The allergic type-2 polarization of the airway epithelial barrier is crucial in childhood asthma and allergies. Variants in the 17q21 genetic locus compromise mucosal viral defense and barrier integrity, increasing susceptibility to asthma. This project aims to uncover IL-4-independent mechanisms driving E2 polarization in the airway epithelium and their role in allergic sensitization. Employing advanced techniques such as in silico analysis of nasal transcriptomes, qPCR, mRNA microarrays, single-cell RNA sequencing (scRNAseq), confocal microscopy, flow cytometry, inhibition assays, CRISPR/Cas9 knock-outs, and DNA methylation arrays, we will identify novel genes and transcription factors involved. The tandem approach combines ex vivo sample collection and analysis by the medical trainee with functional in vitro work by the PhD student. This collaboration will comprehensively elucidate disease mechanisms, paving the way for targeted therapeutic interventions.

Atopic dermatitis (AD) is a multifactorial chronic disease with growing prevalence worldwide. Affected patients have an increased risk of developing other atopic diseases such as asthma, but the exact mechanisms and the underlying immune events have not yet been fully elucidated. We developed a mouse model for early AD and identified a central role of the induction of Interleukin (IL-) 4 and IL-13 in the skin driving early AD. Interestingly, we found that subtle alterations of the skin barrier and in the cutaneous microbiome, which are key factors of the pathogenesis of AD, already lead to immune consequences detectable in the lungs. Of note, these alterations were induced in a limited area of the skin only but elicited systemic effects. We now want to investigate in depth the extent to which these skin-derived changes in the lungs lay the cornerstone for increased susceptibility to sensitization and the development of allergic asthma. To answer this question, in addition to well-established pre-clinical models for AD and asthma, we have several transgenic mouse lines, including reporter mice, at our disposal. In particular, we have a double reporter mouse line allowing us to monitor simultaneously the induction of IL-4/IL-13 producing cells, which are underlying both AD and asthma. As it has been shown in patients that blocking the IL-4/IL-13 pathway leads to an improvement of both AD and asthma, we will focus on their role, but also investigate the upstream inducers of these signature cytokines, especially alarmins such as IL-25, TSLP, and IL-33, and their role in percutaneous asthma induction.

As a specialized center in a university hospital, we take care of large AD/asthma patient cohorts, conduct various clinical studies, and also have an extensive biobank containing patient samples, allowing us to translationally develop insights from pre-clinical analyses to the clinic.

We have a well-equipped laboratory and our research group is highly experienced in analytical methods such as flow cytometry, cell sorting, single-cell RNA sequencing analysis, multiplex expression analysis, immunohistochemical staining, and ex vivo cell culture experiments. Furthermore, we have well-established cooperations for high-end analyses, such as those established in the core facilities of the Technical University.

Wheat-derived food products are dominant in Western diets.  Yet the human immune system may fail to tolerate it and mount adverse immune responses to wheat. Thus, wheat proteins can elicit both autoimmune (celiac disease) and allergic diseases (wheat allergy, protein dermatitis), which are common diagnoses in patient care. However, the underlying mechanisms leading to sensitization to wheat proteins is much less well understood. Recently, it has been discovered that percutaneous sensitization is an important mechanism for the development of food allergy in atopic dermatitis (AD) and that the most common wheat allergy in adults, called wheat-dependent exercise-induced anaphylaxis (WDEIA), can also be elicited through the skin. Being a center for patients with food allergy, we take care of one of the largest cohorts of patients with WDEIA.

In our large WDEIA and AD patient cohorts, we established new methods for patient characterization, including atopy skin tests, skin microdialysis, tape stripping, microbiopsies, transcriptome and microbiome analyses. Furthermore, we have developed models for percutaneous sensitization and initiation of food allergy to several allergens and identified dominant immune targets in the process of establishing a type 2 dominant immune response using single-cell RNA sequencing analyses and reporter mice for Interleukin (IL-)4 and IL-13 as well as the corresponding knock-out mice. These models allow us to decipher the immune cascade underlying percutaneously acquired allergies, including wheat allergy. To successfully accomplish these investigations, we routinely apply established mouse models for cutaneous barrier disruption and dermatitis, food allergy, and asthma and perform, among others ex-vivo cellular analyses and culture, quantitative PCR, single-cell RNAseq analysis, high dimensional flow cytometry and sorting from different organs including the skin, multiplex and other immune assays, histology and fluorescent immunohistology.

These human and mouse models will explore the function of the skin barrier and of upstream signals driving IL-4/ IL-13 in the development of food allergy. This will lead to the discovery of novel targets for diagnosis, treatment, and possibly even prevention of wheat allergy and beyond. Joining our team and working on this project provides the opportunity to participate in state-of-the-art research activities close to medicine and based on high-end technologies and our ample experience in research and supervision, also within the research training group 2668, we secure successful research and training.

The IgE:FcεRI module on mast cells is one of the most fascinating switches in immunology. Mast cells continuously acquire secreted antibodies (IgE) from the circulation and utilize them as antigen receptors, thereby reflecting acute and chronic B cell responses. When IgE is directed against harmless substances (allergens), allergen exposure leads to mast cell degranulation with potentially dramatic short and long-term consequences for the host. We are addressing critical mast cell functions with systems biological approaches. We determined global mast cell secretomes, also under conditions mimicking chronic type 2 inflammation, by mass spectrometry, and we are defining the biology of individual released mediators. Furthermore, we optimized the kinetics of allergen-induced degranulation to determine phosphoproteomes, as well as to conduct small and large-scale CRISPR-Cas9 screens for degranulation mediators.

We are investigating candidate critical regulators of mast cell activation and degranulation that emerged from our kinetic phosphoproteomic profiling and our CRISPR screens in molecular detail. Discovery and detailed functional studies are conducted in primary mouse mast cells, followed by cross-species validation in human mast cell lines and primary human skin mast cells. Further screens, data integration and follow-up studies in mouse models aim to provide a systems view of mast cell degranulation. In addition, we are developing mast cell activation tests for allergy diagnostics based on genetically modified conditionally immortalized mast cell progenitors and novel mast cell lines.

Allergen-specific immunotherapy (AIT) is a tolerogenic vaccination and the only causal therapy for allergies. While this therapy is curative for insect venom anaphylaxis, it is only partially effective for other forms of allergy and is rarely used in autoimmune diseases. Despite extensive research, there are still many unanswered questions about how repetitive allergen injections induce allergen-specific tolerance and which parameters promote tolerance induction.

The aim of this proposal is to explore the mechanisms of AIT, specifically focusing on the molecular key regulators and hub genes that promote tolerance and help to overcome allergies. Our recent studies have observed a transient increase in type-1 and type-3 immunity, such as elevated frequencies of Th1, Th17, and CCR6+ IL-17+ FoxP3+ T-cells (Tr17). In murine studies, Th17 cells have been shown to transdifferentiate into Tregs via an intermediate subset resembling human Tr17 cells. Additionally, Tregs can transdifferentiate into Th17 cells. Tr17 and Th17 cells decrease in the initial treatment phase but recover and increase significantly during the tolerance induction phase in AIT. These results suggest a role for this subset in AIT. However, the factors that initiate these cells are still unknown.

Based on our bioinformatic analysis in the first generation RTG2668 project we were able to show that therapy-success correlating Tr17 cells are progressing to differentiated inti iTregs and identify genes that support this differentiation progress. The results suggest that TNF-family members play an important role, particularly TNFR2 and LTA. As non-cannonical Nf-kB signalling was previously suggested to play a role in anti-inflammatory immunity, we hypothesise that TNF triggers non-cannonical Nf-kB signalling to drive Treg induction. A balance of pro- and anti- TNF signalling may represent a critical switch factor in the induction of allergen tolerance.

The developmental origins of health and disease (DOHaD) concept has revealed the profound impact of the prenatal environment on postnatal health outcomes. We have previously shown that chronic maternal infection during pregnancy shapes the fetal immune system and thus alters responses to allergic challenges later in life. These in utero effects were partially driven by the concurrent maternal immune responses and were distinctly dependent of the cytokine milieu. To explore the underlying mechanisms and communication pathways between mothers and their offspring as a molecular switches driving the propensity to develop allergies, we established the so-called maternal immune activation (MIA) model which allows a very focused exploration of in utero exposure to cytokines elicited by a microbial compound. Steady-state analyses of diverse relevant immunological anatomical sites at different developmental stages of offspring revealed alterations in the hematopoietic stem cells (HSCs) and other precursor cells in the bone marrow, indicating a shift towards activated hematopoiesis. In lungs of adult MIA-offspring, a decrease of cDCs, especially cDC2 with decreased expression of activation markers were observed especially in females, whereas male offspring reacted more vigorously to intranasal house-dust mite (HDM) challenge as a model for allergic airway inflammation, indicating as yet unclear sex-dependent outcomes of maternal exposures. Further research will explore in greater detail the imprinting of the bone marrow and lung environment using scRNA and scATAC sequencing and data integration methods as well as offspring cytokine sensing modalities via cytokine administration and cytokine receptor knock-out mice.

Over recent years, the incidence of many autoimmune diseases, such as Multiple Sclerosis (MS) and Type 1 Diabetes (T1D), has been on the rise. However, the pathogenesis of most autoimmune diseases remains poorly understood, and current treatments are often broadly immunosuppressive or merely slow disease progression. Therefore, a deeper understanding of the initiation, maintenance, and progression of autoimmune diseases is highly desired to develop new therapeutic approaches with greater specificity and efficacy.

In this context, targeting and eliminating pathogenic T cells could be particularly rewarding, as these have been identified as potential drivers of multiple autoimmune diseases. Here, Adoptive Cellular Therapy (ACT) could be a valuable approach as it has shown remarkable success in treating hematologic malignancies, and its application is rapidly expanding to other fields, including infections and autoimmune disorders. Current ACT approaches, however, often involve the broad depletion of entire cell populations (e.g., the entire B cell compartment). Thus, specific elimination of identified pathogenic T cell subsets could be more effective and minimize adverse effects.

Secondly, a major challenge in ACT remains its reliance on autologous donor material, underscoring the need for universal, off-the-shelf cell products. In that regard, we have recently demonstrated that reducing HLA expression could be a viable strategy for achieving universal compatibility. The generation of a functional and safe T cell product is central to the success of ACT. A considerable effort is being made to improve its profile, particularly since the advent of CRISPR/Cas9, which has revolutionized the field of genome engineering and is progressively replacing traditional viral-based approaches.

Building on these recent advancements, our objective is to establish and characterize enhanced, universal T cell products in vitro through the application of base editing, a highly efficient genome-editing tool for precise and simultaneous multiplexed gene disruption. We have already implemented base editing technique in primary human T cells using novel Base Editors (BEs). Additionally, we are actively investigating autoreactive T cells in T1D to identify key pathogenic clones. These findings will be translated into preclinical mouse models to develop adoptive cellular therapies that selectively target and deplete the pathogenic T cell subsets driving autoimmunity. By focusing on the generation of universal T cell products, we seek to create a standardized therapeutic platform for treating multiple autoimmune diseases, simplifying treatment and reducing costs by eliminating the dependence on patient-specific, autologous donor material.

Human endogenous retroviruses (HERVs) are ancient viral remnants embedded in the human genome. Although normally inactive, environmental triggers such as infections or cellular stress can reactivate these sequences, leading to the expression of viral RNAs and proteins. Such reactivation can mimic pathogen-associated signals and activate innate immune receptors, promoting cytokine production and chronic inflammation. Persistent inflammation is a hallmark of autoimmune and inflammatory skin diseases. Therefore we aim to understand how HERV misregulation contributes to inflammatory signalling and barrier dysfunction in the skin. By integrating molecular, genomic, and functional approaches, we investigate how environmental triggers, HERV regulation, and immune pathways interact. This work will help elucidate how HERV-driven molecular switches influence autoimmune skin diseases and may ultimately pave the way for therapeutic strategies that modulate HERV activity.

B cells are known to play a substantial role in the pathogenesis of various autoimmune disorders including autoimmune bullous diseases. The metabolic composition of the B cell microenvironment changes in a dynamic manner in response to infection or inflammation. Access to metabolites not only drives energy generation but also shapes cell signaling and cell fate decisions. Our overarching goal is to determine whether the access to specific nutrients affects B cell redox balance, BAFF- and B cell receptor mediated signaling as well as differentiation to plasma cells and regulatory B cells in the context of autoimmune bullous diseases. Moreover, we seek to determine whether targeting redox homeostasis of normal and aberrant B cells can alter humoral immune responses. To this end we will use a combination of in vivo and in vitro models and assess metabolic reprogramming, redox balance and cell fate decisions. In summary, our goal is to determine whether the metabolic microenvironment affects B cell fate decisions in an autoimmune setting and to test how ROS scavengers affect B cell responses.

Autoinflammatory disorders are a complex group of severe diseases characterized by hyperactivation of macrophage-dendritic cell lineages and excessive production of inflammatory cytokines, resulting in tissue damage and potentially multiorgan failure. Understanding the molecular basis of these diseases is crucial for developing novel therapies and biomarkers for disease stratification. Recently, we found that DC-intrinsic CARD11 gain-of-function (CARD11-GOF) signalling can trigger autoinflammatory pathology by engaging BCL10 and MALT1 to form an aberrant CBM complex and that this aberrant CBM signalling can drive hemophagocytic lymphohistiocytosis (HLH)-like autoinflammation (Isay et al., PNAS 2024). Building on this discovery, we aim to dissect the underlining mechanism. We will employ methods such as primary immune cell culture, stimulation experiments, histopathology, and immune cell infiltrate analysis. RNA sequencing and bioinformatic analysis will correlate our findings with clinical disease parameters. This research seeks to provide a comprehensive understanding of aberrant CBM signaling in autoinflammation, potentially leading to novel therapeutic approaches.

Foxp3+ regulatory T (Treg) cells are indispensable to maintaining peripheral immune tolerance. Depletion of Treg cells or loss of function of Foxp3 results in multiorgan autoimmunity. More recently, it has become clear that Treg cells can take residence in a variety of non-lymphoid tissues. At these sites, Treg cells do not subserve immune functions but are engaged in the homeostatic function of their specific niche. For instance, in the visceral adipose tissue, Treg cells control insulin resistance. In the central nervous system, the number of Treg cells is exceedingly low in steady state. However, after an autoimmune attack, a Treg cell „niche“ is established in the CNS that exists for extended periods of time even after the recovery from the autoimmune inflammatory episode. The conditions of Treg cell maintenance in the CNS and their function in this niche are essentially unknown. This project will focus on this topic:

Aim 1: Generation and analysis of spatial transcriptomics data of the post-inflammatory Treg cell niche in the CNS.

Aim 2: Genetic ablation of a major transcription factor in CNS Treg cells and investigation of the functional stability and localization of these „perturbed“ Treg cells in the post-inflammatory Treg cell niche.

Aim 3: Fate mapping of „unstable“ wild-type CNS Treg cells and analysis of their conversion into alternative fates upon loss of Foxp3+ expression, specifically in the CNS.

Immune-mediated inflammatory diseases have emerged as important drivers of clinically relevant organ-specific diseases. The mechanisms determining the switch from homeostatic immune responses in tissue and protective immune responses during infections with pathogens towards tissue-damaging immune responses have remained largely elusive. We have recently reported that the pro-inflammatory mediator IL-15 triggers the differentiation of CD8 T cells towards cells that have the potential to kill tissue cells independently from MHC-restricted cognate antigen recognition and T cell receptor signalling. We termed this antigen-independent killing of tissue cells by CD8 T cells “auto-aggression”. We reported CD8 T cell auto-aggression as a key feature of metabolic liver disease in mice and MASH patients. During the last funding period of the RTG we have discovered the molecular determinants underpinning human CD8 T cell auto-aggression. Importantly, we found that CD8 T cells with a characteristic transcriptional profile of cells with auto-aggressive function are present in high numbers in tissues of patients with immune mediated inflammatory diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis. We will continue to explore the determinants that act as switches for the generation of CD8 T cells with auto-aggressive function and for the activation of these cells that lead to execution of auto-aggressive killing. Here, we will focus on the role metabolic CD8 T cell programming and metabolites as triggers of activation of CD8 T cells with auto-aggressive function.

AD ranges among the most common inflammatory disease in the Western world but it is yet unknown which factors drive the initiation of eczematous lesions. The research project draws on the established human disease model of AD, the atopy patch test (APT) in which early stages of AD initiation can be investigated even when signs of inflammation are not visible, yet. The project will prospectively investigate the changes of the local skin microbiome in the development of AD and simultaneously the influence of these changes on skin resident Trm cells with the help of human skin swaps, razor scrapings and biopsies. The project will investigate Trm cytokine profiles and surface molecules by flow cytometry and relevant human skin microbial species will be determined by 16S rRNA sequencing. The temporal dynamics and specificity of interactions in the activation of Trm cells will be investigated by cross culture of early lesional immune cells with late lesional bacteria lysates and vice versa. Finally, the influence of routine treatments such as antiseptic UV-light, calcineurin inhibitors and systemic cyclosporine on the hereby identified targets will be studied to open new therapeutic options for AD.

Atopic dermatitis (AD) is a frequent inflammatory skin disease and type 2 immune responses are crucially involved in AD pathogenesis, in development of AD comorbidities, in the severe itch in AD, and in driving co-existing allergies. Despite recent insights highlighting the role of skin barrier disruption and cutaneous microbial dysbiosis, the exact interplay of immune cells initiating type 2 immunity in AD development ist still unclear. New targeted therapies for AD (e.g. therapeutic antibodies blocking interleukin (IL-)4 and/or IL-13) may also allow early interventions but a better understanding of the cascade of immune events leading to IL-4 and IL-13 induction is needed. Investigations in human AD and in appropriate pre-clinical models will decipher the cellular network of immune cells underlying type 2 inflammation. In mice, where the IL-4 and/or IL-13 promoters are fluorescently tagged, cells that turn on production of IL-4 and/or IL-13 will be monitored. Localization, time points and cellular composition of IL-4 and/or IL-13 producing cells will be assessed. Established protocols of titrated skin barrier disruption and/or forced cutaneous dysbiosis for the initiation of AD along with AD models will be investigated using these mice. The aim is to decipher specific or redundant roles of IL-4+ and IL-13+ cells for induction of type 2 immunity and for AD also using the respective knock-out mice. Findings will be validated a) in humans with AD including in those from our clinical trial unit with novel therapies, b) in samples from induced barrier disruption, and c) in AD-specific skin tests.

AD is a complex and heterogeneous disease leading to cutaneous and systemic inflammation. While there is an overall consensus that Th2 immunity plays a major role in diseases pathogenesis, about 30% of patients treated with targeted therapies against Th2 key pathways do not achieve sufficient improvement of skin symptoms. This clinical observation implicates that there are different, so far unidentified disease endotypes. Therefore, this research project aims to identify cutaneous immune switches mediated by recently approved systemic therapies for AD with different modes of action (MOA). Patients treated with systemic therapies in the outpatient clinic of the department of Dermatology and Allergology will be included in the study. We will perform in depth clinical and immunological phenotyping including full-body, three-dimensional photography, measurements of skin functions, such as transepidermal water loss, collect skin microbiome samples, blood for flow cytometry analysis and skin biopsies for single cell RNA-seq. Correlating clinical outcomes with single cell RNA-seq data as well as microbiome composition will allow to create a network of genes and microbes correlated to full or partial disease regression or treatment failures. Newly identified hub genes will further be investigated by stimulating primary keratinocytes and three-dimensional skin equivalents with disease specific T cell supernatant, collected from re-stimulated lesional T Cells after CRISPR/Cas induced knock out. This translational approach will allow further mechanistic insight into AD pathogenesis and a better understanding of features predicting optimal therapeutic responses.

We aim to define a core IgE:FcεRI-dependent gene expression module from combined in vitro and ex vivo experiments. Insights will be derived of established CRISPR/Cas9 mediated inducible loss of function approaches in peritoneal mast cells. These experiments will yield a global view on mast cell-derived mediators that could elicit long-lasting effects on immune responses. Targeted and genome-wide CRISPR screens were designed to obtain a systems biological overview over processes critically influencing the surface presence of the IgE:FcεRI complex and downstream consequences, which constitute critical allergic switches. Mass spectrometry-based proteomics will yield a comprehensive overview on mast cell secretomes, how mast cells reconstitute their granule components and how allergic signals (IgE, IL-4) influence this process. Our preliminary results show that mast cell degranulation profoundly affects macrophage differentiation and polarization via multiple mechanisms. Our studies will also set the stage to establish the intracellular localization of newly identified mediators within mast cells and within the mast cell granule network as well as their biological actions upon release from the cells. These insights will have great impact on understanding mast cell biology and the role mast cells play in allergy and homeostasis.

The switch between Th17 and Tregs is also the switch between health and disease and therefore a very major topic not only in allergy and autoimmune disease. More recently we also observe that Tregs and Tr17 cells occur on site of local inflammation in the airway lumen and therefore intend to analyze the function of the cells in fascinating organoid cultures. These models are suitable to explore the function of novel genes that are coming from our single cells sequencing studies (hot and unknown), but they also represent novel targets for diagnosis and treatment of diseases. Technologies are: Cell culture, organoid cultures, quantitative PCR, single cell seq, DNA array technology (mRNA, miRNA, methlome), high dimensional flow cytometry, western blot, targeted metabolomics, mesoscale protein analysis, Luminex, fluorescent immunohistology, life cell imaging, optional also murine disease models including sophisticated tracer systems). For both tandem team member this project provides an institute and supervision 100% dedicated for research.

Helminth parasites not only exert strong immunomodulatory effects on infected hosts, but also influence the allergic predisposition of offspring born to infected mothers. We hypothesized that transmaternal exposure to schistosomiasis drives in utero effects that enhance tolerogenic immune processes in later life. Recently, we have shown that maternal schistosomiasis induces steady-state changes in CD4+ T cell polarization and B cell priming, alongside an altered dendritic cell phenotype sustained into adulthood, providing evidence for complex priming effects imparted by infection via feto-maternal crosstalk. Our continuing work focuses on exploring i) the mechanism of reduced allergic predisposition of these offspring ii) the gestational environment created by chronic helminth infection, particularly at the feto-maternal interface (i.e. in the placenta), and iii) the key gestational factors, such as cytokines, acting as molecular switches for differentially programming the fetal immune system. Furthermore, we will explore the role of trained immunity as a possible driving mechanism for these modifications. To answer these questions, we will build upon our established experimental mouse models evaluating altered inflammatory responses in transmaternally-exposed murine offspring. We assess the immunophenotype, epigenetic and metabolic alterations of key immune compartments that predispose the enhanced resolution of inflammation. Our main methods include amongst others adoptive transfer experiments in allergy models and in vitro co-culture systems. In parallel, using cytokine receptor knock-out or reporter mice we will identify the cellular sources of cytokines produced under chronic helminth infection at the feto-maternal interface, alongside with a developmental assessment of when previously identified immune modifications occur in offspring.

Incidence of type 1 diabetes (T1D) is increasing and infections as well as CD8+ T cells have been identified as potential drivers. However, it is not well understood how ‘healthy’ infection-induced CD8+ T cells that provide protective immunity towards the relevant pathogen differ from ‘pathogenic’ CD8+ T cell responses that mediate T1D. With novel technologies, it is now possible to precisely characterize polyclonal T cell receptor (TCR) repertoires and associated T cell functionality. We will use novel tools, such as single cell mRNA sequencing, Crispr/Cas9-guided orthotopic TCR replacement and TCR avidity measurement by reversible MHC multimer staining (the latter two originally developed in our research groups) to characterize TCR repertoires, T cell maintenance and differentiation in well-established preclinical mouse models of T1D. Our working hypothesis is that ‘healthy’, infection-induced and ‘pathogenic’ T1D-mediating TCR repertoires significantly differ, even when they are directed against exactly the same epitope. In addition, we will investigate the relevance of T effector (Teff) and T memory (Tm) cells for induction and maintenance of T1D and will probe the clonal composition of autoimmune T cell responses over time. Here our working hypothesis is that cooperation of Teff and Tm cells is essential for induction and maintenance of T1D and that distinct T cell clones dominate the induction vs. maintenance phase of T1D. We will in the long-run compare findings from preclinical models with data directly derived from T1D patients.

A plethora of autoimmune phenomena are associated with chronic hepatitis C virus (HCV) infection. HCV infection e.g. causes type II/III mixed cryoglobulinemia (MC), which is characterized by immune complexes containing rheumatoid factor (RF), IgG, and HCV RNA. However, the distinct triggers and cellular networks involved in the activation of RF-synthesizing B cells and inducing autoimmunity are poorly understood. We found a germ-line integrated silent human endogenous retroviral (HERV) element, HERV-K, to be reactivated in HCV-infected patient blood samples Interestingly, the gag protein of HERV-K has amino acid sequence similarities with IgG1-Fc that is targeted by the rheumatoid factor. Scientific question: We reason that reactivation of HERV-K by HCV infection triggers RF-synthesis and in consequence immune complex formation. Thus, we ask whether RF-synthesis by B cells in response to viral mimicry constitutes the Immune Master Switch for autoimmunity in hepatitis C.

Psoriasis is a chronic inflammatory skin disease with a prevalence of 2% in the Western population. It is characterized by an exaggerated type 17 immune response that in turn induces disease hallmarks such as a thickened epidermal layer and infiltration of neutrophils. Until now, it is not well understood if specific antigens are early events or epiphenomena in the pathogenesis of psoriasis – or whether psoriasis is actually autoimmune or auto-inflammatory. In the last decades, auto-antigens derived from human skin have been described, amongst them keratin 17, LL37, ADAMTSL5, Desmoglein3 and PsoP27. However, insights into the causal function of these auto-antigens during psoriasis development and their pathophysiological importance for chronification are mostly missing and an approach delivering a comprehensive overview on auto-antigenic events has not been performed so far. We hypothesize, that immune responses against auto-antigens are common in psoriasis and auto-reactive T cells are causative for the chronic course of inflammation in the skin of patients. Using the HLA ligandome technology and mass spectrometry we identified putative candidates in lesional biopsies of psoriatic skin. Pre-liminary in vitro experiments on the immunogenic role of the peptides confirmed our hypothesis.  To deliver a comprehensive understanding of auto-reactive events in the pathogenesis of psoriasis, ambitious techniques of cellular and molecular biology such as in vitro proliferation assays and FACS analysis using human material will be applied. Moreover, advanced murine in vivo experiments will be performed, thereby getting the unique chance to address the functional role of putative psoriasis auto-antigens in vivo.

There is a long-lasting debate on how autoimmune diseases transform into chronic disease commencing with auto-reactivity, early inflammation as transmitter with ongoing disease as end stage. Is it alterations within tissues, the immune system or both? An important susceptibility locus for human psoriasis contains the gene for CARD14. CARD14 encodes for an inflammatory adapter molecule, which can link external signals in keratinocytes to the activation of BCL10-MALT1 complex and gain-of-mutations in CARD14 can be found in some 24 patients with psoriasis but not in others. To better understand the role of keratinocyte intrinsic BCL10-MALT1 for the human autoimmune disease psoriasis, the respective keratinocytespecific knockouts will be investigated. A broad screening of putative keratinocyte activators and the production of central inflammatory cytokines and chemokines will be used to determine the role of BCL10, MALT1 and MALT1 paracaspase. For the downstream consequences of BCL10-MALT1 activation typical MALT1 substrates will be analyzed as well as the transcriptome of activated keratinocytes. Importantly, linking these analyses to psoriasis, keratinocytes will be activated with IL-17, IL-1β or TNF. Given that BCL10-MALT1 complexes may be activated in humans also in the absence of a CARD14 mutation by still unknown external signals, analyses from defined human samples will be performed to determine such a role. Next to primary human psoriasis samples this includes analyses of small molecule MALT1 paracaspase inhibitors that will be evaluated for their interventional potential in human keratinocytes undergoing activation of the BCL10-MALT1 complex.

Regulatory T (Treg) cells are indispensable for the maintenance of immune tolerance, and deficiency of Treg cells results in multiorgan autoimmunity. However, in recent years, it is increasingly becoming clear that Treg cells are very heterogeneous in terms of specificity and functional phenotype. Treg cells have distinct features according to the tissue and anatomical niche they reside in. In particular, tissue resident Treg cells contribute to the homeostasis and structural integrity of various organs, including the central nervous system (CNS). In previous work, we found that Treg cells that persist in the CNS after an inflammatory episode almost uniformely express the transcription factor Blimp1 (encoded by Prdm1). In preliminary data, we have generated extensive RNAseq, single cell RNAseq and ATACseq data of CNS Treg cells, and identified a variety of Blimp1 target genes to be regulated in CNS Treg cells. We have also set up a system to specifically manipulate Treg cells in vivo in the CNS by CRISPR/Cas9 gene editing. In this project, we will validate distinct Blimp1 target genes in Treg cells in the CNS by loss-of-function approaches in vivo. We will read out immunologic functions of Treg cells but also non-canoncial functions of Treg cells in terms of maintenance of homeostatic functions of CNS-intrinsic cells like astrocytes and lining cells of the cerebrospinal fluid spaces in order to better understand the biology of post-inflammatory CNS tissue.

NAFLD and NASH develop in the context of the metabolic syndrome also frequently observed in patients with psoriasis. Recent insights especially by the group of P. Knolle have elucidated much deeper understanding of the cascade of events and immune cells involved in NAFLD and NASH pathogenesis. It became evident that metabolic signals as well as tissue-specific triggers such as short chain fatty acids and extracellular ATP are involved in orchestrating CXCR6+ CD8 T cells to destroy and harm hepatocytes utilizing a newly described pathway of “auto-aggression”. These insights ask for further exploration to identify specific factors 26 governing this process and will allow to explore the skin as the `other organ´ next to the liver harboring CXCR6+ CD8 T cells in psoriasis. Combining their well-established models and methods for NAFLD and NASH with preclinical models of psoriasis provided by groups of this consortium (A2 (Biedermann), B3 (Eyerich/Garzorz-Stark), B4 (Ruland)) such as the imiquimod-induced or antigen-specific skin inflammation will allow to extend the molecular understanding of T cell aggression from NAFLD and NASH also to skin autoimmunity/auto aggression as well as a causal connection of these diseases through common immune pathological mechanisms. These analyses will also allow to dissect general from tissuespecific mechanisms and those that are driven by the metabolic dysfunction versus those attributable solely to immune activation or both.