Publications by authors named "Georg Stary"

46 Publications

Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells.

EMBO Mol Med 2021 Apr 16;13(4):e12409. Epub 2021 Mar 16.

Department of Medicine I, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.

Toll-like receptor (TLR) stimulation induces innate immune responses involved in many inflammatory disorders including psoriasis. Although activation of the AP-1 transcription factor complex is common in TLR signaling, the specific involvement and induced targets remain poorly understood. Here, we investigated the role of c-Jun/AP-1 protein in skin inflammation following TLR7 activation using human psoriatic skin, dendritic cells (DC), and genetically engineered mouse models. We show that c-Jun regulates CCL2 production in DCs leading to impaired recruitment of plasmacytoid DCs to inflamed skin after treatment with the TLR7/8 agonist Imiquimod. Furthermore, deletion of c-Jun in DCs or chemical blockade of JNK/c-Jun signaling ameliorates psoriasis-like skin inflammation by reducing IL-23 production in DCs. Importantly, the control of IL-23 and CCL2 by c-Jun is most pronounced in murine type-2 DCs. CCL2 and IL-23 expression co-localize with c-Jun in type-2/inflammatory DCs in human psoriatic skin and JNK-AP-1 inhibition reduces the expression of these targets in TLR7/8-stimulated human DCs. Therefore, c-Jun/AP-1 is a central driver of TLR7-induced immune responses by DCs and JNK/c-Jun a potential therapeutic target in psoriasis.
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http://dx.doi.org/10.15252/emmm.202012409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033525PMC
April 2021

Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease.

Sci Transl Med 2020 11;12(570)

Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.

The skin contains a population of tissue-resident memory T cells (T) that is thought to contribute to local tissue homeostasis and protection against environmental injuries. Although information about the regulation, survival program, and pathophysiological roles of T has been obtained from murine studies, little is known about the biology of human cutaneous T Here, we showed that host-derived CD69 αβ memory T cell clones in the epidermis and dermis remain stable and functionally competent for at least 10 years in patients with allogeneic hematopoietic stem cell transplantation. Single-cell RNA sequencing revealed low expression of genes encoding tissue egress molecules by long-term persisting T in the skin, whereas tissue retention molecules and stem cell markers were displayed by T The transcription factor RUNX3 and the surface molecule galectin-3 were preferentially expressed by host T cells at the RNA and protein levels, suggesting two new markers for human skin T Furthermore, skin lesions from patients developing graft-versus-host disease (GVHD) showed a large number of cytokine-producing host-derived T, suggesting a contribution of these cells to the pathogenesis of GVHD. Together, our studies highlighted the relationship between the local human skin environment and long-term persisting T, which differs from murine skin. Our results also indicated that local tissue inflammation occurs through host-derived T after allogeneic hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1126/scitranslmed.abb7028DOI Listing
November 2020

A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses.

Sci Immunol 2020 10;5(52)

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses and how such functions are regulated at the molecular level. Here, we identify and characterize a discrete population of CD49aCD16 NK cells in the human liver that displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49aCD16 NK cells when compared with conventional CD49aCD16 NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49aCD16 NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.
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http://dx.doi.org/10.1126/sciimmunol.aba6232DOI Listing
October 2020

Alum triggers infiltration of human neutrophils ex vivo and causes lysosomal destabilization and mitochondrial membrane potential-dependent NET-formation.

FASEB J 2020 10 29;34(10):14024-14041. Epub 2020 Aug 29.

Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Aluminium salts have been used in vaccines for decades. However, the mechanisms underlying their adjuvant effect are still unclear. Neutrophils, the first immune cells at the injection site, can release cellular DNA together with granular material, so-called neutrophil extracellular traps (NETs). In mice, NETs apparently play a role in aluminium hydroxide (alum)-adjuvant immune response to vaccines. Although no experimental data exist, this effect is assumed to be operative also in humans. As a first step to verify this knowledge in humans, we demonstrate that the injection of alum particles into human skin biopsies ex vivo leads to similar tissue infiltration of neutrophils and NET-formation. Moreover, we characterized the mechanism leading to alum-induced NET-release in human neutrophils as rapid, NADPH oxidase-independent process involving charge, phagocytosis, phagolysosomal rupture, Ca -flux, hyperpolarization of the mitochondrial membrane, and mitochondrial ROS. Extracellular flow and inhibition experiments suggested that no additional energy from oxidative phosphorylation or glycolysis is required for NET-release. This study suggests a so far unappreciated role for neutrophils in the initial phase of immune responses to alum-containing vaccines in humans and provides novel insights into bioenergetic requirements of NET-formation.
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http://dx.doi.org/10.1096/fj.202001413RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589265PMC
October 2020

Short-course radiotherapy promotes pro-inflammatory macrophages via extracellular vesicles in human rectal cancer.

J Immunother Cancer 2020 08;8(2)

Department of Visceral Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Vienna, Austria

Background: Tumor-associated macrophages (TAM) constitute the most abundant immune cells in the tumor stroma initiating pro-inflammatory (M1) or immunosuppressive (M2) responses depending on their polarization status. Advances in tumor immunotherapy call for a detailed understanding of potential immunogenic mechanisms of irradiation routinely applied in rectal cancer patients.

Methods: To test the effects of radiotherapy on TAM, we ex vivo irradiated tissue samples of human rectal cancer and assessed the phenotype by flow cytometry. We furthermore evaluated the distribution of leucocyte subsets in tissue sections of patients after short-course radiotherapy and compared findings to non-pretreated rectal cancer using an immunostaining approach. Organotypic assays (OTA) consisting of macrophages, cancer-associated fibroblast and cancer cell lines were used to dissect the immunological consequences of irradiation in macrophages.

Results: We demonstrate that short-course neoadjuvant radiotherapy in rectal cancer patients is associated with a shift in the polarization of TAM towards an M1-like pro-inflammatory phenotype. In addition, ex vivo irradiation caused an increase in the phagocytic activity and enhanced expression of markers associated with stimulatory signals necessary for T-cell activation. In OTA we observed that this alteration in macrophage polarization could be mediated by extracellular vesicles (EV) derived from irradiated tumor cells. We identified high mobility group box 1 in EV from irradiated tumor cells as a potential effector signal in that crosstalk.

Conclusions: Our findings highlight macrophages as potential effector cells upon irradiation in rectal cancer by diminishing their immunosuppressive phenotype and activate pro-inflammation. Our data indicate that clinically applied short-term radiotherapy for rectal cancer may be exploited to stimulate immunogenic macrophages and suggest to target the polarization status of macrophages to enhance future immunotherapeutic strategies.
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http://dx.doi.org/10.1136/jitc-2020-000667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437887PMC
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

NK Cell-Mediated Recall Responses: Memory-Like, Adaptive, or Antigen-Specific?

Front Cell Infect Microbiol 2020 14;10:208. Epub 2020 May 14.

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Mounting experimental evidence hints to an import role for natural killer (NK) cells in adaptive immune responses to pathogens. NK cells with adaptive features are heterogeneous and belong to different subsets according to their phenotype as well as the nature of their adaptive recall reactions. Three types of adaptive NK cell responses have been described: (i) NK cells with long-lived memory of multiple different haptens and viral antigens were described in murine liver tissue with a possible human counterpart; (ii) infection of human and mouse cytomegalovirus is associated with an expansion of NKG2C and Ly49H NK cells, respectively, that selectively recognize CMV-encoded peptides thereby facilitating recall responses; (iii) cytokine-stimulated NK cells respond to different stimuli with enhanced production of IFN-γ after re-stimulation. These exciting findings not only support the idea of NK cells with adaptive features, but define a novel field of harnessing memory NK cell subsets for therapeutic strategies.
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http://dx.doi.org/10.3389/fcimb.2020.00208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240046PMC
June 2021

Perianale Ulzeration als Primärpräsentation bei einem Patienten mit disseminierter multiresistenter Tuberkulose.

J Dtsch Dermatol Ges 2020 Apr;18(4):372-374

Universitätsklinik für Dermatologie, Medizinische Universität Wien, Wien, Österreich.

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http://dx.doi.org/10.1111/ddg.14031_gDOI Listing
April 2020

Anti-Apoptotic Molecule BCL2 Is a Therapeutic Target in Steroid-Refractory Graft-Versus-Host Disease.

J Invest Dermatol 2020 11 2;140(11):2188-2198. Epub 2020 Apr 2.

Department of Dermatology, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. Electronic address:

Graft-versus-host disease (GVHD) is the leading cause of mortality after hematopoietic stem cell transplantation and primarily affects barrier organs such as the skin. One-third of cases are refractory to steroid treatment resulting in poor outcomes and the need for novel therapies. Longitudinal analysis of T-cell transcriptomes in patients before the appearance of GVHD symptoms revealed the upregulation of anti-apoptotic regulator B-cell lymphoma 2 (BCL2) at GVHD initiation. To determine the potential of BCL2 inhibition in active GVHD, we analyzed tissues of 88 patients with acute or chronic GVHD. BCL2 RNA was elevated in multiple organs affected by GVHD and expression correlated with transplant-related mortality and steroid-refractory GVHD. BCL2-expressing lymphocytes were present in skin lesions and peripheral blood of patients with acute and chronic GVHD. Inhibition of BCL2 increased the CD4 to CD8 ratio in allogeneic T cells in vitro and induced apoptosis of T cells from patients with steroid-pretreated chronic GVHD ex vivo. In addition, the higher ratio of regulatory to nonregulatory T cells upon blockage of BCL2 could add to the anti-inflammatory effect of BCL2 blockage. Collectively, our results highlight BCL2 as an important factor for GVHD development and introduce BCL2 inhibition as previously unreported and urgently needed targeted therapy in the treatment of steroid-refractory GVHD.
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http://dx.doi.org/10.1016/j.jid.2020.02.029DOI Listing
November 2020

Perianal ulceration as primary presentation in a patient with disseminated multi-drug resistant tuberculosis.

J Dtsch Dermatol Ges 2020 Apr 20;18(4):372-374. Epub 2020 Feb 20.

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/ddg.14031DOI Listing
April 2020

BMP7 aberrantly induced in the psoriatic epidermis instructs inflammation-associated Langerhans cells.

J Allergy Clin Immunol 2020 04 21;145(4):1194-1207.e11. Epub 2019 Dec 21.

Otto Loewi Research Center, Chair of Immunology and Pathophysiology, Medical University of Graz, Graz, Austria. Electronic address:

Background: Epidermal hyperplasia represents a morphologic hallmark of psoriatic skin lesions. Langerhans cells (LCs) in the psoriatic epidermis engage with keratinocytes (KCs) in tight physical interactions; moreover, they induce T-cell-mediated immune responses critical to psoriasis.

Objective: This study sought to improve the understanding of epidermal factors in psoriasis pathogenesis.

Methods: BMP7-LCs versus TGF-β1-LCs were phenotypically characterized and their functional properties were analyzed using flow cytometry, cell kinetic studies, co-culture with CD4 T cells, and cytokine measurements. Furthermore, immunohistology of healthy and psoriatic skin was performed. Additionally, in vivo experiments with JunJunBK5cre-ER mice were carried out to assess the role of bone morphogenetic protein (BMP) signaling in psoriatic skin inflammation.

Results: This study identified a KC-derived signal (ie, BMP signaling) to promote epidermal changes in psoriasis. Whereas BMP7 is strictly confined to the basal KC layer in the healthy skin, it is expressed at high levels throughout the lesional psoriatic epidermis. BMP7 instructs precursor cells to differentiate into LCs that phenotypically resemble psoriatic LCs. These BMP7-LCs exhibit proliferative activity and increased sensitivity to bacterial stimulation. Moreover, aberrant high BMP signaling in the lesional epidermis is mediated by a KC intrinsic mechanism, as suggested from murine data and clinical outcome after topical antipsoriatic treatment in human patients.

Conclusions: These data indicate that available TGF-β family members within the lesional psoriatic epidermis preferentially signal through the canonical BMP signaling cascade to instruct inflammatory-type LCs and to promote psoriatic epidermal changes. Targeting BMP signaling might allow to therapeutically interfere with cutaneous psoriatic manifestations.
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http://dx.doi.org/10.1016/j.jaci.2019.12.011DOI Listing
April 2020

Staphylococcal Scalded Skin Syndrome Caused by a Rare Variant of Exfoliative-toxin-A+ S. aureus in an Adult Immunocompromised Woman.

Acta Derm Venereol 2018 01;98(1):138-139

Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, AT-1090 Vienna, Austria.

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http://dx.doi.org/10.2340/00015555-2778DOI Listing
January 2018

Gonococcal infections in Austria: a long-term observation of prevalence and resistance profiles from 1999 to 2014.

J Dtsch Dermatol Ges 2015 Nov;13(11):1136-45

Outpatient Clinic and Other Venereal/Dermatologic Diseases, Vienna, Austria.

Background And Objectives: The increase in minimum inhibitory concentrations (MICs) of cephalosporins for Neisseria gonorrhoeae has given rise to concerns regarding potentially untreatable gonococcal infections. The goal was to ascertain the prevalence of gonorrhea in a Viennese patient group and determine resistance patterns. Another objective was to evaluate resistance profiles and MIC values of gonococcal isolates in an Austria-wide surveillance project.

Patients And Methods: From 1999 to 2014, 350,000 individuals were tested for gonococci at the Viennese Outpatient Clinic. In addition, from 2010 to 2014, the MICs of recommended antibiotics was determined in 3,584 gonococcal isolates, initially by agar dilution and breakpoint determination, and, from 2012 onwards, by Etest®.

Results: During the observation period, the prevalence of gonorrhea increased eightfold, with a significantly greater number of quinolone, penicillin, and tetracycline- resistant strains. In gonococcal strains isolated from across Austria, there was an increase in cefixime and ceftriaxone MICs toward breakpoints. Twenty-one isolates showed cefixime resistance, and while there was an increase in azithromycin resistance from 0.9 % (2013) to 3.2 % (2014), no resistance to ceftriaxone was observed.

Conclusion: Currently, there is no imminent risk of untreatable gonorrhea in Austria. However, continuing the use of gonococcal cultures as a diagnostic tool for establishing resistance profiles is essential in order to monitor trends in the development of Neisseria (N.) gonorrhoeae resistance.
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http://dx.doi.org/10.1111/ddg.12816DOI Listing
November 2015

VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells.

Science 2015 Jun;348(6241):aaa8205

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.

Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ-producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct-cSAP targeted immunogenic uterine CD11b(+)CD103(-) dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b(-)CD103(+) DCs. Regardless of vaccination route, UV-Ct-cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (T(RM) cells). Optimal Ct clearance required both T(RM) seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct-cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties.
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http://dx.doi.org/10.1126/science.aaa8205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605428PMC
June 2015

CCL7 contributes to the TNF-alpha-dependent inflammation of lesional psoriatic skin.

Exp Dermatol 2015 Jul 4;24(7):522-8. Epub 2015 May 4.

Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Chemokines are small chemotactic proteins that have a crucial role in leukocyte recruitment into tissue. Targeting these mediators has been suggested as a potential therapeutic option in inflammatory skin diseases such as psoriasis. Using quantitative RT-PCR, we found CCL7, a chemokine ligand known to interact with multiple C-C chemokine receptors, to be markedly increased in lesional psoriasis as opposed to atopic dermatitis, lichen planus, non-lesional psoriatic and normal control skin. Surprisingly, this increase in CCL7 mRNA expression exceeded that of all other chemokines investigated, and keratinocytes and dermal blood endothelial cells were identified as its likely cellular sources. In an imiquimod-induced psoriasis-like mouse model, CCL7 had a profound impact on myeloid cell inflammation as well as on the upregulation of key pro-psoriatic cytokines such as CCL20, IL-12p40 and IL-17C, while its blockade led to an increase in the antipsoriatic cytokine IL-4. In humans receiving the TNF-α-blocker infliximab, CCL7 was downregulated in lesional psoriatic skin already within 16 hours after a single intravenous infusion. These data suggest that CCL7 acts as a driver of TNF-α-dependent Th1/Th17-mediated inflammation in lesional psoriatic skin.
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http://dx.doi.org/10.1111/exd.12709DOI Listing
July 2015

Epidermal elafin expression is an indicator of poor prognosis in cutaneous graft-versus-host disease.

J Invest Dermatol 2015 Apr 18;135(4):999-1006. Epub 2014 Nov 18.

Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address:

Graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. In the skin, GVHD can present in an acute (aGVHD), chronic lichenoid (clGVHD), or chronic sclerotic form (csGVHD). Measuring peripheral blood levels of the keratinocyte-derived protease inhibitor elafin has recently emerged as a promising tool for the diagnosis of cutaneous aGVHD. We evaluated whether the analysis of elafin expression in skin would allow distinguishing aGVHD from drug hypersensitivity rashes (DHR) and whether cutaneous elafin expression would correlate with disease severity or altered prognosis of aGVHD and clGVHD/csGVHD. Skin biopsies from aGVHD (n=22), clGVHD (n=15), csGVHD (n=7), and DHR (n=10) patients were collected and epidermal elafin expression and its association with diverse clinical/histological parameters were analyzed. Acute GVHD and DHR displayed varying degrees of elafin expression. No elafin was detectable in csGVHD, whereas the molecule was increased in clGVHD as compared with aGVHD. Elafin-high aGVHD/clGVHD lesions presented with epidermal thickening and were associated with poor prognosis-i.e., decreased overall survival in aGVHD and corticosteroid resistance in clGVHD. Although cutaneous elafin does not seem to discriminate aGVHD from DHR lesions, our study strongly suggests an association between cutaneous elafin expression and poor prognosis for patients with cutaneous GVHD.
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http://dx.doi.org/10.1038/jid.2014.489DOI Listing
April 2015

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease.

Blood 2014 Jan 19;123(2):290-9. Epub 2013 Nov 19.

Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n = 25), clGVHD (n = 17), and csGVHD (n = 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n = 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4(+) T cells. Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-γ- and IL-17-producing CD8(+) T cells. Our findings shed new light on the T-cell responses involved in the different manifestations of cutaneous GVHD and identify molecular signatures indicating the development of the disease.
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http://dx.doi.org/10.1182/blood-2013-07-514372DOI Listing
January 2014

Syphilis: the great mimicker.

Int J Dermatol 2014 Mar 11;53(3):e166-8. Epub 2012 Dec 11.

Departments of Radiology, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/j.1365-4632.2012.05760.xDOI Listing
March 2014

Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial.

Obstet Gynecol 2012 Jul;120(1):152-9

Department of General Gynaecology and Gynaecological Oncology, Comprehensive Cancer Center, the Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, and the Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, and the Karl Landsteiner Institute for Gynecologic Surgery and Oncology, Vienna, Austria.

Objective: Alternatives to surgical therapy are needed for the treatment of high-grade cervical intraepithelial neoplasia (CIN 2-3). We aimed to estimate the efficacy of a treatment with imiquimod, a topical immune-response modulator, in patients with CIN 2-3.

Materials And Methods: Fifty-nine patients with untreated CIN 2-3 were randomly allocated to a 16-week treatment with self-applied vaginal suppositories containing either imiquimod or placebo. The main outcome was efficacy, defined as histologic regression to CIN 1 or less after treatment. Secondary outcomes were complete histologic remission, human papillomavirus (HPV) clearance, and tolerability. Assuming a two-sided 5% significance level and a power of 80%, a sample size of 24 patients per group was calculated to detect a 35% absolute increase in CIN 2-3 regression.

Results: Histologic regression was observed in 73% of patients in the imiquimod group compared with 39% in the placebo group (P=.009). Complete histologic remission was higher in the imiquimod group (47%) compared with the placebo group (14%) (P=.008). At baseline, all patients tested positive for high-risk HPV. Human papillomavirus clearance rates were increased in the imiquimod group (60%) compared with the placebo group (14%) (P<.001). In patients with HPV-16 infection, complete remission rates were 47% in the imiquimod group compared with 0% in the placebo group (P=.003). Microinvasive cancer was observed in three of 59 (5% [1-14%]) patients, all within the placebo group. Topical imiquimod treatment was well tolerated, and no high-grade side effects were observed.

Conclusion: Topical imiquimod is an efficacious and feasible treatment for patients with CIN 2-3.
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http://dx.doi.org/10.1097/AOG.0b013e31825bc6e8DOI Listing
July 2012

CD4+ T cells are necessary and sufficient to confer protection against Chlamydia trachomatis infection in the murine upper genital tract.

J Immunol 2012 Sep 1;189(5):2441-9. Epub 2012 Aug 1.

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Chlamydia trachomatis infection is the most common bacterial sexually transmitted disease in the United States. Chlamydia infections that ascend to the upper genital tract can persist, trigger inflammation, and result in serious sequelae such as infertility. However, mouse models in which the vaginal vault is inoculated with C. trachomatis do not recapitulate the course of human disease. These intravaginal infections of the mouse do not ascend efficiently to the upper genital tract, do not cause persistent infection, do not induce significant inflammation, and do not induce significant CD4⁺ T cell infiltration. In this article, we describe a noninvasive transcervical infection model in which we bypass the cervix and directly inoculate C. trachomatis into the uterus. We show that direct C. trachomatis infection of the murine upper genital tract stimulates a robust Chlamydia-specific CD4⁺ T cell response that is both necessary and sufficient to clear infection and provide protection against reinfection.
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http://dx.doi.org/10.4049/jimmunol.1103032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690950PMC
September 2012

Fc-epsilon-RI, the high affinity IgE-receptor, is robustly expressed in the upper gastrointestinal tract and modulated by mucosal inflammation.

PLoS One 2012 27;7(7):e42066. Epub 2012 Jul 27.

Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: The role of the high affinity IgE receptor, FcεRI, in IgE-mediated immune responses of the gastrointestinal (GI) mucosa is poorly understood. Currently, a detailed characterization of FcεRI expression throughout the human gut is lacking. The aim of this study was to define the expression pattern of FcεRI in the GI tract.

Methods/principal Findings: We compared FcεRI expression in children with gastritis/esophagitis (n = 10), celiac disease (n = 10), inflammatory bowel disease (IBD) (n = 9), and normal mucosa (n = 5). The α-subunit of FcεRI (FcεRIα), detected by immunohistochemistry, was found on cells infiltrating the mucosa of the esophagus, the stomach, and the duodenum, but was rarely detected in more distal sections of the GI tract. Accordingly, quantitative RT-PCR analysis on esophagus, stomach, duodenum, colon, and rectum biopsies revealed that FcεRIα and -β expression levels decreased towards the distal intestine. mRNA transcripts of the common Fc-receptor-γ chain were present in the entire GI mucosa. Double-immunofluorescence staining of esophageal specimens confirmed that FcεRIα was expressed on intraepithelial mast cells and Langerhans cells. The mRNA expression levels of the α, β, and γ subunits of FcεRI did not correlate with total serum IgE but were associated with mucosal inflammation.

Conclusion/significance: Our data define the upper GI tract as the main site for IgE-mediated immune activation via FcεRI. Tissue mRNA levels of FcεRIα are regulated by inflammatory conditions rather than serum IgE, indicating that FcεRI might also play a role in pathologies other than allergy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042066PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407106PMC
January 2013
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