Pawel Durek

Pawel Durek
German Rheumatism Research Centre

About

132
Publications
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Publications

Publications (132)
Article
Modulation of commensal gut microbiota is increasingly recognized as a promising strategy to reduce mortality in patients with malignant diseases, but monitoring for dysbiosis is generally not routine clinical practice due to equipment, expertise and funding required for sequencing analysis. A low-threshold alternative is microbial diversity profil...
Article
Full-text available
Resident memory T lymphocytes (TRM) of epithelial tissues and the bone marrow protect their host tissue. To what extent these cells are mobilized and contribute to systemic immune reactions is less clear. Here we show that in secondary immune reactions to the measles‐mumps‐rubella (MMR) vaccine, CD4+ TRM are mobilized into the blood within 16 to 48...
Article
Full-text available
Successful treatment of chronic inflammatory diseases integrates both the cessation of inflammation and the induction of adequate tissue repair processes. Strikingly, targeting a single proinflammatory cytokine, tumor necrosis factor (TNF), induces both processes in a relevant cohort of inflammatory bowel disease (IBD) patients. However, the molecu...
Article
Full-text available
SARS-CoV-2 is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). Given its acute and often self-limiting course, components of the innate immune system are likely central in controlling virus replication thereby determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a b...
Article
Medullary thymic epithelial cells (mTECs) are key antigen-presenting cells mediating T cell tolerance to prevent harmful autoimmunity. mTECs both negatively select self-reactive T cells and promote the development of thymic regulatory T cells (tTregs) that mediate peripheral tolerance. The relative importance of these two mechanisms of thymic educa...
Article
Full-text available
The generation of lymphoid tissues during embryogenesis relies on group 3 innate lymphoid cells (ILC3) displaying lymphoid tissue inducer (LTi) activity and expressing the master transcription factor RORγt. Accordingly, RORγt-deficient mice lack ILC3 and lymphoid structures, including lymph nodes (LN). Whereas T-bet affects differentiation and func...
Preprint
The commensal microflora is a source for multiple antigens that may induce cross-reactive antibodies against host proteins and pathogens. However, whether commensal bacteria can induce cross-reactive antibodies against SARS-CoV-2 remains unknown. Here we report that several commensal bacteria contribute to the generation of cross-reactive IgA antib...
Article
Innate lymphoid cells (ILCs) are critical effectors of innate immunity and inflammation, whose development and activation pathways make for attractive therapeutic targets. However, human ILC generation has not been systematically explored, and previous in vitro investigations relied on the analysis of few markers or cytokines, which are suboptimal...
Preprint
Objectives: Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy show substantially impaired anti-SARS-CoV-2 vaccine humoral but partly inducible cellular immune responses. However, the complex relationship between antigen-specific B and T cells and the level of B cell repopulation necessary to achieve anti-vac...
Article
Full-text available
Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 D...
Article
Background We recently reported the beneficial clinical responses of the anti-CD38 monoclonal antibody daratumumab in two patients with systemic lupus erythematosus (SLE) [1]. While the primary rationale for its use was the depletion of autoantibody-producing long-lived plasma cells, daratumumab may promote additional therapeutic effects on CD38-ex...
Preprint
Patients with kidney failure are at increased risk during the COVID-19 pandemic and effective vaccinations are needed. It is not known how efficient mRNA vaccines mount B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 25 HC, 44 D...
Article
Full-text available
T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro‐inflammatory cytokines upon re‐stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). Howe...
Article
Full-text available
The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmabl...
Article
Objective Due to the small size of the murine knee joint, extracting the chondrocyte transcriptome from articular cartilage (AC) is a major technical challenge. In this study, we demonstrate a new pragmatic approach of combining bulk RNA-sequencing (RNA-seq) and single cell (sc)RNA-seq to address this problem. Design We propose a new cutting strat...
Article
Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c+ cells. Using gen...
Article
Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of darat...
Preprint
Full-text available
Here we have analyzed the dynamics of the adaptive immune response triggered by SARS-CoV-2 in severely affected COVID-19 patients, as reflected by activated B cells egressing into the blood, at the single cell level. Early on, before seroconversion in response to SARS-CoV-2 spike protein, activated peripheral B cells displayed a type 1 interferon-i...
Article
Full-text available
The persistence of long-lived memory plasma cells in the bone marrow depends on survival factors available in the bone marrow, which are provided in niches organized by stromal cells. Using an ex vivo system in which we supply the known survival signals, direct cell contact to stromal cells, and the soluble cytokine a proliferation-inducing ligand...
Preprint
Objective: Due to the small size of the murine knee joint, extracting the chondrocyte transcriptome from articular cartilage (AC) is a major technical challenge. In this study, we demonstrate a new and pragmatic approach of combining bulk RNA-sequencing (RNA-seq) and single cell (sc)RNA-seq to address this problem. Design: We propose a new cutting...
Article
Full-text available
In humans and mice, mucosal immune responses are dominated by IgA antibodies and the cytokine transforming growth factor beta (TGF‐β), suppressing unwanted immune reactions but also targeting immunoglobulin class switching to IgA. It had been suggested that eosinophils promote the generation and maintenance of mucosal IgA‐expressing plasma cells. H...
Article
Background Depletion of long-lived plasma cells (PC) resembles a novel concept for the treatment of antibody-mediated autoimmune diseases, such as systemic lupus erythematosus (SLE). Therapeutic approaches such as autologuos stem-stem cell transplantation and proteasome inhibition are limited by significant treatment-related toxicity. A novel targe...
Article
Background Plasma Cells (PCs) are implicated in the pathogenesis of Systemic Lupus erythematosus (SLE) and their targeting proved a promising treatment modality. As there is a monoclonal therapeutic antibody targeting CD38 licensed for clinical use in multiple myeloma, plasma cell depletion via CD38 seems to represent a promising path in SLE treatm...
Article
Full-text available
NKG2D is a danger sensor expressed on different subsets of innate and adaptive lymphocytes. Despite its established role as a potent activator of the immune system, NKG2D-driven regulation of CD4 + T helper (Th) cell-mediated immunity remains unclear. In this study, we demonstrate that NKG2D modulates Th1 and proinflammatory T-bet + Th17 cell effec...
Article
Full-text available
At present, it is not clear how memory B lymphocytes are maintained over time, and whether only as circulating cells or also residing in particular tissues. Here we describe distinct populations of isotype-switched memory B lymphocytes (Bsm) of murine spleen and bone marrow, identified according to individual transcriptional signature and B cell re...
Article
Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are...
Preprint
Full-text available
While it is generally accepted that tissue-resident memory T lymphocytes protect host tissues from secondary immune challenges, it is unclear whether, and if so, how they contribute to systemic secondary immune responses. Here we show that in human individuals with an established immune memory to measles, mumps and rubella viruses, when challenged...
Article
Full-text available
Non-invasive biomarkers are necessary for diagnosis and monitoring disease activity in lupus nephritis (LN) to circumvent risks and limitations of renal biopsies. To identify new non-invasive cellular biomarkers in the urine sediment of LN patients, which may reflect kidney inflammation and can be used to predict treatment outcome, we performed in-...
Preprint
Full-text available
Introduction/Abstract T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro 1–29 . Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idio...
Preprint
Full-text available
Persistence of long-lived, memory plasma cells in the bone marrow depends on survival factors available in the bone marrow, provided in niches organized by stromal cells. Here we describe that ex vivo we can prevent apoptosis of bone marrow plasma cells by supplying direct cell contact with stromal cells and the soluble cytokine APRIL. Integrin-med...
Preprint
Full-text available
Here we describe tissue-resident memory B lymphocytes of spleen and bone marrow. Single cell transcriptomes and B cell receptor repertoires identify several exclusive populations of isotype-switched memory B cells (Bsm) in murine spleen and bone marrow, and one interconnected population of 10-20%. A population of marginal zone-like Bsm is located e...
Article
Full-text available
Objective. Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lym-phocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment. Methods. Synovial and blood CD4+...
Article
Full-text available
Bone marrow (BM) stromal cells are important in the development and maintenance of cells of the immune system. Using single cell RNA sequencing, we here explore the functional and phenotypic heterogeneity of individual transcriptomes of 1,167 murine BM mesenchymal stromal cells. These cells exhibit a tremendous heterogeneity of gene expression, whi...
Article
Full-text available
It is a matter of current debate whether the bone marrow is a hub for circulating memory T lymphocytes and/or the home of resident memory T lymphocytes. Here we demonstrate for CD69⁺ murine CD8⁺, and CD69⁺ murine and human CD4⁺ memory T lymphocytes of the bone marrow, making up between 30 and 60% of bone marrow memory T lymphocytes, that they expre...
Article
Full-text available
Objective Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet, CD4⁺ T helper lymphocytes persist over time in such tissue and probably can contribute to chronicity of inflammation. Here we analyze the metabolic adaptation of these cells to the inflamed environment. Methods The dependency for survival of ex vivo isolat...
Article
T follicular helper (Tfh) cells are a specialized T cell subset that regulates the long-lived production of highly specific Abs by B cells during the germinal center (GC) reaction. However, the transcriptional network sustaining the Tfh cell phenotype and function is still incompletely understood. In this study, we identify the transcription factor...
Conference Paper
Career situation of first and presenting author Post-doctoral fellow. Introduction Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease (CID) of unknown origin and is characterized by joint inflammation in children and young adults.¹ Evidence suggests a strong contribution of memory T cells to disease pathogenicity in JIA. While f...
Conference Paper
Full-text available
Career situation of first and presenting author Post-doctoral fellow. Introduction The human intestine is colonized with billions of microorganisms, which form the gut microbiota, consisting of up to 1000 different bacterial species. Recent studies have implicated the intestinal microbiota in the pathogenesis of chronic inflammatory diseases, such...
Article
Full-text available
Proinflammatory type 1 T helper (Th1) cells are enriched in inflamed tissues and contribute to the maintenance of chronic inflammation in rheumatic diseases. Here we show that the microRNA-(miR-) 31 is upregulated in murine Th1 cells with a history of repeated reactivation and in memory Th cells isolated from the synovial fluid of patients with rhe...
Article
Full-text available
Ochratoxin A (OTA) is one of the most abundant food-contaminating mycotoxins. Besides their high toxicity, mycotoxins are highly stable to physical, chemical or biological detoxification. Therefore, the treatment with cold atmospheric plasma could be one approach to reduce the amount of mycotoxins in different products. The aim of this study was to...
Article
Context Antibody‐mediated rejection (ABMR) after kidney transplantation (KTx) remains the crucial obstacle to successful long‐term graft function. The identification of gene signatures involved in ABMR could grant the basis for better prevention and treatment strategies. Objective The identification of gene signatures in whole blood cells specific...
Article
Full-text available
Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+and ALK-anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF compos...
Article
Full-text available
Interstitial fibrosis/tubular atrophy (IFTA) is associated with reduced allograft survival, whereas antibody-mediated rejection (ABMR) is the major cause for renal allograft failure. To identify specific microRNAs and their regulation involved in these processes, total RNA from blood cells of 16 kidney transplanted (KTx) patients with ABMR, stable...
Data
Patient demographics. Scr…serum creatinine; m…male; f…female; l…living; nl…non-living; r…related; ur…unrelated. CNI…calcineurin inhibitor; PI…Proliferation inhibitor; St…steroids; mTORi…mTOR inhibitor; Bela…Belatacept. (DOCX)
Data
Statistical evaluation of Patient parameters. Analysis of variance for continuously distributed parameters and logistic regression analysis for categorical parameters were applied to analyse differences in the distribution between the patient groups, respectively. Differences between the single groups were tested by Post-hoc tests. For the statisti...
Article
There are currently limited insights into the progression of human primary humoral immunity despite numerous studies in experimental models. In this study, we analyzed a primary and related secondary parenteral keyhole limpet hemocyanin (KLH) immunization in five human adults. The primary challenge elicited discordant KLH-specific serum and blood e...
Article
Full-text available
Natural killer (NK) cells are innate lymphocytes that lack antigen-specific rearranged receptors, a hallmark of adaptive lymphocytes. In some people infected with human cytomegalovirus (HCMV), an NK cell subset expressing the activating receptor NKG2C undergoes clonal-like expansion that partially resembles anti-viral adaptive responses. However, t...
Article
Common lymphoid progenitors (CLPs) differentiate to T and B lymphocytes, dendritic cells, natural killer cells, and innate lymphoid cells. Here, we describe culture conditions that, for the first time, allow the establishment of lymphoid-restricted, but uncommitted, long-term proliferating CLP cell lines and clones from a small pool of these cells...
Article
Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK– Anaplastic Large Cell Lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF comp...
Article
Full-text available
The bone marrow maintains memory CD4 T cells, which provide memory to systemic antigens. Here we demonstrate that memory CD4 T cells are reactivated by antigen in the bone marrow. In a secondary immune response, antigen-specific T cells of the bone marrow mobilize and aggregate in immune clusters together with MHC class II-expressing cells, mostly...
Data
Conflicting evidence has been provided as to whether induction of intestinal inflammation by adoptive transfer of naive T cells into Rag−/− mice requires expression of the transcrip- tion factor T-bet by the T cells. Here, we formally show that the intestinal microbiota composition of the Rag−/− recipient determines whether or not T-bet-deficient T...