Cédric Lenormand

Species of Borrelia burgdorferi complex that cause borrelial lymphocytoma in France

Background  Only about 30 cases of borrelial lymphocytoma (BL) with identification of the causative species of Borrelia have been published to date, mainly from Eastern or Central European countries.

Classification of polygenic inflammatory diseases distributed along the lines of Blaschko.

gator for over 30 years in the field of the nosology of Blaschko-linear diseases. He recently introduced the concept of ‘superimposed segmental manifestation’ to describe severe segmental involvement in polygenic diseases [5] , since the designation ‘type 2 segmental manifestation’ should be restricted to diseases with monogenic mendelian inheritance. Indeed, it is (yet) not possible in polygenic diseases to distinguish between type 1 segmental manifestations, which reflect heterozygosity for a post-zygotic new mutation occurring in an otherwise healthy individual, and type 2 segmental manifestations. We are currently working on a comprehensive classification of polygenic inflammatory diseases distributed along the lines of Blaschko, and we reviewed the cases that were managed in our department during the past 10 years [6] . We think that Happle’s proposal should be expanded and that 4 conceptually different situations need to be individualized in order to classify polygenic inflammatory diseases along the lines of Blaschko. In type 1 , disease involvement occurs exclusively along the lines of Blaschko. Obviously, this can never be ascertained, since the patient can develop involvement outside the lines of Blaschko in the future. However, in the case of inflammatory diseases exclusively localized along the lines of Blaschko, 2 situations need to be individualized. In this issue of Dermatology , Boente et al. [1] report an 8-year-old boy with juvenile dermatomyositis who developed Blaschko-linear bands of calcification on the left lower limb. We follow up a patient with similar clinical findings. At the age of 12 years he developed Blaschkolinear lines of calcified nodules on the lower limb ( fig. 1 ) for which he consulted. On examination he was found to have typical signs of dermatomyositis ( fig. 2 ). Boente et al. discuss the possibility that loss of heterozygosity could explain this unusual segmental manifestation of dermatomyositis, by analogy to what has been described under the designation of type 2 segmental manifestations in monogenic diseases [2] . In the latter situation, this mechanism has been proven, as for example in Hailey-Hailey disease [3] . The rationale of this assumption is as follows. If the effect of a pathologic gene that would predispose to a specific disease, for instance dermatomyositis, is not balanced by the effect of the normal gene inherited from the other parent, its effect will be increased. Therefore, in cells where only the pathologic gene is present, either homozygous or hemizygous, the disease expression will be enhanced. However, direct evidence of this mechanism in polygenic inflammatory diseases is missing. Mosaicism has been proved only once in a patient with adult-onset blaschkitis [4] . One of Boente’s co-authors, Rudolf Happle, has been the leading investiPublished online: May 14, 2009

Birbeck Granule-Like “Organized Smooth Endoplasmic Reticulum” Resulting from the Expression of a Cytoplasmic YFP-Tagged Langerin

Langerin is required for the biogenesis of Birbeck granules (BGs), the characteristic organelles of Langerhans cells. We previously used a Langerin-YFP fusion protein having a C-terminal luminal YFP tag to dynamically decipher the molecular and cellular processes which accompany the traffic of Langerin. In order to elucidate the interactions of Langerin with its trafficking effectors and their structural impact on the biogenesis of BGs, we generated a YFP-Langerin chimera with an N-terminal, cytosolic YFP tag. This latter fusion protein induced the formation of YFP-positive large puncta. Live cell imaging coupled to a fluorescence recovery after photobleaching approach showed that this coalescence of proteins in newly formed compartments was static. In contrast, the YFP-positive structures present in the pericentriolar region of cells expressing Langerin-YFP chimera, displayed fluorescent recovery characteristics compatible with active membrane exchanges. Using correlative light-electron microscopy we showed that the coalescent structures represented highly organized stacks of membranes with a pentalaminar architecture typical of BGs. Continuities between these organelles and the rough endoplasmic reticulum allowed us to identify the stacks of membranes as a form of “Organized Smooth Endoplasmic Reticulum” (OSER), with distinct molecular and physiological properties. The involvement of homotypic interactions between cytoplasmic YFP molecules was demonstrated using an A206K variant of YFP, which restored most of the Langerin traffic and BG characteristics observed in Langerhans cells. Mutation of the carbohydrate recognition domain also blocked the formation of OSER. Hence, a “double-lock” mechanism governs the behavior of YFP-Langerin, where asymmetric homodimerization of the YFP tag and homotypic interactions between the lectin domains of Langerin molecules participate in its retention and the subsequent formation of BG-like OSER. These observations confirm that BG-like structures appear wherever Langerin accumulates and confirm that membrane trafficking effectors dictate their physiology and, illustrate the importance of molecular interactions in the architecture of intracellular membranes.

HLA-DQA2 and HLA-DQB2 Genes Are Specifically Expressed in Human Langerhans Cells and Encode a New HLA Class II Molecule

The precise role of human epidermal Langerhans cells (LCs) in immune response is highly controversial. While studying the gene expression profile of these cells, we were intrigued to identify the HLA-DQB2 gene as potentially expressed in LCs. Despite a strong evolutionary conservation of their sequences, the concomitant expression of the poorly polymorphic HLA-DQA2/HLA-DQB2 genes, paralogous to the HLA-DQA1/HLA-DQB1 genes, has never been detected in any cell type. We confirmed by RT-PCR that the HLA-DQA2 and -DQB2 genes are both expressed in LCs, but not in monocyte-derived dendritic cells, or in blood CD1c+ or plasmacytoid dendritic cells. The presence of the HLA-DQβ2 chain in LCs could be demonstrated by Western blotting, whereas immunofluorescence revealed its localization in early endosomes. As in the case of other HLA class II molecules, the HLA-DQα2 and -DQβ2 chains formed heterodimers that had to associate with the invariant chain to reach endosomal compartments. HLA-DQα2/β2 heterodimers were expressed at the cell surface, where they could mediate staphylococcal superantigen stimulation of T cells. Interestingly, HLA-DQα2 and HLA-DQβ1 chains formed mixed heterodimers which efficiently left the endoplasmic reticulum. These observations strongly suggest that the poorly polymorphic HLA-DQA2 and -DQB2 genes should be considered to be of immunological importance. The HLA-DQα2/β2 molecules could influence the complexity of the repertoire of Ags presented by LCs.

Relapsing polychondritis in a patient with lupus erythematosus: another manifestation of neutrophilic lupus?

patients usually have a favourable prognosis of the chondritis [1, 2] . The pathogenesis of RP is not known, and it has been considered as an auto-immune disorder, on the basis of an association with HLA-DR4, and evidence of humoral and cellular responses to cartilaginous components [3] . However, histologically, the inflammatory cell infiltrate initially found in the cartilaginous matrix is predominantly constituted of neutrophils, which are only secondarily replaced by lymphocytes, plasma cells and histiocytes [4] . From an epidemiological point of view, RP shares with neutrophilic dermatoses (e.g. Sweet’s syndrome or pyoderma gangraenosum) the same spectrum of associated diseases: acute and chronic myeloproliferative disorders, myelodysplastic syndromes, inflammatory bowel diseases etc. Besides, coexistence of RP and neutrophilic dermatosis is not rare, and RP is reputed to show clear sensibility to neutrophil-targeting drugs (i.e. dapsone or colchicine). Moreover, high levels of interleukin-8/CXCL8, a potent neutrophil chemotactic factor and a crucial mediator in neutrophil-dependent acute inflammation, are found in serum of patients with RP [5] , consistent with an auto-inflammatory disease pathomechanism. In a precedent issue, Antille et al. [6] reported a well-characterized case of amicrobial pustulosis of skin folds associated with undetermined connective tissue disease, a typical example of ‘neutrophilic cutaneous LE’. Lipsker and Saurat [7] suggested in the same issue the concept of ‘neutrophilic cutaneous LE’ to include all lupus-associated neutrophilic dermatoses. We believe that lupus-associated polychondritis can be seen as another autoinflammatory manifestation of this complex multi-factorial disease, and thus suggest adding this peculiar condition to the new concept of ‘neutrophilic LE’.

Expanding the clinicopathological spectrum of late cutaneous Lyme borreliosis (acrodermatitis chronica atrophicans [ACA]): A prospective study of 20 culture- and/or polymerase chain reaction (PCR)-documented cases

BACKGROUND The diagnosis of acrodermatitis chronica atrophicans (ACA), the late cutaneous manifestation of Lyme borreliosis, can be challenging. Histologic changes in ACA have been described in a few studies from endemic countries, relying on cases documented by serology only. OBJECTIVES We sought to reassess the clinicopathological spectrum of ACA in a series of thoroughly documented cases. METHODS Patients prospectively included in a national prospective study were selected on the basis of positive culture and/or polymerase chain reaction of a skin biopsy sample. The diagnosis of ACA was confirmed by reviewing the clinical and serologic data. Histopathological samples were carefully reviewed. RESULTS Twenty patients were included. Unusual clinical features (ie, numerous small violaceous patches and equidistant small spinous papules with background faint erythema) were observed in 2 patients. Histopathological examination revealed a classic plasma cell-rich perivascular and interstitial pattern with telangiectases in 16 of 25 samples, whereas strikingly prominent granuloma annulare-like or lichenoid features were observed in 4 and 2 of 25 cases, respectively, and discrete nonspecific minor changes in 3 of 25 cases. LIMITATIONS The small number of patients was a limitation. CONCLUSIONS Genuine culture- and/or polymerase chain reaction-proven ACA can rarely present as numerous violaceous patches or cluster of spinous papules clinically, and as a granuloma annulare-like or lichenoid dermatosis histologically.

Multilocus sequence typing of clinical Borreliella afzelii strains: population structure and differential ability to disseminate in humans

BackgroundLyme borreliosis in humans results in a range of clinical manifestations, thought to be partly due to differences in the pathogenicity of the infecting strain. This study compared European human clinical strains of Borreliella afzelii (previously named Borrelia afzelii) using multilocus sequence typing (MLST) to determine their spatial distribution across Europe and to establish whether there are associations between B. afzelii genotypes and specific clinical manifestations of Lyme borreliosis. For this purpose, typing was performed on 63 strains, and data on a further 245 strains were accessed from the literature.ResultsAll 308 strains were categorized into 149 sequence types (STs), 27 of which are described here for the first time. Phylogenetic and goeBURST analyses showed short evolutionary distances between strains. Although the main STs differed among the countries with the largest number of strains of interest (Germany, the Netherlands, France and Slovenia), the B. afzelii clinical strains were less genetically structured than those previously observed in the European tick population. Two STs were found significantly more frequently in strains associated with clinical manifestations involving erythema migrans, whereas another ST was found significantly more frequently in strains associated with disseminated manifestations, especially neuroborreliosis.ConclusionsThe MLST profiles showed low genetic differentiation between B. afzelii strains isolated from patients with Lyme borreliosis in Europe. Also, clinical data analysis suggests the existence of lineages with differential dissemination properties in humans.

Expanding phenotype of hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis caused by FAM111B mutations: Report of an additional family raising the question of cancer predisposition and a short review of early-onset poikiloderma

IPMN: intraductal papillary mucinous neoplasm POIKTMP: hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis RTS: Rothmund-Thomson syndrome H ereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP [MIM#615704]) is an extremely rare syndromic form of autosomal dominant poikiloderma. This genetic disorder was first identified in a South African family in 2006. To date, 3 families and 9 independent sporadic cases have been reported. Here we report an additional family of POIKTMP and expand the clinical spectrum. We describe, for the first time to our knowledge, a pancreatic cancer in the clinical course in 1 patient. We also address the differential diagnosis of inherited poikiloderma and related disorders.

Management of Schnitzler’s syndrome

Introduction: Schnitzler’s syndrome is a paradigm of an acquired autoinflammatory disorder, involving IL-1, which can now be pharmacologically targeted. Areas covered: Management of Schnitzler’s syndrome is covered in detail, by reviewing all published papers on this topic until May 2014. Schnitzler’s syndrome usually affects adult patients in their fifties. The main symptoms are an urticarial rash, fever, joint and/or bone pain, elevated CRP and leukocytosis in a patient with a monoclonal IgM (or rarely IgG) gammopathy. It is a chronic/recurrent disorder and spontaneous remissions are exceedingly rare. Patients are at specific risk of inflammatory anemia and AA-amyloidosis. The risk of associated lymphoid malignancy seems to be comparable to the one associated to monoclonal gammopathy of undetermined significance in general. Diagnosis relies on the Lipsker or the Strasbourg criteria. Expert opinion: Treatment relies on IL-1 inhibitors which allow a rapid and complete control of all signs. The IL-1 receptor antagonist anakinra, which has a short half-life and necessitates daily injections, is the treatment of choice in patients with Schnitzler’s syndrome who have alteration in their quality of life or persistent elevation of markers of inflammation. The other IL-1 inhibitors with longer half-lives need further investigation.

Skin Immunity and Microbiome

Abstract Despite acting as a highly efficient barrier against surface pathogenic microbes, the skin is still the major portal of entry for most arthropod-borne pathogens. Proper understanding of the mechanisms by which these microbial agents circumvent the skin defenses is a critical step in the development of new strategies to fight these major threats to human health. In this chapter, a comprehensive overview of the human skin immune system organization is depicted, providing up-to-date knowledge on the main cellular actors of both the innate and adaptive immunity populating this large organ. The rather scarce data about the skin inflammatory response to vector-competent arthropod bite are also presented. Finally, because accumulating evidence demonstrates an essential role of the human skin microbiome in homeostasis and in defense against pathogens, an overview of its diversity and functions is provided, giving interesting perspectives on its possible implications in arthropod-borne pathogens transmission.