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"Petersen, Frank"
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What Makes Antibodies Against G Protein-Coupled Receptors so Special? A Novel Concept to Understand Chronic Diseases
Expressions of G protein-coupled receptors (GPCR) on immune and tissue resident cells are the consequence of the cellular environment, which is highly variable. As discussed here, antibodies directed to GPCR (GPCR abs), their levels and correlations to other abs, serve as biomarkers for various diseases. They also could reflect the individual interplay between the environment and the immune system. Thus, GPCR abs could display pathogenic chronic conditions and could help to identify disease-related pathways. Moreover, by acting as ligands to their corresponding receptors, GPCR abs modulate autoimmune as well as non-autoimmune diseases. This article introduces GPCR abs as drivers for diseases by their capability to induce a specific signaling and by determining immune cell homeostasis. The identification of the individual GPCR ab function is challenging but might be pivotal in the comprehension of the aetiology of diseases. This, hopefully, will lead to the identification of novel therapeutic strategies. This article provides an overview about concepts and recent developments in research. Accordingly, GPCR abs could represent ideal candidates for precision medicine. Here, we introduce the term antibodiom to cover the network of abs with GPCR abs as prominent players.
Journal Article
The Role of Mast Cells in Autoimmune Bullous Dermatoses
Skin mast cells (MCs), a resident immune cell type with broad regulatory capacity, play an important role in sensing danger signals as well as in the control of the local immune response. It is conceivable to expect that skin MCs regulate autoimmune response and are thus involved in autoimmune diseases in the skin, e.g., autoimmune bullous dermatoses (AIBD). Therefore, exploring the role of MCs in AIBD will improve our understanding of the disease pathogenesis and the search for novel therapeutic targets. Previously, in clinical studies with AIBD, particularly bullous pemphigoid, patients' samples have demonstrated that MCs are likely involved in the development of the diseases. However, using MC-deficient mice, studies with mouse models of AIBD have obtained inconclusive or even discrepant results. Therefore, it is necessary to clarify the observed discrepancies and to elucidate the role of MCs in AIBD. Here, in this review, we aim to clarify discrepant findings and finally elucidate the role of MCs in AIBD by summarizing and discussing the findings in both clinical and experimental studies.
Journal Article
High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19
The coordinated immune response of the host is the key of the successful combat of the body against SARS-CoV-2 infection and is decisive for the development and progression of COVID-19. In this study, we aimed to investigate whether the immunological phenotype of patients are associated with duration of illness in patients with severe COVID-19.
In this single-center study, 69 patients with severe or critical COVID-19 were recruited retrospectively. Immunological parameters including counts of white blood cells, neutrophils, lymphocytes, the neutrophil-to-lymphocyte ratio, and levels of circulating cytokines and cytokine receptors were screened for their association with disease severity, survival and duration of illness of COVID-19.
Our data confirmed previous results that neutrophil-to-lymphocyte ratio and circulating levels of IL-6 represent prominent biomarker for the prediction of disease severity and survival of COVID-19. However, this study shows for the first time that duration of illness in patients with severe COVID-19 is positively associated with serum levels of IL-8 (
=0.004) and soluble IL-2Rα (
=0.025).
The significant association of duration of illness with circulating levels of IL-8 and soluble IL-2Rα in patients with severe COVID-19 implicates that neutrophils and T cells are involved in the evolution of COVID-19.
Journal Article
Granzyme B inhibition reduces disease severity in autoimmune blistering diseases
Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.
Pemphigoid diseases involve autoimmune mediated blistering and immunopathology of the upper dermis. Here, the authors implicate granzyme B in the immunopathology in multiple in vivo models of pemphigoid diseases and utilise a topical granzyme B inhibitor that attenuates disease phenotypes in vivo.
Journal Article
Autoantibodies in Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death worldwide, is characterized by irreversible airflow limitation based on obstructive bronchiolitis, emphysema, and chronic pulmonary inflammation. Inhaled toxic gases and particles, e.g., cigarette smoke, are major etiologic factors for COPD, while the pathogenesis of the disease is only partially understood. Over the past decade, an increasing body of evidence has been accumulated for a link between COPD and autoimmunity. Studies with clinical samples have demonstrated that autoantibodies are present in sera of COPD patients and some of these antibodies correlate with specific disease phenotypes. Furthermore, evidence from animal models of COPD has shown that autoimmunity against pulmonary antigens occur during disease development and is capable of mediating COPD-like symptoms. The idea that autoimmunity could contribute to the development of COPD provides a new angle to understand the pathogenesis of the disease. In this review article, we provide an advanced overview in this field and critically discuss the role of autoantibodies in the pathogenesis of COPD.
Journal Article
Anti-protein arginine methyltransferase 5 (PRMT5) antibodies is associated with interstitial lung disease in rheumatoid arthritis
Recently, anti-protein arginine methyltransferase 5 (PRMT5) antibodies has been identified a novel marker for systemic sclerosis (SSc). The present study aimed to to explore the association between anti-PRMT5 antibodies and rheumatoid arthritis (RA). The study recruited a cohort of 33 patients diagnosed with SSc, 87 patients with RA, and 31 healthy control subjects. Serum levels of the anti-PRMT5 antibodies were measured using a double-antigen sandwich enzyme-linked immunosorbent assay (ELISA). Patients with SSc exhibited higher serum levels (
p
< 0.001) and seropositivity rates (48.5% vs. 0%,
p
< 0.0001) of anti-PRMT5 antibodies compared to healthy subjects. Notably, serum levels of anti-PRMT5 antibodies were significantly elevated in patients with RA compared to healthy controls (
p
< 0.001), with a corresponding increase in the rate of seropositivity (14.9% vs. 0%,
p
< 0.05). Receiver operating curve analysis for anti-PRMT5 antibody levels yielded area under the curve values of 0.768 for distinguishing RA patients from healthy controls, and 0.903 for distinguishing SSc patients from controls. Furthermore, elevated levels of anti-PRMT5 antibodies were significantly associated with the presence of interstitial lung disease (ILD) (
p
< 0.0001) and antinuclear antibody positivity (
p
< 0.01). This study not only confirms the association of the anti-PRMT5 antibodies with SSc but also, for the first time, demonstrates a significant association between the anti-PRMT5 antibodies and RA, particularly in the context of RA-associated ILD.
Journal Article
Autoimmunomic Signatures of Aging and Age-Related Neurodegenerative Diseases Are Associated With Brain Function and Ribosomal Proteins
Biological aging is a complex process featured by declined function of cells and tissues, including those of the immune system. As a consequence, aging affects the expression and development of autoantibodies and autoreactive T cells, which can be seen in their sum as the autoimmunome of an individual. In this study we analyzed whether sets of autoimmune features are associated with specific phenotypes which form autoimmunomic signatures related to age and neurodegenerative diseases. The autoantibody profile data of healthy subjects and patients from the GEO database was used to explore autoimmunomic signatures of aging and three neurodegenerative diseases including Parkinson's disease (PD), Alzheimer disease (AD) and Multiple Sclerosis (MS). Our results demonstrate that the autoimmunomic signature of aging is featured by an undulated increase of IgG autoantibodies associated with learning and behavior and a consistent increase of IgG autoantibodies related to ribosome and translation, and the autoimmunomic signature of aging are also associated with age-related neurodegenerative diseases. Intriguingly, Differential Expression-Sliding Window Analysis (DE-SWAN) identified three waves of changes of autoantibodies during aging at an age of 30, 50, and 62 years, respectively. Furthermore, IgG autoantibodies, in particular those against ribosomal proteins, could be used as prediction markers for aging and age-related neurodegenerative diseases. Therefore, this study for the first time uncovers comprehensive autoimmunomic signatures for aging and age-related neurodegenerative diseases.
Journal Article
Tocilizumab but not Siltuximab prevents systemic inflammation in a humanized mouse model
The present study aimed to assess the therapeutic efficacy of neutralizing monoclonal antibodies targeting a prominent proinflammatory cytokine in a PBMC transfer-induced humanized mouse model of systemic inflammation.
Inflammatory cytokines were measured in human and murine sera using the LEGENDplex™ cytokine panel. Humanized mice were treated with neutralizing antibodies against human IL-6 (Siltuximab) or the human IL-6 receptor (Tocilizumab), along with matched IgG isotype controls.
Cytokine responses in the humanized mouse model were predominantly of human, not murine, origin. Elevated levels of human IL-6 were observed in both SSc patients and their corresponding mouse models. Preventive administration of Tocilizumab reduced anti-nuclear antibody production and mitigated disease severity in the PBMCs-transfer-induced humanized mouse model. In contrast, treatment with Siltuximab, an antibody targeting human IL-6, did not prevent disease development in the humanized mouse model. The lack of efficacy of Siltuximab was associated with the accumulation of human IL-6/anti-human IL-6 monoclonal antibody immune complexes.
These findings highlight the pivotal role of IL-6 signaling in the SSc related systemic inflammation within the humanized mouse model and underscore the therapeutic potential of IL-6 receptor blockade. Furthermore, the PBMCs-based humanized mouse model offers a valuable preclinical platform for evaluating human-specific therapeutic interventions in systemic inflammation.
Journal Article
Study of Pressure Distribution in Floor Tiles with Printed P(VDF:TrFE) Sensors for Smart Surface Applications
Pressure sensors integrated in surfaces, such as the floor, can enable movement, event, and object detection with relatively little effort and without raising privacy concerns, such as video surveillance. Usually, this requires a distributed array of sensor pixels, whose design must be optimized according to the expected use case to reduce implementation costs while providing sufficient sensitivity. In this work, we present an unobtrusive smart floor concept based on floor tiles equipped with a printed piezoelectric sensor matrix. The sensor element adds less than 130 µm in thickness to the floor tile and offers a pressure sensitivity of 36 pC/N for a 1 cm2 pixel size. A floor model was established to simulate how the localized pressure excitation acting on the floor spreads into the sensor layer, where the error is only 1.5%. The model is valuable for optimizing the pixel density and arrangement for event and object detection while considering the smart floor implementation in buildings. Finally, a demonstration, including wireless connection to the computer, is presented, showing the viability of the tile to detect finger touch or movement of a metallic rod.
Journal Article