Propranolol administered orally at 2 to 3 mg/kg per day has a consistent, rapid, therapeutic effect, leading to considerable shortening of the natural course of IHs, with good clinical tolerance.

Schnitzler's syndrome is characterized by recurrent urticarial rash and monoclonal gammopathy, associated with clinical and biological signs of inflammation and a long-term risk of AA amyloidosis and overt lymphoproliferation. An extensive literature review was performed, and the following questions were addressed during an expert meeting: In whom should Schnitzler

We here distinguish three different clinical presentations of BPDCN. A nodular pattern is a more common feature than the originally reported 'bruise-like' pattern. Despite the fact that BPDCN may initially appear as a localized skin tumour, aggressive management including allogeneic bone marrow transplantation should be considered immediately, as it is currently the only option associated with long-term survival.

The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections.In many aspects, the Schnitzler syndrome resembles the genetically determined auto-inflammatory syndromes involving activating mutations of the NLRP3 inflammasome. This latter point and its consequences will be addressed.

Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) represents the malignant counterpart derived from plasmacytoid dendritic cells. This rare entity is usually revealed and diagnosed on cutaneous lesions associated or not with a leukaemic component. The prognosis associated with BPDCN is very poor. Objectives To perform a retrospective review of BPDCN cases registered in the French Study Group on Cutaneous Lymphoma database from June 1995 to May 2008. Methods Forty-seven patients were included. Demographic data, initial staging, therapeutic management and outcome were recorded. Results The mean survival was 16.7 months (95% confidence interval 12.6-20.8). Only eight (17%) and one (2%) patients reached respectively 2 and 5 years of survival. Initial spreading of the disease did not represent, in this cohort, a reliable prognosis factor. The outcome was overall influenced by treatment provided. While radiation therapy, monochemotherapy or even polychemotherapy regimens did not significantly affect the course of the disease, the survival of bone marrow transplanted patients was significantly higher. Conclusions Despite the fact that BPDCN is often initially limited to the skin, only an aggressive initial therapy may improve the patients' prognosis. Local treatments, such radiation therapy, are definitively useless. Regardless of the initial extension of the disease, in our experience only bone marrow transplantation significantly improved the outcome.

Birbeck granules are unusual rod-shaped structures specific to epidermal Langerhans cells, whose origin and function remain undetermined. We investigated the intracellular location and fate of Langerin, a protein implicated in Birbeck granule biogenesis, in human epidermal Langerhans cells. In the steady state, Langerin is predominantly found in the endosomal recycling compartment and in Birbeck granules. Langerin internalizes by classical receptor-mediated endocytosis and the first Birbeck granules accessible to endocytosed Langerin are those connected to recycling endosomes in the pericentriolar area, where Langerin accumulates. Drug-induced inhibition of endocytosis results in the appearance of abundant open-ended Birbeck granule-like structures appended to the plasma membrane, whereas inhibition of recycling induces Birbeck granules to merge with a tubular endosomal network. In mature Langerhans cells, Langerin traffic is abolished and the loss of internal Langerin is associated with a concomitant depletion of Birbeck granules. Our results demonstrate an exchange of Langerin between early endosomal compartments and the plasma membrane, with dynamic retention in the endosomal recycling compartment. They show that Birbeck granules are not endocytotic structures, rather they are subdomains of the endosomal recycling compartment that form where Langerin accumulates. Finally, our results implicate ADP-ribosylation factor proteins in Langerin trafficking and the exchange between Birbeck granules and other endosomal membranes. INTRODUCTIONLangerhans cells (LCs), the representatives of the dendritic cell lineage in the epidermis and mucosal tissues, capture antigen in the skin before migrating to the T-cell-dependent areas of draining lymph nodes. During this migration, they undergo a maturation process that allows them to present antigens to naive T cells (Kripke et al., 1990;Moll et al., 1993). Notably, Langerhans cells are the only epidermal cells to constitutively express major histocompatibility complex class II molecules (Klareskog et al., 1977;Rowden et al., 1977), CD1a molecules (Fithian et al., 1981), and Langerin (Valladeau et al., 2000) at their cell surface. In addition, Langerhans cells differ ultrastructurally from other dendritic cells through the presence of Birbeck granules (BGs), distinctive rod-shaped structures of variable length with a central, periodically striated lamella (Birbeck et al., 1961).Despite the use of "dynamic" electron microscope studies (reviewed in Schuler et al., 1991), Birbeck granules remain enigmatic. Specifically, conflicting theories exist regarding Article published online ahead of print. Mol. Biol. Cell 10.1091/ mbc.01-06-0300. Article and publication date are at www.molbiolcell.org/cgi/doi/10.1091/mbc.01-06-0300.† These authors contributed equally to this work and are listed in alphabetical order. # Corresponding author. E-mail address: daniel.hanau@efs-alsace.fr. Abbreviations used: Au, gold-labeled; BG, Birbeck granule; ERC, endosomal recycling compartment; Fi, freshl...

Previous work has suggested that the peptide‐carrier, heat‐shock protein (hsp)70, could directly activate APC. Here we show that this ability is related to endotoxin contamination of the humanrhsp70 produced in Escherichia coli. Hence, the ability of 1–3 μg/ml of rhsp70 to induce the maturation of human monocyte‐derived DC is abrogated in the presence of the LPS‐antagonist polymyxin B or when the rhsp70 contains less than 60 IU/mg endotoxin. Such a level of contamination of the rhsp70 is, however, sufficient — in the presence of soluble rCD14, the LPS co‐receptor — toinduce cytokine secretion from monocytes and DC, despite the presence of polymyxin B. However, when endotoxin contamination is below 10 IU/mg, rhsp70 does not induce cytokine secretion — even in the presence of soluble rCD14 — or activate p38 mitogen‐activated protein kinase signaling pathways, thus showing that an "endotoxin free" hsp70 does not activate APC.

This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.