Stefan Kuchen

Rheumatology and Immunology Bern

Cytokine-primed neutrophils can undergo a nonapoptotic type of cell death using components of the necroptotic pathway, including receptor-interacting protein kinase-3 (RIPK3), mixed lineage kinase-like (MLKL) and NADPH oxidase. In this report, we provide evidence for a potential role of serine proteases in CD44-mediated necroptotic death of GM-CSF-...

We report the case of a 58-year-old Caucasian woman who presented with a subacute cerebellar syndrome accompanied by disturbance of the hypothalamic–pituitary axis and was diagnosed with isolated neurosarcoidosis based on radiological findings including typically located cerebral lesions (infratentorial and pituitary stalk). Due to persistent clini...

Although T H 1, T H 2, and T H 17 cells are well-defined T H cell lineages in humans, it remains debated whether IL-9–producing T H cells represent a bona fide “T H 9” lineage. Our understanding of the cellular characteristics and functions of IL-9–producing T H cells in humans is still nascent. Here, we report that human IL-9–producing T H cells e...

Entzündlich-rheumatische Erkrankungen stellen typische Systemerkrankungen dar. Sie können sich deshalb neben den Symptomen am Bewegungsapparat an allen anderen Organsystemen manifestieren. Je nach Befall und Ausprägung entstehen so unterschiedliche Leitsymptome oder Symptomkomplexe wie z. B. Fieber, Dyspnoe, Hautveränderungen oder neurologische Aus...

Objective: Tocilizumab is effective in inducing and maintaining remission of GCA. Despite clinical and serological control of disease, magnetic resonance angiography may show persistence of inflammatory signals of unknown significance in arterial walls. Thus, there is an unmet need for tools to detect subclinical disease activity. Methods: Immun...

Myelodysplastic syndromes (MDS) and associated diseases, like chronic myelomonocytic leukemias (CMML), are heterogeneous, clonal disorders affecting the hematopoietic stem cells. They are characterized by dysplasia and a propensity to evolve toward acute myeloid leukemia. Systemic inflammatory and autoimmune manifestations (SIAMs) occur with a prev...

Objective: To analyse magnetic resonance angiographic (MRA) vessel wall signals from a randomized controlled trial of tocilizumab (TCZ) to treat GCA. Methods: Participants were assigned in a 2:1 ratio to receive either TCZ + glucocorticoids (GCs) or placebo + GC infusions at 4-week intervals for 52 weeks. GCs were started at 1 mg/kg/day, then ta...

Arthrogenic pain is a common problem in equids. Frequently used treatments such as systemic NSAIDs or intra-articular steroids can lead to severe side effects if used repeatedly. Gold has been used since ancient times to treat a variety of conditions and has anti-inflammatory and immunomodulating properties. Results from clinical and in vitro studi...

Multiple osteochondromas (also called hereditary multiple exostoses) is an autosomal dominant disorder characterized by multiple cartilaginous tumors, which are caused by mutations in the genes for exostosin-1 (EXT1) and exostosin-2 (EXT2). The goal of this study was to elucidate the genetic alterations in a family with three affected members. Isol...

Background: Giant cell arteritis is an immune-mediated disease of medium and large-sized arteries that affects mostly people older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. Tocilizumab, a humanised monoclonal antib...

Additional file containing supplementary information (Figure S1 and Table S1).

Key Points Mice that express a mutation in STAT3 phenocopy patients with HIES. Bone marrow transplantation does not fully correct the susceptibility of these animals to bacterial infection.

For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium versus dysregulated immunity remain unresolved. Here, we take a top-down systems approach to this question. Multigene transcriptional signatures from infected lungs suggested that elevated activation of inflammatory signaling net...

Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions, but constitutive NF-κB activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutatio...

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors...

Distinct CD4(+) T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (T(reg)...

The cytidine deaminase AID hypermutates immunoglobulin genes but can also target oncogenes, leading to tumorigenesis. The extent of AID's promiscuity and its predilection for immunoglobulin genes are unknown. We report here that AID interacted broadly with promoter-proximal sequences associated with stalled polymerases and chromatin-activating mark...

The cytidine deaminase AID hypermutates immunoglobulin genes but can also target oncogenes, leading to tumorigenesis. The extent of AID's promiscuity and its predilection for immunoglobulin genes are unknown. We report here that AID interacted broadly with promoter-proximal sequences associated with stalled polymerases and chromatin-activating mark...

Although the cellular concentration of miRNAs is critical to their function, how miRNA expression and abundance are regulated during ontogeny is unclear. We applied miRNA-, mRNA-, and ChIP-Seq to characterize the microRNome during lymphopoiesis within the context of the transcriptome and epigenome. We show that lymphocyte-specific miRNAs are either...

Chronic myeloid leukemia (CML) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC b...

We have identified a distinct pre-naive B cell population circulating in human peripheral blood that exhibits an intermediate phenotype between transitional and naive B cells. Like human transitional B cells, these cells express CD5 but have intermediate densities of CD38, CD10, CD9, and the ABCB1 transporter compared with transitional and naive B...

Interleukin 21 (IL21) belongs to a family of cytokines that bind to a composite receptor consisting of a private receptor (IL21R) and the common cytokine receptor gamma chain (gamma(C)). The IL21R is widely distributed on lympho-haematopoietic cells and IL21 impacts a number of cell types, including CD8+ memory T cells, NK cells and subsets of CD4...

Interleukin-21 (IL-21) belongs to a family of cytokines that includes IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private (or shared) receptors as well as the common cytokine receptor gamma-chain as a component. Most cytokines in this family are critically important for both the maintenance and function of T cells and B cells. The recep...

During T cell-B cell collaboration, plasma cell (PC) differentiation and Ig production are known to require T cell-derived soluble factors. However, the exact nature of the cytokines produced by activated T cells that costimulate PC differentiation is not clear. Previously, we reported that costimulation of purified human B cells with IL-21 and ant...

IL-21 promotes plasma cell (PC) differentiation while BAFF promotes B-cell survival. Here, we report that IL-21 synergizes with BAFF to elicit BLIMP-1 induction, PC differentiation and IgG production from a novel population of human splenic memory B cells. These human marginal zone analogue B cells are exquisitely sensitive to IL-21 and BAFF in the...

Both constitutive Ig secretion by long-lived plasma cells (PC) and the recurrent differentiation of memory (mem) B cells into PC contribute to the maintenance of serologic mem. However, the relative contribution of each is unknown. In this study, we describe a novel population of human postswitched mem B cells that rapidly differentiate into PC and...

The chapter focuses on the detection of specific mRNA by in situ hybridization (ISH) in synovial tissue specimens. This technique is widely applied, reliable, specific, and sensitive, because even small quantities of mRNA can be detected. Presented here contemporary protocols for ISH using a combined nonradioactive immunohistochemical detection sys...

To study the specific contribution of MAP kinase activator c-Raf-1 and one of its downstream transcription factors, c-Myc, to the growth and invasive behavior of rheumatoid arthritis synovial fibroblasts (RASFs). RASFs were transduced with retroviral constructs expressing dominant-negative mutants of c-Raf-1 or c-Myc (DN c-Raf-1 or DN c-Myc, respec...

The present study was undertaken to examine whether ribozymes cleaving specifically cathepsin L (CL) mRNA are able to decrease the synthesis of CL protease in rheumatoid arthritis synovial fibroblasts (RA-SF) and thereby reduce the invasiveness into cartilage both in vitro and in the SCID mouse coimplantation model of RA. Two different ribozymes th...

To describe cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) expression in muscle tissue in patients with idiopathic inflammatory myopathies (IIM) - dermatomyositis (DM) and polymyositis (PM) and to find out if any differences between affected and non-affected muscles detected by MRI exist. Samples of muscle tissue from...

We characterized a full length L1 mRNA in a rheumatoid arthritis (RA) synovial tissue and determined the degree of methylation of its 5'-UTR. We asked whether not only intact but also altered L1s can exert biological activities by transfecting RA synovial fibroblasts (SF) with either retrotransposition-competent or incompetent L1s and examined thei...

To analyse the functional response of p53 in rheumatoid arthritis synovial fibroblasts (RASF) in vitro and in vivo and to investigate whether activation of p53 modulates the destructive process of RASF. RASF and controls grown on chamber slides were either directly examined with DO7 anti-p53 antibodies by immunofluorescence or irradiated with 10 Gy...

To characterize the expression pattern and role of galectin 3 and galectin 3 binding protein (G3BP) in rheumatoid arthritis (RA), in comparison with galectin 1, and to explore whether soluble galectin 3 and G3BP, investigated in serum, synovial fluid, or cell culture supernatant, are associated with disease. Synovial tissues from patients with RA o...

Galectin-3 (Gal-3) is one of the soluble lectins that has key functions in inflammation, chemotaxis, cell adhesion and apoptosis. We examined the role of Gal-3 and Gal-3 binding protein (Gal-3BP) in rheumatoid arthritis (RA). Localization of Gal-3 and Gal-3BP in rheumatoid synovium was examined by immunohistochemistry and in situ hybridisation. Gal...

The aim of the study was to investigate the relationship between invasion and proliferation in rheumatoid arthritis synovial fibroblasts (RASFs). In vitro, RASFs, normal synovial fibroblasts (NSFs), and RASFs transformed with SV40 T-antigen (RASF(SV40)) were analyzed for the expression of cell surface markers (Thy1, VCAM-1, ICAM-1, CD40, CD44) and...

To investigate the regulatory potential of early growth response 1 (Egr-1) on tissue inhibitor of metalloproteinases 1 (TIMP-1) expression in synovial fibroblasts. Egr-1 and TIMP-1 transcripts were detected by in situ hybridization in synovial tissue. Egr-1-regulated TIMP expression was studied in immortalized fibroblast lines using gel retardation...

Der Einfluss genetischer Faktoren bei Erkrankungen des Bindegewebes ist aus verschiedenen Perspektiven offensichtlich (McCurdy 1999). Besonders gut untersucht und dokumentiert ist deren Bedeutung bei der seronegativen ankylosierenden Spondylitis, der rheumatoiden Arthritis und der juvenile Polyarthritis. Im Zentrum standen bisher Assoziationen mit...

Synovial fibroblasts represent an important source of matrix degrading enzymes mediating joint destruction in rheumatoid arthritis.1 In our search for new pathways for the activation of synovial fibroblasts we have detected endogenous retroviral sequences, like the line 1 element (L1).2 To study the functional …

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is mainly characterized by synovial hyperplasia, pathological immune phenomena and progressive destruction of the affected joints. Various cell types are involved in the pathogenesis of RA including T cells, antigen presenting cells, and endothelial cells. Recent experimental eviden...

Die Pathophysiologie der rheumatoiden Arthritis (RA) ist durch eine synoviale Hyperplasie, pathologische Immunphänomene und eine progressive Gelenkzerstörung gekennzeichnet. Eine Vielzahl verschiedener Zelltypen, darunter T-Zellen, Antigen-präsentierende Zellen und Endothelzellen sind in die Pathogenese der RA involviert. Kürzlich veröffentlichte S...

Objectives To investigate pathogenesis of inflammation in muscles of patients with idiopathic inflammatory myopathies (IIM) – dermatomyositis (DM), polymyositis (PM) by studying expression of cox, lox and neuropeptides, using in situ hybridization and immunohistochemistry. Methods Muscle tissue samples were obtained by needle biopsy from affected...

Background The progression of the cell cycle is tightly controlled by cyclins and cyclin-dependent kinases. The p16Ink4a protein was identified as a specific inhibitor of cdk4. P16 inhibits the cdk4-dependent phosphorylation of the tumour suppressor retinoblastoma protein (Rb) and thereby leads to a G1 arrest. It is suggested that p16 acts as a tum...

Background Galectin-3 is a beta-galactoside-binding protein and belongs to the large family of lectins, which play important roles in a variety of physiological and pathophysiological processes via their recognition of glycoconjugates. Galectin-3 is involved in the regulation of cell growth and apoptosis, cell aggregation/adhesion and differentiati...

Objectives The aim of this study was to investigate, whether the destructive process of synovial fibroblasts in rheumatoid arthritis is dependent on the expression of p53. Moreover, we searched for the expression of p53 in RA-SF in vitro and in vivo. In addition, we examined the inducibility of p53 in RA-SF by X-rays in vitro. Methods Paraffin emb...

Objective Rheumatoid arthritis (RA) is characterized by a progressive destruction of joints by invasive synovial fibroblasts (SF). We searched for retroviral sequences in RA synovial fluid pellets, identified a sequence similar to that of open reading frame 2 (ORF2)/L1 retrotransposable elements, explored the expression of L1 in RA synovial tissues...

To study the expression of messenger RNA (mRNA) for different membrane-type matrix metalloproteinases (MT-MMPs) and compare their expression pattern in rheumatoid arthritis (RA) and normal synovium. Polymerase chain reaction (PCR) with specific primers was performed to analyze the presence of MT1-, MT2-, MT3-, and MT4-MMP in synovial tissue and syn...

Diss. med. Zürich. Literaturverz.