None of the 18 patients developed systemic lupus erythematosus. Of the 10 complete responders, 9 were rapid acetylators (RA), while 4 of the 5 who failed to respond were slow acetylators (SA). Leukopenia and photosensitization were observed in SA patients, while different side effects occurred in RA patients (headaches, diarrhea, moderate increase in liver enzymes and antinuclear antibodies). CONCLUSION These findings confirm our earlier reports and demonstrate that sulfasalazine can be used successfully to treat severe CLE. NAT2 genotyping before initiating treatment helps to identify potential responders and avoid side effects. In RA patients, sulfasalazine can be an alternative to thalidomide after antimalarial drugs, whereas in SA patients, it should remain a third-line treatment, to be used only after antimalarials and thalidomide.Resume Objectif Evaluer l’efficacite et la tolerance de la sulfasalazine dans le traitement du lupus erythemateux chronique (LEC). Methodes Des malades atteints d’un LEC severe, en echec ou ayant une contre-indication aux antipaludeens de synthese (APS) et au thalidomide, ont ete traites par sulfasalazine a la dose de 2 g/j. Nous avons analyse la reponse au traitement et sa duree, les motifs d’arret, les effets indesirables et le phenotype d’acetylation de la N-acetyltransferase 2 (NAT2). Resultats Dix-huit malades ont ete inclus depuis 1991. Dix malades ont obtenu une reponse complete (RC) et 3 une reponse partielle (RP). L’efficacite etait maintenue pendant au moins 7 ans chez 4 malades en RC. Huit malades ont eu des effets secondaires, tous survenant dans les 3 premiers mois, dont 2 ont necessite un arret definitif du traitement (erytheme photodistribue et apparition d’autoanticorps) et 2 un arret transitoire (cytolyse hepatique et leucopenie moderees). Aucune complication tardive ni evolution vers un lupus systemique n’ont ete constatees. Neuf malades en RC sur 10 etaient acetyleurs rapides (AR) pour la NAT2 et 4 des 5 malades en echec etaient acetyleurs lents (AL). Les episodes de leucopenie et l’erytheme photodistribue ont ete observes chez des sujets AL tandis que les effets digestifs, les cephalees, la cytolyse hepatique et l’apparition d’anticorps antinucleaires l’ont ete chez des sujets AR. Conclusion Bien qu’il s’agisse d’une indication hors de l’autorisation de mise sur le marche, la sulfasalazine est une alternative interessante dans le traitement du LEC severe. Chez les sujets AR, la sulfasalazine peut etre une alternative au thalidomide apres les APS, alors que chez les sujets AL, elle doit rester un traitement de troisieme ligne apres les APS et le thalidomide.

Efficacy of combining pulse corticotherapy and methotrexate in alopecia areata: Real-life evaluation

Dear Editor, Treatment of severe alopecia areata (AA) is challenging. In 2012, Droitcourt et al. published a retrospective study on the efficacy of high-dose pulse corticosteroid (PCT) combined with methotrexate (MTX) in 50% of patients (10/20) with AA. We have previously reported a significant response (≥50% hair regrowth) obtained after PCT in 30% of patients with multiplepatch AA and in less than 25% of patients with alopecia totalis or universalis. Here, we describe a monocentric uncontrolled prospective study on AA patients treated with i.v. PCT alone or in combination with MTX between June 2012 and April 2015. Our objective in this study was to evaluate in our daily practise the efficacy of PCT, followed by, in the majority of patients, low dose of oral MTX in treating AA. The study included 20 patients, aged 21–72 years, who had recent-onset AA (actual hair loss noted during the past 12 months), and no contraindications to systemic corticotherapy or MTX. Five patients had multiple-patch AA, nine had ophiasic type, two had AA totalis and four had alopecia universalis. Only patients who attained 50% or more hair regrowth during the treatment interval were considered responders (3/5). All patients received i.v. methylprednisolone at 500 mg daily for 3 days consecutively. This treatment was repeated monthly for 3 months. At the end of the third cycle, the patients were informed about the possible beneficial effect of MTX in treating AA. Those who accepted were started on oral treatment with MTX at a dose of 10 mg/week, which was progressively increased to 20 mg/week over the next 6 months. At the 6-month follow-up visit, we observed in the MTX group that nine of 14 patients had significant regrowth of more than 50% (multiple-patch AA, 4/4; ophiasis type, 2/4; alopecia totalis, 2/2; and alopecia universalis, 3/ 4). This was in contrast to the other group where only two patients among six were responders (both patients had multiple-patch AA type) (Table 1). We also assessed the impact of this treatment on the patients’ quality of life. The initial Dermatology Life Quality Index (DLQI) before PCT ranged from 1/30 to 18/30 (average, 10.5/30). At the time of the third PCT cycle,

Piel y eosinofilia

El eosinofilo es una celula citotoxica y proinflamatoria, implicada en la regulacion de la respuesta inmunitaria. Su distribucion es fundamentalmente tisular. Se encuentra sobre todo en las zonas de contacto con el entorno, y en especial, en la piel. Aunque las propiedades del eosinofilo pueden resultar beneficiosas (enfermedades parasitarias y neoplasicas), su acumulacion en la piel es casi siempre perjudicial. Su papel patogeno esta bien establecido en algunas dermatosis alergicas (dermatitis atopica, urticaria) y autoinmunitarias (penfigoide). En estas afecciones, el eosinofilo es una de las celulas efectoras, que cuando se activan y liberan mediadores pre y neoformados inducen la formacion de las lesiones tisulares y la persistencia de la reaccion inflamatoria. Recientemente ha surgido el concepto de «dermatosis eosinofilicas». Se trata de un grupo heterogeneo de dermatosis que no pertenecen a ningun cuadro nosologico conocido, para las que la eosinofilia tisular, y a veces periferica, constituye el principal criterio diagnostico. Por ultimo, la frecuencia y la diversidad de los signos cutaneos observados en el sindrome hipereosinofilico justifican que se trate en este articulo de esta enfermedad sistemica.