Reinhart Speeckaert

Acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts

Acute generalized exanthematous pustulosis (AGEP) is a significant adverse cutaneous reaction, most often provoked by drugs and acute infections. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. The clinical hallmark is the presence of multiple disseminated sterile pustules on an erythematous background, associated with fever and a massive neutrophilia and sometimes eosinophilia. The disease is characterised by an acute onset and a spontaneous resolution within 2 weeks. The involvement of drug-specific T cells in the pathomechanism can be confirmed by positive skin patch tests and lymphocyte transformation tests. In this review, we highlight the main clinical, pathophysiological and diagnostic aspects of this peculiar form of drug allergy.

Identification of miR-145 as a Key Regulator of the Pigmentary Process

The current treatments for hyperpigmentation are often associated with a lack of efficacy and adverse side effects. We hypothesized that microRNA (miRNA)-based treatments may offer an attractive alternative by specifically targeting key genes in melanogenesis. The aim of this study was to identify miRNAs interfering with the pigmentary process and to assess their functional role. miRNA profiling was performed on mouse melanocytes after three consecutive treatments involving forskolin and solar-simulated UV (ssUV) irradiation. Sixteen miRNAs were identified as differentially expressed in treated melan-a cells versus untreated cells. Remarkably, a 15-fold downregulation of miR-145 was detected. Overexpression or downregulation of miR-145 in melan-a cells revealed reduced or increased expression of Sox9, Mitf, Tyr, Trp1, Myo5a, Rab27a, and Fscn1, respectively. Moreover, a luciferase reporter assay demonstrated direct targeting of Myo5a by miR-145 in mouse and human melanocytes. Immunofluorescence tagging of melanosomes in miR-145-transfected human melanocytes displayed perinuclear accumulation of melanosomes with additional hypopigmentation of harvested cell pellets. In conclusion, this study has established an miRNA signature associated with forskolin and ssUV treatment. The significant down- or upregulation of major pigmentation genes, after modulating miR-145 expression, suggests a key role for miR-145 in regulating melanogenesis.

Tumor Necrosis Factor Receptors: Biology and Therapeutic Potential in Kidney Diseases

The major evolutionary advance represented in the human immune system is a mechanism of antigen-directed immunity in which tumor necrosis factor (TNF)-α and TNF receptors (TNFRs) play essential roles. Binding of TNF-α to the 55-kDa type I TNFR (TNFR1, TNFRSF1A, CD120a, p55) or the 75-kDa type II TNFR (TNFR2, TNFRSF1B, CD120b, p75) activates signaling pathways controlling inflammatory, immune and stress responses, as well as host defense and apoptosis. Multiple studies have investigated the role of TNFRs in the development of early and late renal failure (diabetic nephropathy, nephroangiosclerosis, acute kidney transplant rejection, renal cell carcinoma, glomerulonephritis, sepsis and obstructive renal injury). This article reviews the general characteristics, the analytical aspects and the biology of TNFRs in this domain. In addition, the potential therapeutic application of specific TNFR blockers is discussed.

Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients

BACKGROUND Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunosuppressive properties is considered as a factor that impairs the antitumour immune response in melanoma. In this study, we investigated the expression of IDO in sentinel nodes of melanoma patients to determine its prognostic relevance. PATIENTS AND METHODS One hundred and sixteen melanoma patients were enrolled in this study with a median follow-up time after diagnosis of 71 months. The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. In 42 patients, regulatory T cells were investigated by flow cytometry. RESULTS Cox regression survival analysis showed a significant negative effect of IDO expression on progression-free survival (p = 0.015) and overall survival (p = 0.010). High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019). After CD3CD28 stimulation, peripheral blood mononuclear cells of patients with high IDO expression showed a lower production of interferon-gamma (IFN-γ) (p = 0.025). CONCLUSIONS This study points to an independent predictive role of IDO on survival, especially in melanoma patients with uninvolved sentinel nodes. Investigating IDO expression in the sentinel nodes of melanoma patients may be a useful marker to pre-identify patients with a less favourable prognosis in stage I and II disease.

Clinical significance of Koebner phenomenon in vitiligo

Background  The clinical significance of Koebner phenomenon (KP) in vitiligo with respect to disease activity and course is still debatable. Recently, a new classification was introduced for the assessment of KP.

Why treatments do(n't) work in vitiligo: An autoinflammatory perspective.

Vitiligo is a recalcitrant depigmentary skin disorder with significant effects on the quality of life and a frequent association with other autoimmune disorders. The results of the current therapeutic options remain variable and treatment resistance is often encountered. The mainstay of treatment remains topical corticosteroids, topical calcineurin inhibitors and UVB therapy. In more extensive or progressive cases, systemic corticosteroids are effective although their prolonged use is hampered due to safety concerns. A lot of topical and systemic treatments have been investigated during the last decades. Given the elevated TNF-α levels in vitiligo lesions, the failure and even paradoxal effects of TNF-α inhibitors were highly remarkable. Nonetheless, a lot of progress has been made to unravel the pathophysiology of vitiligo. In this review, we provide an overview of the currently known underlying mechanisms leading to vitiligo and link this to the success or failure of treatments that have been used in clinical trials. We believe that this overview can direct future vitiligo research and rationalise the treatment options.

miR-145 overexpression suppresses the migration and invasion of metastatic melanoma cells

MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression which play important roles in tumorigenesis and cancer metastasis. Since they are often highly deregulated in various types of cancer, miRNAs may be effective treatment targets. miRNA profiling studies of melanoma have led to the identification of several tumor suppressor miRNAs. One of these include miR-145, although functional data proving its specific function are limited. Therefore, in this study, we examined the expression levels of miR-145 in three melanoma cell lines (BLM, FM3P and WM793). Additional gain-of-function experiments revealed that miR-145 exerts an anti-proliferative effect in the primary, non-invasive melanoma cell line, WM793, whereas cell migration and the invasive potential of metastatic melanoma cells was suppressed following transfection with miR-145 mimics. In order to investigate the mechanisms by which miR-145 exerts its invasion suppressor function, we examined the expression level of target genes [fascin homolog 1 (FSCN1), myosin‑Va (MYO5A and SOX9] and that of an indirect target (RAB27A) following the overexpression of miR-145. The results showed that SOX9, MYO5A and RAB27A were not involved in the biological effects caused by miR-145 mimics. Surprisingly, we discovered that miR-145 in melanoma, in contrast to many other tumor types, does not necessarily act via the target, FSCN1, since the downregulation of FSCN1 did not inhibit cell proliferation or migration but, on the contrary, increased cell invasion in two out of the three melanoma cell lines examined. Our in vitro data is in accordance with previously reported in vivo data describing the low expression of FSCN1 in malignant melanomas when compared to dysplastic nevi, suggesting that the expression of FSCN1 decreases as the formation and progression stage of melanoma advances. In conclusion, our data provide evidence that miR-145 is an invasion suppressor in metastatic melanoma cells. Despite the fact that it remains unclear which genes or pathways are regulated by miR-145 in melanoma, miR-145 may serve as a useful therapeutic agent in melanoma when re-expressed in situ.

Koebner's phenomenon in vitiligo: European position paper.

Koebner’s phenomenon (KP) has been observed in a number of skin diseases, including vitiligo. Its clinical significance in vitiligo with respect to disease activity and course is still debatable, while its relevance for surgical techniques has been demonstrated in some reports. We present a literature review on the currently known facts about KP in vitiligo, including details of clinical, experimental, and histopathological changes. The consensus view is that there are still no methods to define and assess KP in vitiligo. A new classification is proposed to allow an evaluation of KP in daily practice or in experimental studies. However, many unanswered questions still remain after redefining KP in patients with vitiligo. Active research focusing on KP in vitiligo may not only provide unexpected clues in the pathogenesis of vitiligo but also help to tailor novel therapies against this chronic and often psychologically devastating skin disease.

Vitamin D binding protein: a multifunctional protein of clinical importance.

Since the discovery of group-specific component and its polymorphism by Hirschfeld in 1959, research has put spotlight on this multifunctional transport protein (vitamin D binding protein, DBP). Besides the transport of vitamin D metabolites, DBP is a plasma glycoprotein with many important functions, including sequestration of actin, modulation of immune and inflammatory responses, binding of fatty acids, and control of bone development. A considerable DBP polymorphism has been described with a specific allele distribution in different geographic area. Multiple studies have shed light on the interesting relationship between polymorphisms of the DBP gene and the susceptibility to diseases. In this review, we give an overview of the multifunctional character of DBP and describe the clinical importance of DBP and its polymorphisms. Finally, we discuss the possibilities to use DBP as a novel therapeutic agent.

Behind the scenes of vitamin D binding protein: More than vitamin D binding.

Although being discovered in 1959, the number of published papers in recent years reveals that vitamin D binding protein (DBP), a member of the albuminoid superfamily, is a hot research topic. Besides the three major phenotypes (DBP1F, DBP1S and DBP2), more than 120 unique variants have been described of this polymorphic protein. The presence of DBP has been demonstrated in different body fluids (serum, urine, breast milk, ascitic fluid, cerebrospinal fluid, saliva and seminal fluid) and organs (brain, heart, lungs, kidneys, placenta, spleen, testes and uterus). Although the major function is binding, solubilization and transport of vitamin D and its metabolites, the name of this glycoprotein hides numerous other important biological functions. In this review, we will focus on the analytical aspects of the determination of DBP and discuss in detail the multifunctional capacity [actin scavenging, binding of fatty acids, chemotaxis, binding of endotoxins, influence on T cell response and influence of vitamin D binding protein-macrophage activating factor (DBP-MAF) on bone metabolism and cancer] of this abundant plasma protein.