A crack in the armor: Wolf isotopic response manifesting as cutaneous lupus.

Wolf isotopic response represents the development of skin lesions of one particular morphology occurring at the same site as another morphologically distinct and unrelated skin lesion. Cutaneous lupus erythematosus (CLE) is an autoimmune connective tissue disorder encompassing a wide range of phenotypes that may be associated with systemic involvement. Although CLE is a well-described entity with a broad spectrum, the occurrence of lesions manifesting as an isotopic response is rare. We present a patient with systemic lupus erythematosus who developed CLE in a dermatomal distribution following herpes zoster. When CLE lesions present in a dermatomal distribution, these cases may be difficult to distinguish from recurrent herpes zoster infection in an immunosuppressed patient. Therefore, they pose a diagnostic challenge and require balancing antiviral therapy with immunosuppression to sufficiently maintain adequate control of the autoimmune disease while addressing possible infections. To avoid treatment delay, clinicians should have elevated suspicion for an isotopic response when disparate lesions erupt in areas previously affected by herpes zoster or in cases of persistent eruptions at sites of prior herpes zoster. We discuss this case within the context of Wolf isotopic response and review the literature for similar cases.

Pathogenesis of skin ulcers: lessons from the Mycobacterium ulcerans and Leishmania spp. pathogens.

Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1 % of the population and their incidence is expected to follow those observed for diabetes and obesity. In tropical and subtropical countries, an additional issue is the occurrence of ulcers of infectious origins with diverse etiologies. While the severity of cutaneous Leishmaniasis correlates with protective immune responses, Buruli ulcers caused by Mycobacterium ulcerans develop in the absence of major inflammation. Based on these two examples, this review aims to demonstrate how studies on microorganism-provoked wounds can provide insight into the molecular mechanisms controlling skin integrity. We highlight the potential interest of a mouse model of non-inflammatory skin ulceration caused by intradermal injection of mycolactone, an original lipid toxin with ulcerative and immunosuppressive properties produced by M. ulcerans.

Parabiotic heterogenetic pairing of Abcc6-/-/Rag1-/- mice and their wild-type counterparts halts ectopic mineralization in a murine model of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE), a pleiotropic heritable disorder, is characterized by ectopic mineralization of the connective tissues. This disease is caused by mutations in the ABCC6 gene, which is expressed primarily in the baso-lateral surface of hepatocytes, and Abcc6(-/-) mice develop progressive mineralization mimicking human PXE. To investigate the hypothesis that PXE is a metabolic disorder, potentially caused by the absence of antimineralization factor(s) in circulation, we used parabiotic pairing, ie, surgical joining of two mice, to create a shared circulation between various Abcc6 genotypic mice. To prevent immune reaction between the parabiotic animals, all mice were bred to be Rag1(-/-). Shared circulation between the parabiotic animals was confirmed by Evans blue dye injection and by quantitative PCR of blood cell genotypes. Pairing of Abcc6(-/-) mice with their wild-type counterparts halted the connective tissue mineralization in the knockout mice. Homogenetic wild-type and heterozygous pairings serving as controls were phenotypically unaffected by parabiosis. Consequently, the observations on the parabiotic mice support the notion that PXE is a metabolic disease, potentially due to absence of systemic antimineralization factor(s). These observations suggest that reintroduction of the critical antimineralization factors into circulation could provide a potential treatment for this, currently intractable, disease.

Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages.

Phenolic glycolipids (PGLs) are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here, we show that in addition, PGLs exert antibactericidal activity by limiting the production of nitric oxide synthase (iNOS) in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor 3-dependent and comparably induced by bacterial and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the toll-like receptor (TLR)4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-ß (TRIF) protein level. PGL-driven decrease in TRIF operated posttranscriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-ß and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4.

Pathogenic and immunosuppressive properties of mycobacterial phenolic glycolipids.

Phenolic glycolipids (PGL) are polyketide synthase products that are uniquely produced by a subset of pathogenic mycobacteria and are displayed at the bacterial cell surface, in a strategic position to interfere with host immune cells. Their expression has been associated with enhanced mycobacterial virulence in vivo, and suppression of the inflammatory responses of host phagocytes in vitro. In this review, we will present our current understanding of the mode of operation of PGL, along with functional evidence that demonstrates the evolutionary advantage conferred by PGL production for host cell invasion, intracellular persistence and evasion of host immune and bactericidal responses.

Combined inflammatory and metabolic defects reflected by reduced serum protein levels in patients with Buruli ulcer disease.

Buruli ulcer is a skin disease caused by Mycobacterium ulcerans that is spreading in tropical countries, with major public health and economic implications in West Africa. Multi-analyte profiling of serum proteins in patients and endemic controls revealed that Buruli ulcer disease down-regulates the circulating levels of a large array of inflammatory mediators, without impacting on the leukocyte composition of peripheral blood. Notably, several proteins contributing to acute phase reaction, lipid metabolism, coagulation and tissue remodelling were also impacted. Their down-regulation was selective and persisted after the elimination of bacteria with antibiotic therapy. It involved proteins with various functions and origins, suggesting that M. ulcerans infection causes global and chronic defects in the host's protein metabolism. Accordingly, patients had reduced levels of total serum proteins and blood urea, in the absence of signs of malnutrition, or functional failure of liver or kidney. Interestingly, slow healers had deeper metabolic and coagulation defects at the start of antibiotic therapy. In addition to providing novel insight into Buruli ulcer pathogenesis, our study therefore identifies a unique proteomic signature for this disease.

Overexpression of fetuin-a counteracts ectopic mineralization in a mouse model of pseudoxanthoma elasticum (abcc6(-/-)).

The pathologic hallmark of pseudoxanthoma elasticum (PXE) is ectopic mineralization of soft connective tissues. Recent studies have suggested that PXE is a metabolic disease, and perturbations in a number of circulatory factors have been postulated. One of them is fetuin-A, a 60-kDa glycoprotein synthesized in the liver and secreted into blood. Observations in targeted mutant mice (Ahsg(-/-)) and in cell culture model systems have shown that fetuin-A is a powerful anti-mineralization factor in circulation, and the serum levels of fetuin-A in patients with PXE as well as in a mouse model of PXE (Abcc6(-/-)) have been shown to be reduced by up to 30%. In this study, we tested the hypothesis that overexpression of fetuin-A in Abcc6(-/-) mice counteracts the ectopic mineralization. Delivery of an expression construct containing full-length mouse fetuin-A complementary DNA (cDNA), linked to a His-tag, to the liver of these mice resulted in elevated serum levels of this protein. As a consequence, soft tissue mineralization, which is a characteristic of Abcc6(-/-) mice, was reduced by approximately 70% at 12 weeks of age, but the effect was transient when examined 4 weeks later. The results suggest that normalization of serum fetuin-A, either through gene therapy approaches or by direct protein delivery to the circulation, may offer strategies for treating PXE and perhaps other heritable disorders of soft tissue mineralization.

Selective amplification of rare mutations using locked nucleic acid oligonucleotides that competitively inhibit primer binding to wild-type DNA.

Detection of mutated genomic DNA from cancer cells circulating in blood may improve tumor staging and patient selection for targeted therapy. However, the task of detecting a few mutated cells in the presence of a large excess of wild-type cells requires a sensitive and selective assay. We describe a novel approach to detect circulating melanoma cells harboring a common point mutation in the BRAF kinase. In the first step, primer binding to wild-type BRAF is competitively blocked by a locked nucleic acid (LNA) oligonucleotide. In the second step, the LNA-blocking approach is combined with a mutant-specific forward primer. This two-step approach easily detected 10 BRAF g[1799T>A]-mutated melanoma cells mixed with 10(5) wild-type cells. To determine the clinical utility of this method, we tested its ability to detect human blood spiked with a defined number of BRAF1799T>A-mutated melanoma cells. Blood was first enriched for melanoma cells using an antibody-mediated negative selection procedure before whole genome amplification (WGA). Mutant BRAF in the WGA-amplified genomic DNA was further amplified by a two-step real-time PCR protocol. Using this approach, we could readily identify mutant DNA from as few as 10 melanoma cells in 1 ml of human blood.