Publications by authors named "Knut Schäkel"

88 Publications

Spesolimab, an Anti-Interleukin-36 Receptor Antibody, in Patients with Palmoplantar Pustulosis: Results of a Phase IIa, Multicenter, Double-Blind, Randomized, Placebo-Controlled Pilot Study.

Dermatol Ther (Heidelb) 2021 Apr 4;11(2):571-585. Epub 2021 Mar 4.

Innovaderm Research Inc., Montreal, Quebec, Canada.

Introduction: Palmoplantar pustulosis (PPP) is a chronic, inflammatory skin disease, with high disease burden, that is often refractory to treatment. There is a high unmet clinical need for the treatment of patients with PPP. The objectives of this study were to evaluate the safety and efficacy of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients with PPP.

Methods: This was a phase IIa, multicenter, double-blind, randomized, placebo-controlled pilot study comparing 900 mg spesolimab (n = 19), 300 mg spesolimab (n = 19), and placebo (n = 21) administered intravenously every 4 weeks until week 12 in patients with PPP. The primary efficacy endpoint was the achievement of Palmoplantar Pustulosis Area and Severity Index 50 (PPP ASI50) at week 16, defined as achieving an ≥ 50% decrease from baseline PPP ASI.

Results: At week 16, 31.6% of patients in both spesolimab dose groups achieved PPP ASI50 versus 23.8% receiving placebo (risk difference 0.078; 95% confidence interval -0.190, 0.338). Thus, the primary endpoint was not met. Spesolimab was well tolerated with no clinically relevant treatment-emergent safety signals observed.

Conclusions: PPP severity declined over time in all treatment groups after the start of treatment, with a faster decline in the spesolimab arms than in the placebo arm, indicating a potential treatment effect for spesolimab. Limitations to the study included a small sample size and lower overall disease severity than expected at baseline. It is possible that the primary efficacy endpoint may have coincided with natural disease resolution in some patients. Further effects of the efficacy of spesolimab in PPP are being explored in a phase IIb trial.
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http://dx.doi.org/10.1007/s13555-021-00504-0DOI Listing
April 2021

Detection of Inflammasome Activation for Predicting Sepsis Mortality.

Front Immunol 2020 4;11:613745. Epub 2021 Feb 4.

Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany.

Sepsis is a severe life-threatening syndrome caused by dysregulated host responses to infection. Biomarkers that allow for monitoring the patient's immune status are needed. Recently, a flow cytometry-based detection of inflammasome activation by formation of cytoplasmic aggregates of ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) has been proposed. Here we report on the frequency of ASC-speck leukocytes correlating with the survival of sepsis. 25 patients with sepsis were sampled consecutively for 7 days. Blood, serum samples and patient data were collected according to the guidelines of the PredARRT-Sep-Trial. Flow cytometric analysis was performed on fresh whole blood samples to investigate the formation of ASC-specks in leukocyte subsets. Serum samples were analyzed for production of IL-1ß, IL-18 and additional inflammatory markers. ASC-speck formation was found to be increased in leukocytes from sepsis patients compared to healthy donor controls. The absolute number of ASC-speck neutrophils peaked on day 1. For monocytes, the highest percentage and maximum absolute number of ASC-speck cells were detected on day 6 and day 7. Inflammatory cytokines were elevated on day 1 and declined thereafter, with exception of IL-18. Survival analysis showed that patients with lower absolute numbers of ASC-speck monocytes (<1,650 cells/ml) on day 6 had a lower probability to survive, with a hazard ratio (HR) of 10.178. Thus, the frequency of ASC-speck monocytes on day 6 after onset of sepsis may serve to identify patients at risk of death from sepsis.
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http://dx.doi.org/10.3389/fimmu.2020.613745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889521PMC
February 2021

Healthcare provision for insect venom allergy patients during the COVID-19 pandemic.

Allergo J Int 2020 8;29(8):257-261. Epub 2020 Dec 8.

Department and Outpatient Clinic for Dermatology and Allergology, University Hospital Munich, Munich, Germany.

The population prevalence of insect venom allergy ranges between 3-5%, and it can lead to potentially life-threatening allergic reactions. Patients who have experienced a systemic allergic reaction following an insect sting should be referred to an allergy specialist for diagnosis and treatment. Due to the widespread reduction in outpatient and inpatient care capacities in recent months as a result of the COVID-19 pandemic, the various allergy specialized centers in Germany, Austria, and Switzerland have taken different measures to ensure that patients with insect venom allergy will continue to receive optimal allergy care. A recent data analysis from the various centers revealed that there has been a major reduction in newly initiated insect venom immunotherapy (a 48.5% decline from March-June 2019 compared to March-June 2020: data from various centers in Germany, Austria, and Switzerland). The present article proposes defined organizational measures (e.g., telephone and video appointments, rearranging waiting areas and implementing hygiene measures and social distancing rules at stable patient numbers) and medical measures (collaboration with practice-based physicians with regard to primary diagnostics, rapid COVID-19 testing, continuing already-initiated insect venom immunotherapy in the outpatient setting by making use of the maximal permitted injection intervals, prompt initiation of insect venom immunotherapy during the summer season, and, where necessary, using outpatient regimens particularly out of season) for the care of insect venom allergy patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1007/s40629-020-00157-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722411PMC
December 2020

Human innate immune cell crosstalk induces melanoma cell senescence.

Oncoimmunology 2020 08 30;9(1):1808424. Epub 2020 Aug 30.

Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany.

Mononuclear phagocytes and NK cells constitute the first line of innate immune defense. How these cells interact and join forces against cancer is incompletely understood. Here, we observed an early accumulation of slan (6-sulfo LacNAc) non-classical monocytes (slanMo) in stage I melanoma, which was followed by an increase in NK cell numbers in stage III. Accordingly, culture supernatants of slanMo induced migration of primary human NK cells via the chemotactic cytokine IL-8 (CXCL8), suggesting a role for slanMo in NK cell recruitment into cancer tissues. High levels of TNF-α and IFN-γ were produced in co-cultures of TLR-ligand stimulated slanMo and NK cells, whereas much lower levels were contained in cultures of slanMo and NK cells alone. Moreover, TNF-α and IFN-γ concentrations in slanMo/NK cell co-cultures exceeded those in CD14 monocyte/NK cell and slanMo/T cell co-cultures. Importantly, TNF-α and IFN-γ that was produced in TLR-ligand stimulated slanMo/NK cell co-cultures induced senescence in different melanoma cell lines, as indicated by reduced melanoma cell proliferation, increased senescence-associated β-galactosidase expression, p21 upregulation, and induction of a senescence-associated secretory phenotype (SASP). Taken together, we identified a role for slanMo and NK cells in a collaborative innate immune defense against melanoma by generating a tumor senescence-inducing microenvironment. We conclude that enhancing the synergistic innate immune crosstalk of slanMo and NK cells could improve current immunotherapeutic approaches in melanoma.
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http://dx.doi.org/10.1080/2162402X.2020.1808424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470184PMC
August 2020

COVID-19 and immunological regulations - from basic and translational aspects to clinical implications.

J Dtsch Dermatol Ges 2020 08 6;18(8):795-807. Epub 2020 Aug 6.

Department of Dermatology, Westfälische Wilhelms University Münster, Germany.

The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.
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http://dx.doi.org/10.1111/ddg.14169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436872PMC
August 2020

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Am J Hum Genet 2020 09 5;107(3):527-538. Epub 2020 Aug 5.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany. Electronic address:

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477008PMC
September 2020

The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis.

J Clin Invest 2020 11;130(11):5765-5781

Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.

Psoriasis is a frequent, inflammatory skin disease characterized by keratinocyte hyperproliferation and a disease-related infiltration of immune cells. Here, we identified a novel proinflammatory signaling pathway driven by cyclin-dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid target for psoriasis therapy. Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby triggering a methylation-induced activation of STAT3. Subsequently, active STAT3 resulted in the induction of IκBζ, which is a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis-related proinflammatory gene expression by suppressing IκBζ induction in keratinocytes. Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to fully prevent the development of psoriasis in various mouse models by suppressing STAT3-mediated IκBζ expression. Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin lesions. Thus, this study not only identifies a novel psoriasis-relevant proinflammatory pathway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option for patients with psoriasis.
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http://dx.doi.org/10.1172/JCI134217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598068PMC
November 2020

Urticaria: Collegium Internationale Allergologicum (CIA) Update 2020.

Int Arch Allergy Immunol 2020 30;181(5):321-333. Epub 2020 Mar 30.

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU.
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http://dx.doi.org/10.1159/000507218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265766PMC
November 2020

Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis.

Nat Commun 2020 01 8;11(1):105. Epub 2020 Jan 8.

Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany.

Psoriasis is an inflammatory skin disease with strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37. LL37 in complex with DNA and RNA is thought to initiate disease exacerbation via plasmacytoid dendritic cells. However, the source of nucleic acids supposed to start this initial inflammatory event remains unknown. We show here that primary murine and human PMNs mount a fulminant and self-propagating neutrophil extracellular trap (NET) and cytokine response, but independently of the canonical NET component, DNA. Unexpectedly, RNA, which is abundant in NETs and psoriatic but not healthy skin, in complex with LL37 triggered TLR8/TLR13-mediated cytokine and NET release by PMNs in vitro and in vivo. Transfer of NETs to naive human PMNs prompts additional NET release, promoting further inflammation. Our study thus uncovers a self-propagating vicious cycle contributing to chronic inflammation in psoriasis, and NET-associated RNA (naRNA) as a physiologically relevant NET component.
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http://dx.doi.org/10.1038/s41467-019-13756-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949246PMC
January 2020

Skin-Selective CD8 T-Cell Depletion by Photoimmunotherapy Inhibits Human Cutaneous Acute Graft-Versus-Host Disease.

J Invest Dermatol 2020 07 24;140(7):1455-1459.e6. Epub 2019 Dec 24.

Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.12.009DOI Listing
July 2020

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation.

JCI Insight 2019 11 14;4(22). Epub 2019 Nov 14.

Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.

The transcriptional activator IκBζ is a key regulator of psoriasis, but which cells mediate its pathogenic effect remains unknown. Here we found that IκBζ expression in keratinocytes triggers not only skin lesions but also systemic inflammation in mouse psoriasis models. Specific depletion of IκBζ in keratinocytes was sufficient to suppress the induction of imiquimod- or IL-36-mediated psoriasis. Moreover, IκBζ ablation in keratinocytes prevented the onset of psoriatic lesions and systemic inflammation in keratinocyte-specific IL-17A-transgenic mice. Mechanistically, this psoriasis protection was mediated by IκBζ deficiency in keratinocytes abrogating the induction of specific proinflammatory target genes, including Cxcl5, Cxcl2, Csf2, and Csf3, in response to IL-17A or IL-36. These IκBζ-dependent genes trigger the generation and recruitment of neutrophils and monocytes that are needed for skin inflammation. Consequently, our data uncover a surprisingly pivotal role of keratinocytes and keratinocyte-derived IκBζ as key mediators of psoriasis and psoriasis-related systemic inflammation.
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http://dx.doi.org/10.1172/jci.insight.130835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948851PMC
November 2019

Platelets Aggregate With Neutrophils and Promote Skin Pathology in Psoriasis.

Front Immunol 2019 16;10:1867. Epub 2019 Aug 16.

Department of Immunology, University of Tübingen, Tübingen, Germany.

Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes, but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well-defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental mouse model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease incidence directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in mice ameliorated disease severity significantly, indicating that both PMNs and platelets may be relevant for psoriasis pathology and disease severity.
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http://dx.doi.org/10.3389/fimmu.2019.01867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706802PMC
October 2020

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin.

Cell Mol Immunol 2020 04 19;17(4):380-394. Epub 2019 Jul 19.

Institute of Immunology, Section Molecular Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.

The interplay between keratinocytes and immune cells, especially T cells, plays an important role in the pathogenesis of chronic inflammatory skin diseases. During psoriasis, keratinocytes attract T cells by releasing chemokines, while skin-infiltrating self-reactive T cells secrete proinflammatory cytokines, e.g., IFNγ and IL-17A, that cause epidermal hyperplasia. Similarly, in chronic graft-versus-host disease, allogenic IFNγ-producing Th1/Tc1 and IL-17-producing Th17/Tc17 cells are recruited by keratinocyte-derived chemokines and accumulate in the skin. However, whether keratinocytes act as nonprofessional antigen-presenting cells to directly activate naive human T cells in the epidermis remains unknown. Here, we demonstrate that under proinflammatory conditions, primary human keratinocytes indeed activate naive human T cells. This activation required cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1. Naive T cells costimulated by keratinocytes selectively differentiated into Th1 and Th17 cells. In particular, keratinocyte-initiated Th1 differentiation was dependent on costimulation through CD58/CD2. The latter molecule initiated STAT1 signaling and IFNγ production in T cells. Costimulation of T cells by keratinocytes resulting in Th1 and Th17 differentiation represents a new explanation for the local enrichment of Th1 and Th17 cells in the skin of patients with a chronic inflammatory skin disease. Consequently, local interference with T cell-keratinocyte interactions may represent a novel strategy for the treatment of Th1 and Th17 cell-driven skin diseases.
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http://dx.doi.org/10.1038/s41423-019-0261-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109061PMC
April 2020

Current Concepts on 6-sulfo LacNAc Expressing Monocytes (slanMo).

Front Immunol 2019 22;10:948. Epub 2019 May 22.

Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany.

The human mononuclear phagocytes system consists of dendritic cells (DCs), monocytes, and macrophages having different functions in bridging innate and adaptive immunity. Among the heterogeneous population of monocytes the cell surface marker slan (6-sulfo LacNAc) identifies a specific subset of human CD14 CD16 non-classical monocytes, called slan monocytes (slanMo). In this review we discuss the identity and functions of slanMo, their contributions to immune surveillance by pro-inflammatory cytokine production, and cross talk with T cells and NK cells. We also consider the role of slanMo in the regulation of chronic inflammatory diseases and cancer. Finally, we highlight unresolved questions that should be the focus of future research.
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http://dx.doi.org/10.3389/fimmu.2019.00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540605PMC
September 2020

Neoadjuvant Radiochemotherapy Significantly Alters the Phenotype of Plasmacytoid Dendritic Cells and 6-Sulfo LacNAc Monocytes in Rectal Cancer.

Front Immunol 2019 29;10:602. Epub 2019 Mar 29.

Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Neoadjuvant radiochemotherapy (nRCT) can significantly influence the tumor immune architecture that plays a pivotal role in regulating tumor growth. Whereas, various studies have investigated the effect of nRCT on tumor-infiltrating T cells, little is known about its impact on the frequency and activation status of human dendritic cells (DCs). Plasmacytoid DCs (pDCs) essentially contribute to the regulation of innate and adaptive immunity and may profoundly influence tumor progression. Recent studies have revealed that higher pDC numbers are associated with poor prognosis in cancer patients. 6-sulfo LacNAc-expressing monocytes (slanMo) represent a particular proinflammatory subset of human non-classical blood monocytes that can differentiate into DCs. Recently, we have reported that activated slanMo produce various proinflammatory cytokines and efficiently stimulate natural killer cells and T lymphocytes. slanMo were also shown to accumulate in clear cell renal cell carcinoma (ccRCC) and in metastatic lymph nodes from cancer patients. Here, we investigated the influence of nRCT on the frequency of rectal cancer-infiltrating pDCs and slanMo. When evaluating rectal cancer tissues obtained from patients after nRCT, a significantly higher density of pDCs in comparison to pre-nRCT tissue samples was found. In contrast, the density of slanMo was not significantly altered by nRCT. Further studies revealed that nRCT significantly enhances the proportion of rectal cancer-infiltrating CD8 T cells expressing the cytotoxic effector molecule granzyme B. When exploring the impact of nRCT on the phenotype of rectal cancer-infiltrating pDCs and slanMo, we observed that nRCT markedly enhances the percentage of inducible nitric oxide synthase (iNOS)- or tumor necrosis factor (TNF) alpha-producing slanMo. Furthermore, nRCT significantly increased the percentage of mature CD83 pDCs in rectal cancer tissues. Moreover, the proportion of pDCs locally expressing interferon-alpha, which plays a major role in antitumor immunity, was significantly higher in post-nRCT tissues compared to pre-nRCT tumor specimens. These novel findings indicate that nRCT significantly influences the frequency and/or phenotype of pDCs, slanMo, and CD8 T cells, which may influence the clinical response of rectal cancer patients to nRCT.
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http://dx.doi.org/10.3389/fimmu.2019.00602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450462PMC
August 2020

Pyodermatitis-pyostomatitis vegetans with histological and immunohistological aspects of autoimmune blistering disease treated with infliximab.

J Dtsch Dermatol Ges 2019 05 1;17(5):540-542. Epub 2019 Apr 1.

University Hospital Heidelberg, Department of Dermatology, Heidelberg, Germany.

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http://dx.doi.org/10.1111/ddg.13830DOI Listing
May 2019

Psoriasis Pathogenesis and Treatment.

Int J Mol Sci 2019 Mar 23;20(6). Epub 2019 Mar 23.

Department of Dermatology, Heidelberg University, 69120 Heidelberg, Germany.

Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.
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http://dx.doi.org/10.3390/ijms20061475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471628PMC
March 2019

[Painful to the touch, subcutaneous tumor on the palm of the hand].

Hautarzt 2018 Nov;69(11):960-963

Universitäts-Hautklinik Heidelberg, Ruprecht-Karls Universität Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Deutschland.

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http://dx.doi.org/10.1007/s00105-018-4270-yDOI Listing
November 2018

No need to change the drug class: ixekizumab- following secukinumab-therapy in psoriasis.

J Dermatolog Treat 2019 May 11;30(3):216-220. Epub 2018 Sep 11.

a Department of Dermatology , Ruprecht-Karls-University Heidelberg , Heidelberg , Germany.

Background: Regarding treatment of psoriasis, dermatologists now use new, highly effective targeted therapies. Among such, biologic therapies have become a mainstay in patients with moderate to severe psoriasis; yet, a substantial proportion of patients show insufficient or no treatment response. Current literature has insufficient evidence for successful treatment when switching biologics after multiple failures, in particular when the biologics share a common mechanism of action.

Objectives: To compile a case series of patients with moderate to severe psoriasis who had primary or secondary loss of response to multiple previous systemic treatments. We specifically focused on patients recently treated with the anti-IL-17A antibody secukinumab, who further received the anti-IL-17A antibody ixekizumab as subsequent therapy.

Patients And Methods: We performed a retrospective cohort analysis. Inclusion criteria were patients with moderate to severe psoriasis vulgaris (as defined by European consensus and the German guidelines), who have previously been treated with systemic therapies including three or more biological therapies. All patients treated with anti-IL-17A antibody secukinumab experienced a primary and/or secondary treatment failure and subsequently received the anti-IL-17A antibody ixekizumab. The primary outcome was treatment response to ixekizumab using PASI score; the secondary outcome was incidence of adverse events.

Results: Twelve patients were included. At week 6 of ixekizumab treatment, PASI 75 was achieved in 91.7%, PASI 90 in 66.7%, PASI 100 in 8.3% of patients. At week 12, PASI 75 was achieved in 100%, PASI 90 in 100%, PASI 100 in 58.3% of the cohort. Throughout the observation period, no severe adverse events were observed.

Conclusions: Ixekizumab proved to be an effective and safe therapeutic option for patients with prior systemic therapies, including biological treatments with the same mechanism of action. Thus, failure of secukinumab does not preclude future therapy success with a second IL-17A-directed therapy.
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http://dx.doi.org/10.1080/09546634.2018.1506081DOI Listing
May 2019

Phenotype, Function, and Mobilization of 6-Sulfo LacNAc-Expressing Monocytes in Atopic Dermatitis.

Front Immunol 2018 21;9:1352. Epub 2018 Jun 21.

Department of Dermatology, Medical Faculty, University of Heidelberg, Heidelberg, Germany.

Mononuclear phagocytes (MPs) are important immune regulatory cells in atopic dermatitis (AD). We previously identified 6-sulfo LacNAc-expressing monocytes (slanMo) as TNF-α- and IL-23-producing cells in psoriatic skin lesions and as inducers of IFN-γ-, IL-17-, and IL-22-producing T cells. These cytokines are also upregulated in AD and normalize with treatment, as recently shown for dupilumab-treated patients. We here asked for the role of slanMo in AD. Increased numbers of slanMo were found in AD skin lesions. In difference to other MPs in AD, slanMo lacked expression of FcɛRI, CD1a, CD14, and CD163. slanMo from blood of patients with AD expressed increased levels of CD86 and produced IL-12 and TNF-α at higher amounts than CD14 monocytes and myeloid dendritic cells. While CD14 monocytes from patients with AD revealed a reduced IL-12 production, we observed no difference in the cytokine production comparing slanMo in AD and healthy controls. Interestingly, experimentally induced mental stress, a common trigger of flares in patients with AD, rapidly mobilized slanMo which retained their high TNF-α-producing capacity. This study identifies slanMo as a distinct population of inflammatory cells in skin lesions and as proinflammatory blood cells in patients with AD. slanMo may, therefore, represent a potent future target for treatment of AD.
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http://dx.doi.org/10.3389/fimmu.2018.01352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021776PMC
June 2018

Intracapillary immune complexes recruit and activate slan-expressing CD16+ monocytes in human lupus nephritis.

JCI Insight 2018 06 7;3(11). Epub 2018 Jun 7.

Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany.

Lupus nephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Among the different types of lupus nephritis, intracapillary immune complex (IC) deposition and accumulation of monocytes are hallmarks of lupus nephritis class III and IV. The relevance of intracapillary ICs in terms of monocyte recruitment and activation, as well as the nature and function of these monocytes are not well understood. For the early focal form of lupus nephritis (class III) we demonstrate a selective accumulation of the proinflammatory population of 6-sulfo LacNAc+ (slan) monocytes (slanMo), which locally expressed TNF-α. Immobilized ICs induced a direct recruitment of slanMo from the microcirculation via interaction with Fc γ receptor IIIA (CD16). Interestingly, intravenous immunoglobulins blocked CD16 and prevented cell recruitment. Engagement of immobilized ICs by slanMo induced the production of neutrophil-attracting chemokine CXCL2 as well as TNF-α, which in a forward feedback loop stimulated endothelial cells to produce the slanMo-recruiting chemokine CX3CL1 (fractalkine). In conclusion, we observed that expression of CD16 equips slanMo with a unique capacity to orchestrate early IC-induced inflammatory responses in glomeruli and identified slanMo as a pathogenic proinflammatory cell type in lupus nephritis.
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http://dx.doi.org/10.1172/jci.insight.96492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124405PMC
June 2018

Restrictive Dermopathy: Four Case Reports and Structural Skin Changes.

Acta Derm Venereol 2018 Aug;98(8):807-808

Department of Dermatology, University of Heidelberg, DE-69120 Heidelberg, Germany.

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http://dx.doi.org/10.2340/00015555-2970DOI Listing
August 2018

Regulation of IL-22BP in psoriasis.

Sci Rep 2018 03 23;8(1):5085. Epub 2018 Mar 23.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

IL-22 is a potent pro-inflammatory cytokine upregulated in psoriasis and in other inflammatory diseases. The function of IL-22 is regulated by the soluble scavenging receptor, IL-22 binding protein (IL-22BP or IL-22RA2). However, the role and regulation of IL-22BP itself in the pathogenesis of inflammatory disease remain unclear. We used the TLR7 agonist Imiquimod (IMQ) to induce a psoriasis-like skin disease in mice and found a strong downregulation of IL-22BP in the affected skin as well as in the lymph nodes of animals treated with IMQ. We also analysed psoriatic skin of patients and compared this to skin of healthy donors. Interestingly, IL-22BP expression was similarly downregulated in skin biopsies of psoriasis patients compared to the skin of healthy donors. Since IL-22BP is expressed foremost in dendritic cells, we characterized its expression in monocyte-derived dendritic cells (MoDC) during maturation. In this way, we found Prostaglandin E2 (PGE) to be a potent suppressor of IL-22BP expression in vitro. We conclude that regulation of IL-22BP by inflammatory mediators is an important step for the progression of inflammation in the skin and possibly also in other autoimmune diseases.
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http://dx.doi.org/10.1038/s41598-018-23510-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865214PMC
March 2018

Mattenartig konfigurierte Teleangiektasien.

J Dtsch Dermatol Ges 2018 Jan;16(1):92-95

Universitäts-Hautklinik, Ruprecht-Karls-Universität Heidelberg.

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http://dx.doi.org/10.1111/ddg.13375_gDOI Listing
January 2018