Publications by authors named "Matthias Hose"

7 Publications

  • Page 1 of 1

An Early Wave of Macrophage Infiltration Intertwined with Antigen-Specific Proinflammatory T Cells and Browning of Adipose Tissue Characterizes the Onset of Orbital Inflammation in a Mouse Model of Graves' Orbitopathy.

Thyroid 2022 Jan 11. Epub 2022 Jan 11.

Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Graves' orbitopathy (GO) is an autoimmune-driven manifestation of Graves' disease (GD) where pathogenic autoantibodies to the thyrotropin receptor (TSHR) activate orbital fibroblasts/preadipocytes in the orbital tissue to induce inflammation and extracellular matrix deposition. Since there are significant limitations to study immunological and proinflammatory mediator expression in early and during disease progression in GO patients, we used our experimental mouse model to elucidate early pathogenic processes. We have developed a robust mouse model of GD/GO induced by electroporation immunization of plasmid encoding human TSHR A-subunit, comprising multiple injections over a course of 15 weeks to fully recapitulate the orbital pathology. In this study, we investigated kinetics of GO development in the model by serial analyses of immunological and cellular parameters during course of orbital inflammation. Pathogenic anti-TSHR antibodies with thyroid-stimulating properties developed early after the second immunization step with concomitant induction of hyperthyroidism. Examination of orbital tissue showed an early wave of macrophage infiltration followed subsequently by CD3 T cells into the orbital tissue. Examination of antigen-specific T cell activity using recombinant human A-subunit protein showed high CD8 T cell proliferation during this early phase of disease onset, whereas effector CD4 T cells and CD25FOXP3 regulatory T cells (Tregs) were downregulated. The early phase of disease was also characterized by abundant presence of proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Moreover, as the disease progressed, there was significant increase in browning of orbital fat tissue, which may be dependent on the proinflammatory milieu and/or the increased thyroid hormone levels during the established hyperthyroid status. This work revealed early infiltration of macrophages in the orbital region and induction of pathogenic anti-TSHR antibodies during disease onset in the model. This was followed subsequently by influx of CD8 T cells specific for TSHR coupled with reduction in Tregs and substantial increase in brown adipose tissue. These new insights into the development of orbital inflammation in the model have implications for testing new therapeutic regimens by targeting macrophage function during early phases of orbital inflammation in the model.
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http://dx.doi.org/10.1089/thy.2021.0464DOI Listing
January 2022

Intestinal Acid Sphingomyelinase Protects From Severe Pathogen-Driven Colitis.

Front Immunol 2019 19;10:1386. Epub 2019 Jun 19.

Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Inflammatory diseases of the gastrointestinal tract are emerging as a global problem with increased evidence and prevalence in numerous countries. A dysregulated sphingolipid metabolism occurs in patients with ulcerative colitis and is discussed to contribute to its pathogenesis. In the present study, we determined the impact of acid sphingomyelinase (Asm), which catalyzes the hydrolysis of sphingomyelin to ceramide, on the course of -driven colitis. is an enteric pathogen and induces colonic inflammation very similar to the pathology in patients with ulcerative colitis. We found that mice with Asm deficiency or Asm inhibition were strongly susceptible to infection. These mice showed increased levels of in the feces and were prone to bacterial spreading to the systemic organs. In addition, mice lacking Asm activity showed an uncontrolled inflammatory T1 and T17 response, which was accompanied by a stronger colonic pathology compared to infected wild type mice. These findings identified Asm as an essential regulator of mucosal immunity to the enteric pathogen .
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http://dx.doi.org/10.3389/fimmu.2019.01386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594205PMC
September 2020

Fingolimod Improves the Outcome of Experimental Graves' Disease and Associated Orbitopathy by Modulating the Autoimmune Response to the Thyroid-Stimulating Hormone Receptor.

Thyroid 2019 09;29(9):1286-1301

Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Graves' disease (GD) and Graves' orbitopathy are associated with stimulating thyrotropin receptor (TSHR) autoantibodies and autoreactive T cells. Recent studies suggested that sphingosine-1-phosphate (S1P) signaling is involved in the pathogenesis of orbitopathy. In this study, we explored the immune modulatory potential of S1P receptor antagonist fingolimod in a murine model for GD. Fingolimod was orally administered preventively during disease onset or therapeutically after disease onset. Administration of fingolimod during disease onset completely prevented the formation of TSHR-stimulating autoantibodies. Intervention after disease onset rarely reduced TSHR-stimulating autoantibodies and blocking autoantibodies were induced in some animals. Consequently, autoimmune hyperthyroidism characterized by elevated serum thyroxin levels, hyperplastic thyroid morphology accompanied by T cell infiltration, weight gain, enhanced body temperature, and tachycardia did not manifest preventively and showed milder manifestation in therapeutically treated animals. Importantly, examination of orbital tissue showed significant amelioration of orbitopathy manifestations through reduction of T cell infiltration, adipogenesis, and hyaluronan deposition. Autoimmune hyperthyroidism and orbitopathy were accompanied by changes in peripheral and splenic T cell proportions with high CD3, CD4, and CD8 T cells. Activated T cells CD4CD25 were elevated whereas regulatory T cells CD4Foxp3 cells remained unchanged in spleens. Fingolimod decreased elevated T cell levels and increased CD4CD25Foxp3 regulatory T cell populations. Analysis of total disease outcome revealed that treatment during disease onset protected animals against autoimmune hyperthyroidism and orbitopathy. Of note, therapeutic intervention after disease onset suppressed disease in half of the animals and in the other half disease remained at mild stages. The results of this study support a clinical trial to investigate the immunologic and clinical benefits of early treatment with S1P-based drugs in GD.
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http://dx.doi.org/10.1089/thy.2018.0754DOI Listing
September 2019

T Cell-Specific Overexpression of Acid Sphingomyelinase Results in Elevated T Cell Activation and Reduced Parasitemia During Infection.

Front Immunol 2019 31;10:1225. Epub 2019 May 31.

Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

The enzyme acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and is thereby involved in several cellular processes such as differentiation, proliferation, and apoptosis in different cell types. However, the function of ASM in T cells is still not well characterized. Here, we used T cell-specific ASM overexpressing mice (t-ASM/CD4cre) to clarify the impact of cell-intrinsic ASM activity on T cell function and . We showed that t-ASM/CD4cre mice exhibit decreased frequencies of Foxp3 T regulatory cells (Tregs) within the spleen. Enforced T cell-specific ASM expression resulted in less efficient induction of Tregs and promoted differentiation of CD4CD25 naïve T cells into IFN-γ producing Th1 cells . Further analysis revealed that ASM-overexpressing T cells from t-ASM/CD4cre mice show elevated T cell receptor (TCR) signaling activity accompanied with increased proliferation upon stimulation . infection of t-ASM/CD4cre mice resulted in enhanced T cell activation and was associated with reduced parasitemia in comparison to infected control mice. Hence, our results provide evidence that ASM activity modulates T cell function and .
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http://dx.doi.org/10.3389/fimmu.2019.01225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554418PMC
August 2020

CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine-1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy.

Invest Ophthalmol Vis Sci 2018 11;59(13):5391-5397

Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany.

Purpose: Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation.

Methods: OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays.

Results: GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration.

Conclusions: The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management.
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http://dx.doi.org/10.1167/iovs.18-25466DOI Listing
November 2018

DC-Derived IL-10 Modulates Pro-inflammatory Cytokine Production and Promotes Induction of CD4IL-10 Regulatory T Cells during Infection.

Front Immunol 2017 28;8:152. Epub 2017 Feb 28.

Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen , Essen , Germany.

The cytokine IL-10 plays a crucial role during malaria infection by counteracting the pro-inflammatory immune response. We and others demonstrated that infection results in enhanced IL-10 production in CD4 T cells accompanied by the induction of an immunosuppressive phenotype. However, it is unclear whether this is a direct effect caused by the parasite or an indirect consequence due to T cell activation by IL-10-producing antigen-presenting cells. Here, we demonstrate that CD11cCD11bCD8 dendritic cells (DCs) produce elevated levels of IL-10 after infection of BALB/c mice. DC-specific ablation of IL-10 in -infected IL-10/CD11c-cre mice resulted in increased IFN-γ and TNF-α production with no effect on MHC-II, CD80, or CD86 expression in CD11c DCs. Accordingly, DC-specific ablation of IL-10 exacerbated systemic IFN-γ and IL-12 production without altering blood stage progression. Strikingly, DC-specific inactivation of IL-10 in -infected mice interfered with the induction of IL-10-producing CD4 T cells while raising the frequency of IFN-γ-secreting CD4 T cells. These results suggest that infection promotes IL-10 production in DCs, which in turn dampens secretion of pro-inflammatory cytokines and supports the induction of CD4IL-10 T cells.
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http://dx.doi.org/10.3389/fimmu.2017.00152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328999PMC
February 2017

Plasmodium yoelii infection of BALB/c mice results in expansion rather than induction of CD4(+) Foxp3(+) regulatory T cells.

Immunology 2016 06 23;148(2):197-205. Epub 2016 Mar 23.

Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Recently, we demonstrated elevated numbers of CD4(+) Foxp3(+) regulatory T (Treg) cells in Plasmodium yoelii-infected mice contributing to the regulation of anti-malarial immune response. However, it remains unclear whether this increase in Treg cells is due to thymus-derived Treg cell expansion or induction of Treg cells in the periphery. Here, we show that the frequency of Foxp3(+) Treg cells expressing neuropilin-1 (Nrp-1) decreased at early time-points during P. yoelii infection, whereas percentages of Helios(+) Foxp3(+) Treg cells remained unchanged. Both Foxp3(+) Nrp-1(+) and Foxp3(+) Nrp-1(-) Treg cells from P. yoelii-infected mice exhibited a similar T-cell receptor Vβ chain usage and methylation pattern in the Treg-specific demethylation region within the foxp3 locus. Strikingly, we did not observe induction of Foxp3 expression in Foxp3(-) T cells adoptively transferred to P. yoelii-infected mice. Hence, our results suggest that P. yoelii infection triggered expansion of naturally occurring Treg cells rather than de novo induction of Foxp3(+) Treg cells.
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http://dx.doi.org/10.1111/imm.12602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863568PMC
June 2016
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