Peter Häusermann

Cutaneous Graft-versus-Host Disease: A Guide for the Dermatologist

Graft-versus-host disease (GVHD) is defined by the aggregation of clinical and pathological manifestations in a recipient of allogeneic stem cells or bone marrow transplantation in which specific immunological as well as nonspecific phenomena lead to characteristic features. GVHD is one of the major complications after hematopoietic stem cell transplantations and responsible for posttherapeutic morbidity, mortality and decrease in quality of life of those patients. GVHD is critically induced and maintained by donor immunocompetent cells that particularly attack epithelia of fast proliferating tissues such as those from the liver, gastrointestinal tract and skin. On the basis of the time of presentation, cutaneous GVHD has been originally divided into an acute and chronic disease. The latter has traditionally been further subclassified into a more epithelial or lichenoid and a predominantly dermal or sclerodermoid form. With respect to the growing importance of this therapeutic procedure and increasing numbers of outpatients presenting with chronic GVHD, this article summarizes the updated knowledge on this disease focused for the dermatologist, and additionally it emphasizes the recent consensus documents on the various aspects of chronic GVHD of the National Institute of Health.

Cutaneous Plasmablastic Lymphoma in an HIV-Positive Male: An Unrecognized Cutaneous Manifestation

Plasmablastic lymphoma (PBL) is a rare and relatively new entity originally described in HIV-infected individuals. This subset of Epstein-Barr-virus (EBV)-related non-Hodgkin lymphomas is now regarded as a distinct clinicopathological category of AIDS-associated lymphomas occurring preferentially in the oral cavity and showing a poor prognosis. We describe for the first time an EBV-associated PBL with an isolated cutaneous distribution on the lower extremities in an HIV-infected heterosexual male and point to the unique clinical, morphological and immunophenotypic characteristics of this lymphoma. The patient presented with fast growing solid and livid nodules on both legs. The large, blastic tumor cells showed the following immunophenotype: CD138+, CD45+, CD20–, CD10–, CD3–, CD30–, bcl-2–, bcl-6–, LMP-1– and EMA–. The proliferation fraction (Mib-1) was >90%. EBV association was demonstrated by in situ hybridization (EBV-encoded RNAs 1/2). Polymerase-chain-reaction-based DNA analysis demonstrated a clonal IgH rearrangement in the absence of a bcl-2/IgH translocation. PBL in HIV patients may occur not only in the oral cavity, but can probably involve any other organs including the skin.

ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2

The leukocyte CD33‐related sialic acid‐binding Ig‐like lectins (Siglecs) are implicated in glycan recognition and host defense against and pathogenicity of sialylated pathogens. Recent studies have shown endocytosis by CD33‐related Siglecs, which is implicated in clearance of sialylated antigens and antigen presentation and makes targeted immunotherapy possible. Using CD33 as a paradigm, we have now investigated the reasons underlying the comparatively slow rate of endocytosis of these receptors. We show that endocytosis is largely limited and determined by the intracellular domain while the extracellular and transmembrane domains play a minor role. Tyrosine phosphorylation, most likely through Src family kinases, increases uptake of CD33 depending on the integrity of the two cytoplasmic immunoreceptor tyrosine‐based inhibitory motifs (ITIMs). Simultaneous depletion of the protein tyrosine phosphatases, Src homology‐2‐containing tyrosine phosphatase 1 (Shp1) and Shp2, which bind to phosphorylated CD33, increases internalization of CD33 slightly in some cell lines, whereas depletion of spleen tyrosine kinase (Syk) has no effect, implying that Shp1 and Shp2 can dephosphorylate the ITIMs or mask binding of the phosphorylated ITIMs to an endocytic adaptor. Our studies show that restraint of CD33 internalization through the intracellular domain is relieved partly when the ITIMs are phosphorylated and show that Shp1 and Shp2 can modulate this process.

Unilesional follicular mycosis fungoides: report of two cases with progression to tumor stage and review of the literature

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma and has protean clinicopathological manifestations. Follicular or folliculotropic MF (FMF) is a rare variant, which histopathologically is characterized by pronounced folliculotropism of neoplastic T cells, with or without follicular mucinosis, and clinically by an impaired prognosis compared to classic MF. In contrast, unilesional MF is a very rare variant with an excellent prognosis, with a single case of large‐cell transformation reported to date. The combination of folliculotropic and unilesional MF is very unusual, with only two cases reported to date. Here we report two patients with unilesional folliculotropic MF with progression to tumor stage in both patients. To the best of our knowledge, this is the first report on the disease evolution with large‐cell transformation and progression of unilesional FMF. Complete remission was achieved by local radiation therapy in both patients. The differential diagnoses, classification and implications for the treatment of unilesional FMF as well as the pertinent literature are discussed.

Phosphorylated ITIMs enable ubiquitylation of an inhibitory cell surface receptor.

Immune responses are modulated by activating and inhibitory receptors that traffic to and from the cell surface. Ligands that bind to inhibitory receptors induce phosphorylation of immunoreceptor tyrosine‐based inhibitory motifs (ITIMs) in their cytoplasmic tails, followed by recruitment of inhibitory signaling molecules. Mechanisms that control the surface levels of inhibitory receptors are largely unexplored. Here, we show, using CD33/sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐3 as a paradigm, that ITIMs can bind to the ubiquitin ligase Cbl and that ITIMs are ubiquitylated following Src family kinase‐mediated tyrosine phosphorylation. Ubiquitylation is a known signal for endocytosis. Accordingly, cells expressing CD33 mutants that cannot become ubiquitylated show significantly increased cell surface expression of CD33 and have impaired CD33 internalization, whereas in‐frame fusion of ubiquitin to CD33 reverses this phenotype. Our results identify a novel function of ITIMs and demonstrate that phosphorylation‐dependent ubiquitylation regulates cell surface expression and internalization, and thus possibly function, of CD33/Siglec‐3, suggesting an important role of ubiquitin in endocytosis of ITIM‐bearing inhibitory immunoreceptors.

The difficulty in diagnosis and treatment of leprosy

Leprosy is still an important and debilitating disease with a broad clinical spectrum. However, this disease occurs most often endemically, and as an imported disease it can also still be recognized in the nonendemic industrialized world.

Homozygosity for the c.917A--<T (p.N306l) polymorphism in the EVER2/TMC8 gene of two sisters with epidermodysplasia verruciformis Lewandowsky-Lutz originally described by Wilhelm Lutz

Background: Epidermodysplasia verruciformis Lewandowsky-Lutz (EV) is a rare genodermatosis, characterised by development of numerous verrucous skin lesions caused by specific genotypes of human papillomaviruses belonging to the β-papillomavirus genus. The EV loci were mapped to chromosome 2p21–p24 (EV2) and 17q25 (EV1). On chromosome 17, 2 adjacent related genes – EVER1/TMC6 and EVER2/TMC8 – were identified. We reinvestigated 2 patients originally described by Wilhelm Lutz in 1946 with the aim to document the natural course of the disease and confirm his diagnosis. Methods: PCR fragments specific for exons with short flanking intron sequences of EVER1/TMC6 and EVER2/TMC8 genes from patients’ DNA were amplified using sequence information. The single-nucleotide polymorphism (SNP) rs7208422 was studied, using restriction fragment length polymorphism analysis. Results: In the index patient, we identified a homozygous TT genotype in exon 8 of the EVER2/TMC8 gene (c.917A → T, p.N306I). The same mutation could thereafter be detected in her sister from paraffin-embedded skin. Conclusion: We have followed one of the first patients described with EV in Basel, Switzerland, in 1930 until today and demonstrated the TT genotype (SNP rs7208422) in the EVER2/TMC8 gene in this index patient and her sister. The results underline the possible relevance of SNP rs7208422 by influencing the susceptibility to β-papillomaviruses and their oncogenic potential.

Future Trends in Hematopoietic Stem Cell Transplantation

The procedure of hematopoietic stem cell transplantation (HSCT) will keep expanding over the next decades. The list of indications for autologous or allogeneic HSCT of nonmalignant and malignant hematological disorders will grow. Other life-threatening diseases such as genetic, metabolic or autoimmune disorders including systemic sclerosis will undergo critical evaluation for that treatment. As a consequence of continuous research and clinical progress in that field, more and more patients will survive HSCT, and physicians will be confronted with organ-specific late and very late effects including chronic graft-versus-host disease (cGVHD). Changes of eligibility criteria for HSCT, quality assessment of the stem cell graft, graft manipulation, and new developments in donor selection might possibly impact patients health status and epidemiology as well as presentations of posttransplant complications. Efforts to diminish GVHD while forcing graft-versus-tumor effects will persist to be one of the major goals, and advances in prophylaxis and treatment of cGVHD will remain high priority. Changes in stem cell sources and graft manipulation might have additional influence on immune reconstitution and posttransplant disorders of infectious and immunological type. The recent publications of the National Institutes of Health consensus development project on various aspects of chronic GVHD has rightly positioned cGVHD as a serious and difficult to treat pleiotropic systemic disease with tremendous impact on long-term outcome. In this chapter, we will point out some of the most important issues and trends related to HSCT.

HIV-positive child with epidermodysplasia verruciformis-like lesions and homozygous mutation in TMC6

First released onto the market in 2008 [1], the HIV-1 integrase inhibitor raltegravir is recommended for the treatment of HIV-1 infection in treatment-naive or experienced patients when combined with other antiretroviral agents. Raltegravir is generally well tolerated, with adverse reactions comparable to placebo [2,3]. Gastrointestinal upset, headaches, transaminase elevation, creatine kinase elevation and pruritis have all been described as occasional side-effects. Rare adverse reactions include myopathy and rhabdomyolysis. There is one case report of raltegravir-induced rhabdomyolysis leading to renal failure [4]. Although central nervous system sideeffects such as dizziness and depression have been observed in patients taking raltegravir, cerebellar ataxia associated with raltegravir has not been previously reported [5].

Shark island pedicle flap for reconstruction of the lateral nasal ala and perialar defects

Epithelial skin tumors such as basal cell carcinoma and squamous cell carcinoma primarily develop in UV-exposed areas of the skin such as the face. The nose is one of the most frequently affected regions. Micrographically controlled surgery (MCS) allows for complete resection of these tumors – while maximally sparing the surrounding tissue – combined with extremely low recurrence rates, thus making it the method of choice [ 1, 2 ] . Following excision of nasal tumors, reconstruction of the lateral nasal ala and perialar region in particular can be challenging as convex and concave areas of the skin as well as defi ned aesthetic units intersect in this region. Within the perialar region, it is of paramount importance to preserve the alar sulcus, which defi nes the boundary between the nasal ala and the cheek. In order to achieve adequate closure of even deep defects, we herein present the shark island pedicle fl ap (SIPF), which has been mentioned only three times in the literature. This fl ap is a modifi cation of the subcutaneously pedicled island fl ap, with the cranial part rotated into the defect.