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Biomedical subjects

Jan L De Bleecker

Publications and source records attributed to Jan L De Bleecker.

13 recordsLinked to original sources
PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗
PubMed2006

Potential therapeutic targets for idiopathic inflammatory myopathies.

The inflammatory myopathies essentially comprise three diseases with different immunopathologic features. Dermatomyositis (DM) is a complement-mediated microangiopathy. The immune response in polymyositis (PM) and sporadic inclusion body myositis (IBM) is a CD8+ T-cell-mediated cellular reaction against an unknown muscle fiber antigen. The multiple immune factors that guide inflammatory cell diapedesis and trafficking have been elucidated over the past two decades. Many of these molecules can now be targeted by monoclonal antibodies and other pharmacologic approaches. Randomized controlled trials are being started on a number of new agents to find out whether more specific immune interventions than the currently used glucocorticosteroids can treat DM and PM patients with fewer side effects, and may represent a first treatment modality for IBM, an entity unresponsive to all currently available pharmacological treatments.

Adrenal Cortex Hormones↗
PubMed2005

Alpha-chemokine receptors CXCR1-3 and their ligands in idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of neuromuscular disorders subdivided into polymyositis (PM), sporadic inclusion body myositis (sIBM) and dermatomyositis (DM). Chemokines play an essential role in sustained inflammation associated with IIM. We studied the distribution of the alpha-chemokine receptors CXCR1, 2, 3 and their ligands interferon-gamma (IFN-gamma)-inducible T cell alpha chemoattractant (I-TAC), IFN-gamma-inducible protein of 10 kDa (IP-10), monokine induced by IFN-gamma (MIG) and growth-related oncogene (GRO) in IIM using immunohistochemistry, immunofluorescence and Western blotting. Abundant expression of IP-10 was observed on macrophages and T cells surrounding and invading non-necrotic muscle fibers in PM and sIBM and in T cells in perimysial infiltrates of DM. IP-10 was also localized to blood vessel endothelial cells in all inflammatory and normal muscle tissues. The distribution of other alpha-chemokines was variable: Only low levels of MIG and I-TAC were detected; GRO was localized to the endomysial infiltrates of some PM and sIBM samples, but not in DM. Muscle tissues were invariably CXCR1 negative, while a subset of inflammatory cells in all IIM were CXCR2 positive. Strong CXCR3 expression was observed on the majority of T cells in each IIM. We describe the differential repertoire of alpha-chemokines in IIM, and offer additional proof of the predominance of Th1-driven reactions in the immunopathogenesis of all three diagnostic subgroups. We suggest the Th1-mediated immunity in general, and the CXCR3/IP-10 interaction in particular, as potential targets for novel therapeutic intervention in IIM.

Blotting, Western↗
PubMed2005

Beta-chemokine receptor expression in idiopathic inflammatory myopathies.

Beta-chemokines attract and activate T cells and monocytes and have a key role in chronic inflammation. Certain beta-chemokines, such as monocyte chemoattractant protein-1 (MCP-1), have been reported to be upregulated in the idiopathic inflammatory myopathies (IIM). We studied the distribution of beta-chemokine receptors in polymyositis (PM), sporadic inclusion-body myositis (sIBM), dermatomyositis (DM), and control samples. CCR1-5 were localized to blood vessels in all samples. In addition, increased endothelial expression of CCR2A was observed in IIM. Subsets of inflammatory cells, identified as macrophages and T cells, in all three types of IIM expressed CCR2A, CCR2B, CCR3, CCR4, and CCR5. In contrast to an earlier report, we found CCR2B to be the most prominent MCP-1 receptor on inflammatory cells in IIM, especially in PM and sIBM. Strong CCR4 expression was present on myonuclei of regenerating muscle fibers. The prominence of the CCR2 receptors further underlines the importance of the interaction with their ligand MCP-1 in the immunopathogenesis of IIM and puts CCR2B forward as a potential target for future therapeutic intervention.

Blood Vessels↗
PubMed2005

How to approach the patient with muscular symptoms in the general neurological practice?

Muscle symptoms and signs are a frequent reason for general neurological consultations. Weakness is the most reliable clinical indicator of myopathy. Fatigue and exercise intolerance and myalgias frequently occur in non-myopathic conditions. Cramps and myoglobinuria are more often due to systemic factors than being a sign of a metabolic or other myopathy. Contractures and myotonia are rare findings but when present are strong leads towards specific myopathic diagnoses. Serum creatine kinase (CK) is the single most useful screening laboratory study. Creatine kinase increase does not only occur in myopathies, and some myopathies cause no CK increase. Rapid recruitment of short duration, low amplitude motor unit potentials is the most typical hallmark of needle electromyography in myopathies. Critical appreciation of the clinical, laboratory and electromyography findings will help general neurologists select the few patients that need referral for muscle biopsy and genetic studies.

Creatine Kinase↗
PubMed2005

Multiple neurological syndromes during Hodgkin lymphoma remission.

We report a young patient who developed a stiff man syndrome (SMS) long after remission of Hodgkin lymphoma. This patient is remarkable because he has had several other potentially autoimmune or paraneoplastic neurological syndromes including limbic encephalitis and demyelinating polyneuropathy which also occurred years after remission from Hodgkin disease.

Adult↗
PubMed2004

Expression and distribution of the nitric oxide synthases in idiopathic inflammatory myopathies.

Different immune effector mechanisms have been characterised in the idiopathic inflammatory myopathies (IIM): in polymyositis (PM) and sporadic inclusion body myositis (sIBM), T-cell-mediated cytotoxicity targets nonnecrotic muscle fibres, whereas in dermatomyositis (DM) the complement-mediated immune response is directed against the microvasculature. As nitric oxide (NO) has an important function in cell signalling and in the cytotoxicity displayed by activated macrophages, it is potentially involved in the immunopathogenesis of IIM. Using immunohistochemical, in situ hybridisation and Western blotting techniques, we visualised the three isoforms of NO synthase (NOS) in muscle tissues from normal controls and from patients diagnosed with IIM. The levels of both constitutive isoforms of NOS (endothelial, i.e., eNOS, and neuronal, i.e., nNOS) were unchanged in IIM as compared with normal muscle. Both protein and mRNA of the inducible form (iNOS) were detected in half of the control biopsies. Constant and increased iNOS protein expression was found in endomysial infiltrates of PM and sIBM, whereas perimysial inflammatory cells in DM were largely negative. We developed a quantitative Western blotting protocol which confirmed the constitutive nature of nNOS and eNOS and the significant induction of iNOS in PM. Our results appoint iNOS with a dual function: a limited and transient role in normal muscle physiology and an active cytotoxic role in PM and sIBM.

Adenocarcinoma↗
PubMed2004

Reversible orofacial dyskinesia after ofloxacin treatment.

We report on a patient who developed orofacial dyskinesia 3 days after starting ofloxacin treatment. The association of orofacial dyskinesia with other fluoroquinolone antibiotics has been reported rarely, chiefly in the elderly with impaired renal or hepatic function or in overdosed patients. It has been ascribed to interference with GABA-ergic neurotransmission.

Adult↗
PubMed2004

Localization of the alpha-chemokine SDF-1 and its receptor CXCR4 in idiopathic inflammatory myopathies.

We studied the distribution of stromal cell-derived factor 1 isoforms alpha and beta, and their receptor CXCR4, in polymyositis, sporadic inclusion body myositis and dermatomyositis using in situ hybridization, immunohistochemistry, immunofluorescence and Western blotting. In control muscle, polymyositis and sporadic inclusion body myositis, stromal cell-derived factor-1alpha expression was noted in muscle fibers, while stromal cell-derived factor-1beta and CXCR4 were predominantly localized to capillaries and arterioles. In dermatomyositis, stromal cell-derived factor-1beta immunoreactivity of blood vessels was focally increased. The vast majority of inflammatory cells in idiopathic inflammatory myopathies were CXCR4 positive. A subset of helper T-cells and macrophages expressed stromal cell-derived factor-1alpha, while only rare inflammatory cells expressed stromal cell-derived factor-1beta. A significant increase of stromal cell-derived factor-1alpha and CXCR4 was observed in protein extracts of idiopathic inflammatory myopathies in comparison with normal controls. The abundance of both CXCR4 and its ligand stromal cell-derived factor-1 implicates their interaction in the pathogenesis of idiopathic inflammatory myopathies and identifies these proteins as possible targets for selective immune therapy.

Antigens, CD↗
PubMed2002

Differential expression of chemokines in inflammatory myopathies.

BACKGROUND: Chemokines represent a family of small-molecular-weight cytokines that recruit and activate inflammatory cells in response to inflammation. Invasion of cytotoxic memory T cells and macrophages in nonnecrotic muscle fibers characterizes polymyositis and sporadic inclusion body myositis. Dermatomyositis is a complement-mediated endotheliopathy. Elucidation of the mechanisms guiding lymphocyte diapedesis and trafficking could lead to selective therapeutic interventions. METHODS: Immunoblots and multistep immunofluorescence studies with non-cross-reactive antibodies recognizing interleukin-8, monocyte chemoattractant protein-1 (MCP-1), MCP-3, TARC (thymus and activation regulated cytokine), and RANTES (regulated upon activation, normal T-cell expressed and secreted), using appropriate positive and negative controls. In situ hybridization was used to localize MCP-1 mRNA. RESULTS: MCP-1 protein was strongly expressed on T cells and a subset of macrophages actively invading a proportion of the nonnecrotic muscle fibers in polymyositis and inclusion body myositis alike. Capillaries and arterioles in the vicinity of endomysial inflammatory foci were immunoreactive for MCP-1, with faint or no expression in unaffected parts of the tissue. By contrast, widespread and strong endothelial MCP-1 expression occurred on perifascicular and perimysial endothelia in dermatomyositis, also at sites remote from inflammatory infiltrates. In some control specimens, a subset of capillaries also expressed MCP-1, possibly reflecting a role of this chemokine in normal immune surveillance. MCP-1 mRNA was detected in scattered macrophages in each inflammatory myopathy. All other chemokines were absent. CONCLUSION: Chemokines are differentially expressed in the symptomatic stage of inflammatory myopathies. MCP-1 plays a major role in the myocytotoxicity in polymyositis and inclusion body myositis. MCP-1 may be induced by membranolytic attack complex binding to endothelial cells in dermatomyositis.

Chemokine CCL2↗