Laurence Feldmeyer

The Inflammasome Mediates UVB-Induced Activation and Secretion of Interleukin-1β by Keratinocytes

It has long been known that human keratinocytes are a potent source of the proinflammatory cytokines proIL-1alpha and -1beta[1], which are activated and released in response to UV irradiation [2]. However, the intracellular pathways, which regulate maturation and secretion of IL-1 in keratinocytes, are unknown. Here we show that the UVB-mediated enhancement of cytoplasmic Ca(2+) is required for activation of the IL-1beta-converting enzyme caspase-1 by the inflammasome, a multiprotein innate immune complex [3, 4]. Caspase-1 in turn activates proIL-1beta, and keratinocytes secrete the cytokine as well as inflammasome components. These results demonstrate the presence of a proIL-1beta-processing inflammasome in nonprofessional immune cells and the necessity of inflammasome components for the UVB-induced secretion of IL-1beta. This supports the concept that keratinocytes are important immuno-competent cells under physiological and pathological conditions [5].

Interleukin-1, inflammasomes and the skin

Interleukin (IL)-1 is a highly active and pleiotropic pro-inflammatory cytokine. Recent data impressively demonstrate that activating mutations in a human gene involved in proIL-1beta maturation or loss-of-function mutations in the gene encoding IL-1 receptor antagonist (IL-1Ra) cause excessive activity of this cytokine. This can result in life-threatening systemic and local inflammation, particularly in the skin. Interestingly, experiments in mice revealed that epidermal keratinocytes can secrete large amounts of IL-1alpha, which induces an inflammatory response in the skin. Secretion of IL-1 requires caspase-1 activity, and activation of the protease takes place in innate immune complexes, called inflammasomes. As keratinocytes express and activate caspase-1 in an inflammasome-dependent manner, these epithelial cells might be critically involved in the innate immunity of the skin. In this review we summarize the current knowledge on IL-1 and inflammasomes in the skin, particularly their involvement in skin homeostasis and disease. In addition, we discuss the hypothesis that keratinocytes are not only static bricks of the epidermal wall, but immunologically active cells critically involved in different (auto)-inflammatory (skin) diseases.

IL-1β drives inflammatory responses to propionibacterium acnes in vitro and in vivo.

Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1β mRNA and the active processed form of IL-1β are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1β processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1β and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1β as possible therapeutic targets in acne.

Not All Intravenous Immunoglobulin Preparations are Equally Well Tolerated

Intravenous immunoglobulin (IVIG) is used for many indications beyond the original substitution in primary antibody deficiency. Whereas many reports mention adverse reactions, no comparative data exist concerning the incidence of side-effects among the different brands of IVIG. We describe here our experience with the use of different IVIG formulations and their tolerability in a select cohort of 40 patients. The IVIG dose ranged from 0.4 to 3 g/kg/day and was given for 1-2742 days. Fourteen patients (35%) experienced mild to severe adverse reactions during or within 48 h of administration of standard IVIG preparation, which did not recur after switching to an alternative preparation. Adverse reactions included headache, fever, chills, nausea, emesis, hypotension and muscle cramps. One patient experienced a severe adverse reaction; he had a 3-day headache following IVIG infusion. Among the 16 patients who received alternative preparation initially, none experienced adverse reactions. In conclusion, this study shows that IVIG preparations are not all equally well tolerated in patients. The data suggest that, perhaps to a comparable extent to the preparation itself, the infusion rate has a major effect. If a reduction in the infusion rate does not minimize side-effects, one should consider switching the IVIG formulation.

Propionibacterium acnes promotes Th17 and Th17/Th1 responses in acne patients

Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. Although the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4(+) T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a T helper type 17 (Th17)-mediated disease. In line with this, we show in this work that, in addition to IL-17A, both Th1 and Th17 effector cytokines, transcription factors, and chemokine receptors are strongly upregulated in acne lesions. Furthermore, we found that, in addition to Th17, P. acnes can promote mixed Th17/Th1 responses by inducing the concomitant secretion of IL-17A and IFN-γ from specific CD4(+) T cells in vitro. Finally, we show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as, to our knowledge, a previously unreported CD4(+) subpopulation involved in inflammatory acne.

Mammalian target of rapamycin (mTOR) inhibitors slow skin carcinogenesis, but impair wound healing.

Summary Background  Recent studies suggest that patients on mammalian target of rapamycin (mTOR) inhibitors experience a reduction in cutaneous carcinogenesis by an estimated 50% or more compared with calcineurin inhibitors. While randomized trials are running, organ transplant recipients are frequently switched from calcineurin inhibitors to mTOR inhibitors when cutaneous carcinogenesis increases.

Malassezia yeasts activate the NLRP3 inflammasome in antigen-presenting cells via Syk-kinase signalling

Although being a normal part of the skin flora, yeasts of the genus Malassezia are associated with several common dermatologic conditions including pityriasis versicolour, seborrhoeic dermatitis (SD), folliculitis, atopic eczema/dermatitis (AE/AD) and dandruff. While Malassezia spp. are aetiological agents of pityriasis versicolour, a causal role of Malassezia spp. in AE/AD and SD remains to be established. Previous reports have shown that fungi such as Candida albicans and Aspergillus fumigatus are able to efficiently activate the NLRP3 inflammasome leading to robust secretion of the pro‐inflammatory cytokine IL‐1β. To date, innate immune responses to Malassezia spp. are not well characterized. Here, we show that different Malassezia species could induce NLRP3 inflammasome activation and subsequent IL‐1β secretion in human antigen‐presenting cells. In contrast, keratinocytes were not able to secrete IL‐1β when exposed to Malassezia spp. Moreover, we demonstrate that IL‐1β secretion in antigen‐presenting cells was dependent on Syk‐kinase signalling. Our results identify Malassezia spp. as potential strong inducers of pro‐inflammatory responses when taken up by antigen‐presenting cells and identify C‐type lectin receptors and the NLRP3 inflammasome as crucial actors in this process.

Clinical variation in X-linked dominant chondrodysplasia punctata (X-linked dominant ichthyosis)

Chondrodysplasia punctata is a heterogeneous group of skeletal dysplasias characterized by an anomaly of enchondral bone formation causing stippled calcifications that can be visualized radiologically or sonographically. The X-linked dominant form (Conradi–Hünermann–Happle syndrome, CDPX2) occurs almost exclusively in women and is characterized by asymmetrical limb shortening and cataract as well as a transitory congenital dermatosis presenting as generalized erythroderma with segmental lesions of prominent follicular keratosis. Later, this congenital dermatosis regresses and leaves behind patchy or segmental atrophic skin lesions, mainly follicular atrophoderma. Scarring alopecia is often present. A diffuse, moderate ichthyotic scaling may persist. The EBP gene, coding for a D,D-sterol isomerase involved in cholesterol biosynthesis, was identified as the gene mutated in CDPX2. To date, at least 45 disease-causing mutations have been reported. The mutation spectrum included 15 nonsense, 16 missense, two deletion, seven frameshift, two splice-site and three intronic mutations, distributed among the five exons as well as introns of the EBP gene, with a majority of mutations encountered in exons 2 and 4. Here we discuss the molecular and clinical correlation of three cases of CDPX2, including a new mutation.

Treatment of vulvar Paget disease with topical imiquimod: a case report and review of the literature

BACKGROUND Extramammary Pagets disease is a cutaneous neoplasm that presents as erythematous crusted patches and plaques reminiscent of contact dermatitis or inverse psoriasis that can be a challenge to treat in a tissue-sparing manner. The most commonly involved site for this rare disorder is the anogenital region. Surgery is considered as the gold standard therapy. In the last years, the topical use of imiquimod cream in the treatment of this condition has been reported. MAIN OBSERVATIONS We present a case of a 59-year-old woman with primary extramammary Pagets disease of the vulva, in which a conservative approach to therapy was desired, and who underwent complete and stable remission with imiquimod cream. We also review the previous reports of patients with extramammary Pagets disease treated with imiquimod cream. CONCLUSIONS Imiquimod therapy may be an alternative for primary as well as recurring extramammary Pagets disease. Treatment-associated morbidity is minimal compared with other therapies, such as surgery which may be debilitating.

Methylaminolaevulinic Acid Photodynamic Therapy in the Treatment of Erythroplasia of Queyrat

Background: Erythroplasia of Queyrat (EQ) is an intra-epithelial carcinoma of the penis. Progression to invasive carcinoma may occur. Its cause is unknown but some evidence suggests infection with human papillomavirus in the pathogenesis of EQ; however, recent data do not confirm this. Therapy is difficult and associated with important recurrence rates. Photodynamic therapy (PDT) employs a photosensitizer excited by visible light. The resulting photodynamic reaction selectively destroys atypical cells. Only few reports exist on the use of topical PDT in the treatment of EQ. Objective: We report 11 cases of EQ treated by topical methylaminolaevulinic acid (MAL) PDT. Results: Out of 11 male patients withEQ treated by topical MAL-PDT, 3 achieved complete remission sustained for 24 and 51 months and 4 a partial remission sustained for 2–45 months with a follow-up period of 4–45 months (1 patient lost to follow-up); surprisingly, 2 of the 4 patients with partial remission presented a complete remission after 20 and 45 months of follow-up, respectively, without further therapy. Four patients showed progression of the disease. Conclusion: Whereas topical MAL-PDT offers the advantages of tumour specificity, preservation of function and a good cosmetic result, side effects may cause treatment discontinuation in some cases. Treatment of EQ with PDT may represent a valuable option in selected cases, but our data do not allow considering it as a first-line therapeutic option.