Lars Philipsen

Lars Philipsen
Otto-von-Guericke-Universität Magdeburg | OvGU · Institut für Molekulare und Klinische Immunologie

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53
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Publications

Publications (53)
Article
Full-text available
Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular nic...
Article
Full-text available
Neutrophils represent one of the first immune cell types recruited to sites of infection, where they can control pathogens by phagocytosis and cytotoxic mechanisms. Intracellular pathogens such as Leishmania major can hijack neutrophils to establish an efficient infection. However the dynamic interactions of neutrophils with the pathogen and other...
Article
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Innate lymphoid cells (ILCs) emerge in the last few years as important regulators of immune responses and biological processes. Although ILCs are mainly known as tissue-resident cells, their precise localization and interactions with the microenvironment are still unclear. Here we combine a multiplexed immunofluorescence technique and a customized...
Article
Background: Kidney injuries that result in chronic inflammation initiate crosstalk between stressed resident cells and infiltrating immune cells. In animal models, whole-body receptor Notch3 deficiency protects from leukocyte infiltration and organ fibrosis. However, the relative contribution of Notch3 expression in tissue versus infiltrating immu...
Article
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The survival of peripheral T cells is dependent on their access to peripheral lymph nodes (pLNs) and stimulation by Interleukin‐7 (IL‐7). In pLNs fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) produce IL‐7 suggesting their contribution to the IL‐7‐dependent survival of T cells. However, IL‐7 production is detectable in m...
Article
Full-text available
The virulence of intracellular pathogens such as Leishmania major (L. major) relies largely on their ability to undergo cycles of replication within phagocytes, release, and uptake into new host cells. While all these steps are critical for successful establishment of infection, neither the cellular niche of efficient proliferation, nor the spread...
Data
mKikume expression in BM cells allows identification of photoconverted phagocytes after 48h of photoconversion. Ubiquitous mKikume expressing mice were infected with non-fluorescent L. major wild type. Photoconversion in the mouse ear was performed 48h prior to analysis. Control samples were photoconverted 0 h prior to analysis or not photoconverte...
Data
Multiparameter microscopy analysis strategy. (A) Example MELC images of different aligned fluorescence channels of an infected tissue site. A nonspecific IgG staining of the same site is shown for comparison. (B) Deconvolved and aligned image stacks of CD11b, CD45 and CD54 stainings were used separately as membrane input, the corresponding propidiu...
Data
A quantitative in vitro analysis approach for parasite cell-to-cell transfer. (A) Analysis of expression levels of uninfected CD11c, F4/80 and MHC class II in bone marrow-derived dendritic cell (green histograms) and macrophage (blue histograms) cultured. Data are representative of two independent experiments. (B) Analysis of CD11c versus F4/80 exp...
Data
Intravital 2-photon microscopy of cell-to-cell transfer of L. major (red) from recipient CD11c-EYFP cells (green) into newly recruited adoptively transferred cells (blue). CD11c-EYFPtg mice were infected in the ear for 16 weeks with monofluorescent L. major DsRed, ECFP-expressing bome marrow cells were adoptively transferred and the site of infecti...
Data
Grid control of the flow-cytometry based proliferation analysis approach. (A) Grid illumination approach for scrambled photoconversion. Left panel, illumination grid (transmitted light image). Middle panel, intravital 2-photon image of a scramble-photoswitched LmSWITCH-infected site in the ear, an image aligned to the grid showing photoswitched 80...
Data
Synchronization of newly recruited cell arrival. (A) Flow cytometry analysis of CD45.1 mice infected with LmSWITCH, adoptively transferred 2 or 5 days before analysis with C57BL/6 (CD45.2) bone marrow cells. Gating strategy on CD45.2+ (newly recruited) and CD45.1+ (steady state) cells, infected and non-infected. (B) Quantification of newly recruite...
Data
Intravital 2-photon microscopy demonstration of de novo infection of newly recruited phagocytes by L. major juxtapositioned to a CD11c+ cell. (A) Two examples de novo infection experiments of newly recruited cells (blue) by L. major (red) initially juxtapositioned to a CD11c+ host cell (green). Images are selected projections of 10–13 slices of 3 μ...
Data
Optimization of RACE conditions for single cell detection. Deconvolved 400 x 400 x 8 micron stacks were segmented with the RACE settings indicated. Three infection sites from different mice (Site1-Site3) and two Z planes per site (ZPl1-ZPl2) were converted into flow cytometry datasets and analyzed as described in the supplementary methods (see S1 T...
Data
Time lapse videomicroscopy of intraperitoneal macrophages infected for 24 h with fluorescently labeled L. major. Three examples of cell-to-cell transfer between two phagocytes are shown. (MOV)
Article
Background and aims In dialysis patients, vascular morbidities are highly prevalent and linked with leukocyte extravasation, especially of polarized monocytes. Experimental data demonstrate that phenotypic changes in monocytes require Y-box binding protein-1 (YB-1) upregulation. Methods We determined YB-1 expression in circulating and vessel-inva...
Article
The bone marrow (BM) consists of multiple, structured micro‐environmental entities—the so called niches, which contain hematopoietic cells as well as stromal cells. These niches fulfill a variety of functions, such as control of the hematopoietic stem cell pool, differentiation of hematopoietic cells, and maintenance of immunological memory. Howeve...
Article
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JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) is marked by dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes and leukocytes. However, the mechanism by which the two major leukocyte integrin chains, β1 and β2, mediate CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integ...
Article
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Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruit...
Article
Tubular cells recruit monocytic cells in inflammatory tubulointerstitial kidney diseases. The cell-cell communication that establishes pro- or anti-inflammatory activities is mainly influenced by cytokines, reactive oxygen species, nitric oxide, and phagocytosis. Key proteins orchestrating these processes such as cold-shock proteins linked with che...
Article
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The deposition of immune complexes is the causal factor in distinct renal pathologies, e.g., lupus nephritis and membranous nephritis. The location of these deposits within a tissue biopsy is often the key to establishing a diagnosis. However, how immune complexes come to be deposited below the vascular endothelium was, until now, a mystery, as was...
Article
Full-text available
Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be s...
Article
The enzymatic activity of the Src family tyrosine kinase p56Lck (Lck) is tightly controlled by differential phosphorylation of two tyrosine residues, Tyr³⁹⁴ and Tyr⁵⁰⁵. Phosphorylation of Tyr³⁹⁴ and the conformational opening of Lck are believed to activate the kinase, whereas Tyr⁵⁰⁵ phosphorylation is thought to generate a closed, inactive conform...
Article
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) is needed for T cell receptor (TCR) induced activation of LFA-1 to promote T cell adhesion and interaction with antigen presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src Kinase-Associated Phosphopro...
Article
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TGFβ1 (Transforming Growth Factor-beta1) is a versatile regulator of T cell immune responses. Depending on its context in the immunological environment, TGFβ1 guides T cells toward specific activation programs including TH17 and regulatory T cell activities. Moreover, TGFβ signals function in immune homeostasis by directly attenuating T cell effect...
Conference Paper
The proper function of the immune system requires correct interactions of a variety of different cells at distinct organs. Within these cells, signalling networks control the behaviour of each individual cell in response to its environment. To investigate the complexity of the immune response, we use multi-epitope ligand cartography (MELC), which i...
Article
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The formation of the immunological synapse between T cells and antigen-presenting cells (APC) begins within minutes of contact and can take hours for full T cell activation. While early phases of the synapse have been extensively studied for a select number of proteins, later phases have not yet been examined in detail. We studied the signaling net...
Article
Full-text available
The lymphocyte-specific Src family protein tyrosine kinase p56(Lck) (Lck) is essential for T cell development and activation and, hence, for adaptive immune responses. The mechanism by which Lck activity is directed toward specific substrates in response to T cell receptor (TCR) activation remains elusive. We used fluorescence lifetime imaging micr...
Article
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Signaling through the TCR is crucial for the generation of different cellular responses including proliferation, differentiation, and apoptosis. A growing body of evidence indicates that differences in the magnitude and the duration of the signal are critical determinants in eliciting cellular responses. Here, we have analyzed signaling dynamics in...
Article
A model of cell population dynamics based on molecular adhesion is explained and discussed in this paper. We consider cancer cells experiencing interactions due to adhesion forces. In the cells' membranes there are proteins directly involved in adhesion. These proteins in the membrane are assembled in complex patterns called Combinatorial Protein P...
Article
Full-text available
Barrett's esophagus (BE) is caused by gastroesophageal reflux with consecutive mucosal inflammation, predisposing patients to the development of esophageal adenocarcinoma (EAC). We investigated changes in T cell-related mucosal combinatorial molecular protein patterns in both diseases using the novel Multi-Epitope-Ligand-Cartography, a unique robot...
Data
Table S2. Color legend figures 2A-C.
Data
Figure S1. Example of the image processing step based on the run, which is demonstrated in figure 2C and figure 2F. Columns A, B, and C show the original (A), corrected (B), and binarized (C) fluorescence image of the respective marker in the same run.
Article
Immunophenotyping is essential for diagnostics of cutaneous lymphomas. In this regard we present a skin tissue-adapted application platform of MELC technology. This topoproteome analysis allows the subcellular colocalization of at least n = 100 epitopes in situ. For this purpose the specimen is processed by a Toponome Imaging Cycler for a n-fold re...
Article
Full-text available
The immune system is a significant determinant of epithelial tumorigenesis, but its role in colorectal cancer pathogenesis is not well understood. The function of the immune system depends upon the integrity of the protein network environment, and thus, we performed MELC immunofluorescence microscopy focusing on the lamina propria. By analyzing str...
Article
Today the pathogenesis of psoriasis is recognized to be a complex and subtle interplay between diverse types of lymphocytes and innate immunity-related accessory cells, capable of antigen presentation resulting in keratinocyte hyperproliferation. These molecular and cellular events take place in a skin microenvironment, which also with regard to ac...
Article
Einleitung: Die CU ist mit der Entwicklung eines CRC assoziiert. Dennoch ist bislang wenig uber gemeinsame Pathomechanismen bekannt. Ziel: Unter Erhalt der Integritat zellularer Gewebestrukturen sollten die mucosalen Proteinexpressionsmuster (CMP=combinatorial molecular phenotype) von Patienten mit CU und CRC untersucht und verglichen werden. Metho...
Article
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Although Crohn's disease (CrD) and ulcerative colitis (UC) share several clinical features, the mechanisms of tissue injury differ. Because the global cellular function depends upon the protein network environment as a whole, we explored changes in the distribution and association of mucosal proteins to define key events involved in disease pathoge...
Article
In a pilot study 6 psoriasis patients were treated over 12 weeks with efalizumab targeting the CD11a subunit of LFA-1. The treatment was well tolerated. Five of these patients proved to be responders with an average decrease in psoriasis area and severity index (PASI) from 21.3 ± 5.4 (day 0) to 3.9 ± 0.6 (week 12). The nonresponder was subsequently...
Article
Efalizumab (Raptiva) is an immunomodulating recombinant humanized IgG1 monoclonal antibody that binds to CD11a, the alpha-subunit of leukocyte function antigen-1 (LFA-1). By blocking the binding of LFA-1 to ICAM-1, efalizumab inhibits the adhesion of leukocytes to other cell types and interferes with the migration of T lymphocytes to sites of infla...
Article
Full-text available
Temporal and spatial regulation of proteins contributes to function. We describe a multidimensional microscopic robot technology for high-throughput protein colocalization studies that runs cycles of fluorescence tagging, imaging and bleaching in situ. This technology combines three advances: a fluorescence technique capable of mapping hundreds of...
Conference Paper
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Article
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A neural cell detection system (NCDS) for the automatic quantitation of fluorescent lymphocytes in tissue sections was used to analyze CD26 expression in muscle-invasive T-cells. CD26 is a cell surface dipeptidyl-peptidase IV (DPP IV) involved in co-stimulatory activation of T-cells and also in adhesive events. The NCDS system acquires visual knowl...

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