Publications by authors named "Martin Herrmann"

351 Publications

Agonistic autoantibodies against ß2-adrenergic receptor influence retinal microcirculation in glaucoma suspects and patients.

PLoS One 2021 7;16(5):e0249202. Epub 2021 May 7.

Department of Ophthalmology, University of Erlangen-Nürnberg, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.

Purpose: Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the β2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to β2-agAAb status in patients with OAG.

Material And Methods: Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with high-resolution OCT. FAZ characteristics were measured by OCT-A scans of superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). FAZ-R was calculated (area FAZ (SVP)/area FAZ (ICP)). Using cardiomyocyte bioassays we analysed serum samples for the presence of β2-agAAb.

Results: (I) Total mean FAZ area [mm2]: 0.34±0.16 (SVP), 0.24±0.12 (ICP), and 0.49±0.24 (DCP); mean FAZ-R 1.58±0.94. No correlation was seen for FAZ-R with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (II) ß2-agAAb have been observed in 91% patients and showed no correlation with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (III) FAZ-R correlated significantly with the β2-agAAb-induced increase of the beat rate of cardiomyocyte (p = 0.028).

Conclusion: FAZ characteristics did not correlate with any glaucoma associated functional and morphometric follow-up parameter in the present cohort. However, level of β2-agAAb showed a significantly correlation with FAZ-ratio. We conclude that β2-agAAb might be a novel biomarker in glaucoma pathogenesis showing association to FAZ-ratio with OCT-A.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249202PLOS
May 2021

Connection between Periodontitis-Induced Low-Grade Endotoxemia and Systemic Diseases: Neutrophils as Protagonists and Targets.

Int J Mol Sci 2021 Apr 28;22(9). Epub 2021 Apr 28.

Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91052 Erlangen, Germany.

Periodontitis is considered a promoter of many systemic diseases, but the signaling pathways of this interconnection remain elusive. Recently, it became evident that certain microbial challenges promote a heightened response of myeloid cell populations to subsequent infections either with the same or other pathogens. This phenomenon involves changes in the cell epigenetic and transcription, and is referred to as ''trained immunity''. It acts via modulation of hematopoietic stem and progenitor cells (HSPCs). A main modulation driver is the sustained, persistent low-level transmission of lipopolysaccharide from the periodontal pocket into the peripheral blood. Subsequently, the neutrophil phenotype changes and neutrophils become hyper-responsive and prone to boosted formation of neutrophil extracellular traps (NET). Cytotoxic neutrophil proteases and histones are responsible for ulcer formations on the pocket epithelium, which foster bacteremia and endoxemia. The latter promote systemic low-grade inflammation (SLGI), a precondition for many systemic diseases and some of them, e.g., atherosclerosis, diabetes etc., can be triggered by SLGI alone. Either reverting the polarized neutrophils back to the homeostatic state or attenuation of neutrophil hyper-responsiveness in periodontitis might be an approach to diminish or even to prevent systemic diseases.
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http://dx.doi.org/10.3390/ijms22094647DOI Listing
April 2021

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts.

Immunity 2021 May 23;54(5):1002-1021.e10. Epub 2021 Mar 23.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Deutsches Zentrum fuer Immuntherapie, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
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http://dx.doi.org/10.1016/j.immuni.2021.03.003DOI Listing
May 2021

Complement Activation in Kidneys of Patients With COVID-19.

Front Immunol 2020;11:594849. Epub 2021 Jan 29.

Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany.

Most patients who became critically ill following infection with COVID-19 develop severe acute respiratory syndrome (SARS) attributed to a maladaptive or inadequate immune response. The complement system is an important component of the innate immune system that is involved in the opsonization of viruses but also in triggering further immune cell responses. Complement activation was seen in plasma adsorber material that clogged during the treatment of critically ill patients with COVID-19. Apart from the lung, the kidney is the second most common organ affected by COVID-19. Using immunohistochemistry for complement factors C1q, MASP-2, C3c, C3d, C4d, and C5b-9 we investigated the involvement of the complement system in six kidney biopsies with acute kidney failure in different clinical settings and three kidneys from autopsy material of patients with COVID-19. Renal tissue was analyzed for signs of renal injury by detection of thrombus formation using CD61, endothelial cell rarefaction using the marker E-26 transformation specific-related gene (ERG-) and proliferation using proliferating cell nuclear antigen (PCNA)-staining. SARS-CoV-2 was detected by hybridization and immunohistochemistry. Biopsies from patients with hemolytic uremic syndrome (HUS, n = 5), severe acute tubular injury (ATI, n = 7), zero biopsies with disseminated intravascular coagulation (DIC, n = 7) and 1 year protocol biopsies from renal transplants (Ctrl, n = 7) served as controls. In the material clogging plasma adsorbers used for extracorporeal therapy of patients with COVID-19 C3 was the dominant protein but collectin 11 and MASP-2 were also identified. SARS-CoV-2 was sporadically present in varying numbers in some biopsies from patients with COVID-19. The highest frequency of CD61-positive platelets was found in peritubular capillaries and arteries of COVID-19 infected renal specimens as compared to all controls. Apart from COVID-19 specimens, MASP-2 was detected in glomeruli with DIC and ATI. In contrast, the classical pathway (i.e. C1q) was hardly seen in COVID-19 biopsies. Both C3 cleavage products C3c and C3d were strongly detected in renal arteries but also occurs in glomerular capillaries of COVID-19 biopsies, while tubular C3d was stronger than C3c in biopsies from COVID-19 patients. The membrane attack complex C5b-9, demonstrating terminal pathway activation, was predominantly deposited in COVID-19 biopsies in peritubular capillaries, renal arterioles, and tubular basement membrane with similar or even higher frequency compared to controls. In conclusion, various complement pathways were activated in COVID-19 kidneys, the lectin pathway mainly in peritubular capillaries and in part the classical pathway in renal arteries whereas the alternative pathway seem to be crucial for tubular complement activation. Therefore, activation of the complement system might be involved in the worsening of renal injury. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury.
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http://dx.doi.org/10.3389/fimmu.2020.594849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878379PMC
February 2021

Neutrophil Extracellular Traps Tied to Rheumatoid Arthritis: Points to Ponder.

Front Immunol 2020 29;11:578129. Epub 2021 Jan 29.

Department of Internal Medicine 3, Universitätsklinik Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

In recent years, neutrophil extracellular traps at the forefront of neutrophil biology have proven to help capture and kill pathogens involved in the inflammatory process. There is growing evidence that persistent neutrophil extracellular traps drive the pathogenesis of autoimmune diseases. In this paper, we summarize the potential of neutrophil extracellular traps to drive the pathogenesis of rheumatoid arthritis and experimental animal models. We also describe the diagnosis and treatment of rheumatoid arthritis in association with neutrophil extracellular traps.
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http://dx.doi.org/10.3389/fimmu.2020.578129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878527PMC
January 2021

Impaired fear learning and extinction, but not generalization, in anxious and non-anxious depression.

J Psychiatr Res 2021 03 21;135:294-301. Epub 2021 Jan 21.

Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany; Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany; Comprehensive Heart Failure Center (CHFC), University Hospital of Würzburg, Am Schwarzenberg 15, 97078, Würzburg, Germany; Medical Park Chiemseeblick, Department of Psychosomatic Medicine and Psychotherapy, Rasthausstr. 25, 83233, Bernau am Chiemsee, Germany.

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.
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http://dx.doi.org/10.1016/j.jpsychires.2021.01.034DOI Listing
March 2021

Aggregated neutrophil extracellular traps occlude Meibomian glands during ocular surface inflammation.

Ocul Surf 2021 Apr 2;20:1-12. Epub 2021 Jan 2.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany. Electronic address:

Purpose: Obstructive Meibomian gland dysfunction (MGD) is one of the leading causes of evaporative dry eye disease. Meibomian glands at the eyelid secrete lipids that prevent evaporation of the aqueous tear film. The pathogenesis of obstructive MGD is incompletely understood to date. Herein, we aim to investigate the pathogenesis of obstructive MGD using murine and human samples with various forms of ocular surface inflammation.

Method: The presence of Neutrophil extracellular Traps (NETs) was detected with immunofluorescence analysis of ocular surface discharge and biopsy samples from patients with blepharitis. Tear fluid from patients with MGD and blepharitis were evaluated for the presence of inflammatory mediators using bead based immunoassay. Murine model of allergic eye disease (AED) was performed to investigate the role of NETs in MG occlusion.

Results: we show that the ocular discharge from patients with blepharitis contains aggregated neutrophil extracellular traps (aggNETs). Furthermore, the ducts of human Meibomian glands affected by blepharitis were largely congested by aggNETs. Tear fluid from patients with MGD showed elevated neutrophil chemoattractants (C5a, IL6, IL8 and IL18). C5a and IL8 correlated with the degree of deficiency of tear fluid. In the murine model of allergic eye disease (AED), aggNETs accumulated in the MG leading to occlusion of their ducts and the retrograde pent-up of the fluid followed by acinar atrophy. Constraining aggNET formation by genetic or pharmacological inhibition of peptidyl arginine deiminase type 4 (PADI4) effectively reduced MG damage.

Conclusion: We conclude that aggNETs occlude MG causing MGD after ocular surface inflammation.
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http://dx.doi.org/10.1016/j.jtos.2020.12.005DOI Listing
April 2021

Micronucleus frequency in buccal mucosa cells of patients with neurodegenerative diseases.

Sci Rep 2020 12 17;10(1):22196. Epub 2020 Dec 17.

Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078, Würzburg, Germany.

Neurodegenerative diseases show an increase in prevalence and incidence, with the most prominent example being Alzheimer's disease. DNA damage has been suggested to play a role in the pathogenesis, but the exact mechanisms remain elusive. We enrolled 425 participants with and without neurodegenerative diseases and analyzed DNA damage in the form of micronuclei in buccal mucosa samples. In addition, other parameters such as binucleated cells, karyolytic cells, and karyorrhectic cells were quantified. No relevant differences in DNA damage and cytotoxicity markers were observed in patients compared to healthy participants. Furthermore, other parameters such as lifestyle factors and diseases were also investigated. Overall, this study could not identify a direct link between changes in buccal cells and neurogenerative diseases, but highlights the influence of lifestyle factors and diseases on the human buccal cytome.
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http://dx.doi.org/10.1038/s41598-020-78832-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747561PMC
December 2020

IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients.

Cells 2020 12 12;9(12). Epub 2020 Dec 12.

Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.
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http://dx.doi.org/10.3390/cells9122676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764693PMC
December 2020

NETs Are Double-Edged Swords with the Potential to Aggravate or Resolve Periodontal Inflammation.

Cells 2020 12 5;9(12). Epub 2020 Dec 5.

Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

Periodontitis is a general term for diseases characterised by inflammatory destruction of tooth-supporting tissues, gradual destruction of the marginal periodontal ligament and resorption of alveolar bone. Early-onset periodontitis is due to disturbed neutrophil extracellular trap (NET) formation and clearance. Indeed, mutations that inactivate the cysteine proteases cathepsin C result in the massive periodontal damage seen in patients with deficient NET formation. In contrast, exaggerated NET formation due to polymorphonuclear neutrophil (PMN) hyper-responsiveness drives the pathology of late-onset periodontitis by damaging and ulcerating the gingival epithelium and retarding epithelial healing. Despite the gingival regeneration, periodontitis progression ends with almost complete loss of the periodontal ligament and subsequent tooth loss. Thus, NETs help to maintain periodontal health, and their dysregulation, either insufficiency or surplus, causes heavy periodontal pathology and edentulism.
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http://dx.doi.org/10.3390/cells9122614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762037PMC
December 2020

Neuronal correlates of the visual-spatial processing measured with functional near-infrared spectroscopy in healthy elderly individuals.

Neuropsychologia 2020 11 9;148:107650. Epub 2020 Oct 9.

Center for Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Margarete-Höppel-Platz 1, D - 97080, Würzburg, Germany. Electronic address:

Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) are a globally rising issue. It is necessary to detect such diseases early to find strategies for prevention. Typically, patients with MCI or AD show deviant neuronal patterns, which could be detected early through brain imaging techniques enabling assumptions about pre-existing diseases. Functional Near-Infrared Spectroscopy (fNIRS) is an appropriate imaging method because of its easy and economical nature with hardly any drawbacks. An early measurable risk factor indicating neurodegenerative processes could be a deficit in visual-spatial processing, which is localized in the parietal cortex. In this study, we aimed to measure the hemodynamic response of the visual-spatial processing in the healthy elderly participants of our long-term Vogel Study with fNIRS during the clock-hand-angle-discrimination task (ADT) to deepen our understanding of healthy brain mechanisms. Our results revealed for our healthy sample a significantly increased neuronal brain activity with increasing task difficulties, namely from the long to the middle to the short clock hand during ADT and significantly higher activation in the right hemisphere compared to the left hemisphere as well as in the superior parietal cortex compared to the inferior parietal cortex. Additionally, our behavioral data demonstrated longer reaction times and more errors with an increasing task requirement. We, therefore, assume that visual-spatial processing can successfully be operationalized with fNIRS for healthy elderly people based on ADT. Further fNIRS analyses are planned to investigate pathological neuronal correlates of visual-spatial function in MCI or AD study participants.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107650DOI Listing
November 2020

A pledge for planetary health to unite health professionals in the Anthropocene.

Lancet 2020 Nov 30;396(10261):1471-1473. Epub 2020 Sep 30.

University of North Dakota School of Medicine and Health Sciences, Family and Community Medicine-INMED Program, Grand Forks, ND, USA; Arctic Indigenous Wellness Foundation, Yellowknife, NT, Canada.

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http://dx.doi.org/10.1016/S0140-6736(20)32039-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527204PMC
November 2020

Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones.

Cells 2020 09 22;9(9). Epub 2020 Sep 22.

Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.

Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
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http://dx.doi.org/10.3390/cells9092139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564068PMC
September 2020

Vascular occlusion by neutrophil extracellular traps in COVID-19.

EBioMedicine 2020 Aug 31;58:102925. Epub 2020 Jul 31.

Department of Internal Medicine 3, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.

Background: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood.

Methods: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry.

Patient Findings: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage.

Interpretation: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage.

Funding: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2020.102925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397705PMC
August 2020

The modulating impact of cigarette smoking on brain structure in panic disorder: a voxel-based morphometry study.

Soc Cogn Affect Neurosci 2020 10;15(8):849-859

Department of Psychology, Humboldt-Universität zu Berlin, Berlin 10117, Germany.

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. In total, 143 PD patients (71 smokers) and 178 healthy controls (62 smokers) participated in a multicenter magnetic resonance imaging (MRI) study. T1-weighted images were used to examine brain structural alterations using voxel-based morphometry in a priori defined regions of the defensive system network. PD was associated with gray matter volume reductions in the amygdala and hippocampus. This difference was driven by non-smokers and absent in smoking subjects. Bilateral amygdala volumes were reduced with increasing health burden (neither PD nor smoking > either PD or smoking > both PD and smoking). As smoking can narrow or diminish commonly observed structural abnormalities in PD, the effect of smoking should be considered in MRI studies focusing on patients with pathological forms of fear and anxiety. Future studies are needed to determine if smoking may increase the risk for subsequent psychopathology via brain functional or structural alterations.
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http://dx.doi.org/10.1093/scan/nsaa103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543937PMC
October 2020

Neutrophils as Main Players of Immune Response Towards Nondegradable Nanoparticles.

Nanomaterials (Basel) 2020 Jun 29;10(7). Epub 2020 Jun 29.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nurnberg (FAU), Universitatsklinikum Erlangen, 90154 Erlangen, Germany.

Many nano/microparticles (n/µP), to which our body is exposed, have no physiological way of removal. Our immune system sense these "small particulate objects", and tries to decrease their harmfulness. Since oxidation, phagocytosis and other methods of degradation do not work with small, chemically resistant, and hydrophobic nanoparticles (nP). This applies to soot from air pollution, nano-diamonds from cosmic impact, polishing and related machines, synthetic polymers, and dietary n/µP. Our body tries to separate these from the surrounding tissue using aggregates from neutrophil extracellular traps (NETs). This effectively works in soft tissues where n/µP are entrapped into granuloma-like structures and isolated. The interactions of hydrophobic nanocrystals with circulating or ductal patrolling neutrophils and the consequent formation of occlusive aggregated NETs (aggNETs) are prone to obstruct capillaries, bile ducts in gallbladder and liver, and many more tubular structures. This may cause serious health problems and often fatality. Here we describe how specific size and surface properties of n/µP can activate neutrophils and lead to aggregation-related pathologies. We discuss "natural" sources of n/µP and those tightly connected to unhealthy diets.
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http://dx.doi.org/10.3390/nano10071273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408411PMC
June 2020

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19.

Front Pharmacol 2020 5;11:870. Epub 2020 Jun 5.

Department of Microbiology, Immunology and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.

There is an urgent need for new therapeutic strategies to contain the spread of the novel coronavirus disease 2019 (COVID-19) and to curtail its most severe complications. Severely ill patients experience pathologic manifestations of acute respiratory distress syndrome (ARDS), and clinical reports demonstrate striking neutrophilia, elevated levels of multiple cytokines, and an exaggerated inflammatory response in fatal COVID-19. Mechanical respirator devices are the most widely applied therapy for ARDS in COVID-19, yet mechanical ventilation achieves strikingly poor survival. Many patients, who recover, experience impaired cognition or physical disability. In this review, we argue the need to develop therapies aimed at inhibiting neutrophil recruitment, activation, degranulation, and neutrophil extracellular trap (NET) release. Moreover, we suggest that currently available pharmacologic approaches should be tested as treatments for ARDS in COVID-19. In our view, targeting host-mediated immunopathology holds promise to alleviate progressive pathologic complications of ARDS and reduce morbidities and mortalities in severely ill patients with COVID-19.
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http://dx.doi.org/10.3389/fphar.2020.00870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291833PMC
June 2020

Ethanol consumption inhibits T cell responses and the development of autoimmune arthritis.

Nat Commun 2020 04 24;11(1):1998. Epub 2020 Apr 24.

Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (T) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by T cells, preventing proper spatial organization of T cells to form T:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.
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http://dx.doi.org/10.1038/s41467-020-15855-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181688PMC
April 2020

The mere physical presence of another person reduces human autonomic responses to aversive sounds.

Proc Biol Sci 2020 01 22;287(1919):20192241. Epub 2020 Jan 22.

Center of Mental Health, Department of Psychiatry, Psychosomatic and Psychotherapy, Translational Social Neuroscience Unit, University of Wurzburg, Wurzburg 97080, Germany.

Social animals show reduced physiological responses to aversive events if a conspecific is physically present. Although humans are innately social, it is unclear whether the mere physical presence of another person is sufficient to reduce human autonomic responses to aversive events. In our study, participants experienced aversive and neutral sounds alone (alone treatment) or with an unknown person that was physically present without providing active support. The present person was a member of the participants' ethnical group (ingroup treatment) or a different ethnical group (outgroup treatment), inspired by studies that have found an impact of similarity on social modulation effects. We measured skin conductance responses (SCRs) and collected subjective similarity and affect ratings. The mere presence of an ingroup or outgroup person significantly reduced SCRs to the aversive sounds compared with the alone condition, in particular in participants with high situational anxiety. Moreover, the effect was stronger if participants perceived the ingroup or outgroup person as dissimilar to themselves. Our results indicate that the mere presence of another person was sufficient to diminish autonomic responses to aversive events in humans, and thus verify the translational validity of basic social modulation effects across different species.
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http://dx.doi.org/10.1098/rspb.2019.2241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015327PMC
January 2020

IgA subclasses have different effector functions associated with distinct glycosylation profiles.

Nat Commun 2020 01 8;11(1):120. Epub 2020 Jan 8.

Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.

Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.
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http://dx.doi.org/10.1038/s41467-019-13992-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949214PMC
January 2020

Effect of CBT on Biased Semantic Network in Panic Disorder: A Multicenter fMRI Study Using Semantic Priming.

Am J Psychiatry 2020 03 16;177(3):254-264. Epub 2019 Dec 16.

Department of Psychiatry and Psychotherapy and Marburg Center for Mind, Brain, and Behavior, Philipps-University Marburg, Marburg, Germany (Yang, Konrad, Straube, Kircher); Department of Psychiatry, Psychosomatics, and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, University of Würzburg, Würzburg, Germany (Lueken, Herrmann, Deckert); Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany (Lueken); Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany (Richter, Hamm); Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany (Wittmann, Ströhle); Department of Psychiatry, Agaplesion Diakonieklinikum Rotenburg (Wümme), Germany (Konrad); Department of Clinical Radiology, University of Münster, Münster, Germany (Pfleiderer); Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany (Lang); Department of Psychiatry and Psychotherapy, University of Hamburg, Hamburg, Germany (Lang); Functional Imaging Unit, Institute for Diagnostic Radiology and Neuroradiology, University of Greifswald, Greifswald, Germany (Lotze); Department of Psychiatry, University of Münster, Münster, Germany (Arolt); and Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany (Wittchen).

Objective: Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder.

Methods: An automatic semantic priming paradigm specifically tailored for panic disorder, in which panic symptoms (e.g., "dizziness") were primed by panic triggers (e.g., "elevator") compared with neutral words (e.g., "bottle"), was performed during functional MRI scanning with 118 patients with panic disorder (compared with 150 healthy control subjects) before and 42 patients (compared with 52 healthy control subjects) after an exposure-based CBT. Neural correlates were investigated by comparing 103 pairs of matched patients and control subjects at the baseline (for patients) or T1 (for control subjects) assessment and 39 pairs at the posttreatment or T2 assessment.

Results: At baseline or T1, patients rated panic-trigger/panic-symptom word pairs with higher relatedness and higher negative valence compared with healthy control subjects. Patients made faster lexical decisions to the panic-symptom words when they were preceded by panic-trigger words. This panic-priming effect in patients (compared with control subjects) was reflected in suppressed neural activation in the left and right temporal cortices and insulae and enhanced activation in the posterior and anterior cingulate cortices. After CBT, significant clinical improvements in the patient group were observed along with a reduction in relatedness and negative valence rating and attenuation of neural activation in the anterior cingulate cortex for processing of panic-trigger/panic-symptom word pairs.

Conclusions: The findings support a biased semantic network in panic disorder, which is normalized after CBT. Attenuation of anterior cingulate cortex activation for processing of panic-related associations provides a potential mechanism for future therapeutic interventions.
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http://dx.doi.org/10.1176/appi.ajp.2019.19020202DOI Listing
March 2020

Theranostic markers for personalized therapy of spider phobia: Methods of a bicentric external cross-validation machine learning approach.

Int J Methods Psychiatr Res 2020 06 8;29(2):e1812. Epub 2019 Dec 8.

Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.

Objectives: Embedded in the Collaborative Research Center "Fear, Anxiety, Anxiety Disorders" (CRC-TRR58), this bicentric clinical study aims at identifying biobehavioral markers of treatment (non-)response by applying machine learning methodology with an external cross-validation protocol. We hypothesize that a priori prediction of treatment (non-)response is possible in a second, independent sample based on multimodal markers.

Methods: One-session virtual reality exposure treatment (VRET) with patients with spider phobia was conducted on two sites. Clinical, neuroimaging, and genetic data were assessed at baseline, post-treatment and after 6 months. The primary and secondary outcomes defining treatment response are as follows: 30% reduction regarding the individual score in the Spider Phobia Questionnaire and 50% reduction regarding the individual distance in the behavioral avoidance test.

Results: N = 204 patients have been included (n = 100 in Würzburg, n = 104 in Münster). Sample characteristics for both sites are comparable.

Discussion: This study will offer cross-validated theranostic markers for predicting the individual success of exposure-based therapy. Findings will support clinical decision-making on personalized therapy, bridge the gap between basic and clinical research, and bring stratified therapy into reach. The study is registered at ClinicalTrials.gov (ID: NCT03208400).
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http://dx.doi.org/10.1002/mpr.1812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301283PMC
June 2020

Updates on NET formation in health and disease.

Semin Arthritis Rheum 2019 12;49(3S):S43-S48

Friedrich Alexander University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, 90154 Erlangen, Germany.

Following a recent presentation at ATT Mallorca in May 2019, this paper gives insight into the current research of neutrophil extracellular traps (NETs) and their role in conditions of health and disease. Though NETs reportedly support disease progression and play a role in the development of autoimmune diseases, we argue that NETs are mandatory for the mammalian immune system. They are especially important to patrol and surveil outer and inner body surfaces and are capable to perform major anti-microbial activities. Neutrophils are the first cells to be recruited to wounds, where they form NETs and aggregated NETs (aggNETs). The latter close the wounds and are ever-present in skinfolds, where the integrity of the skin is impaired. On infected ocular surfaces NETs form an antimicrobial barrier, which prevents bacterial dissemination into the brain. In the oral cavity, NETs display anti-bacterial properties. Although NETs on internal body surfaces like ducts and vessels offer superficial surveillance, exaggerated aggNET formation may directly block vessels and ducts and thus cause thrombi and ductal occlusion, respectively. In the case of biliopancreatic ducts, clogging by aggNETs may even cause acute pancreatitis. Insufficient clearance of apoptotic remnants and NETs can lead to autoimmune diseases or unwanted, chronic inflammation. To prevent this, macrophages cloak dead cells, while apoptotic cells are cleared. We conclude that neutrophils, NETs and aggNETs can be considered double edged swords that orchestrate the innate immune response but carry the risk to precipitate autoimmunity and epithelial damage.
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http://dx.doi.org/10.1016/j.semarthrit.2019.09.011DOI Listing
December 2019

Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls.

Neuroimage Clin 2019 21;24:102029. Epub 2019 Oct 21.

Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.

Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural "fear network". We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli.

Method: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific "Westphal-Paradigm". It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety.

Results: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC).

Discussion: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.
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http://dx.doi.org/10.1016/j.nicl.2019.102029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854061PMC
September 2020

Towards a pro-resolving concept in systemic lupus erythematosus.

Semin Immunopathol 2019 11 6;41(6):681-697. Epub 2019 Nov 6.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death-related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.
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http://dx.doi.org/10.1007/s00281-019-00760-5DOI Listing
November 2019

Citrullination Licenses Calpain to Decondense Nuclei in Neutrophil Extracellular Trap Formation.

Front Immunol 2019 22;10:2481. Epub 2019 Oct 22.

Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Deutsches Zentrum Immuntherapie, Kussmaul Campus for Medical Research and Translational Research Center, Erlangen, Germany.

Neutrophils respond to various stimuli by decondensing and releasing nuclear chromatin characterized by citrullinated histones as neutrophil extracellular traps (NETs). This achieves pathogen immobilization or initiation of thrombosis, yet the molecular mechanisms of NET formation remain elusive. Peptidyl arginine deiminase-4 (PAD4) achieves protein citrullination and has been intricately linked to NET formation. Here we show that citrullination represents a major regulator of proteolysis in the course of NET formation. Elevated cytosolic calcium levels trigger both peptidylarginine deiminase-4 (PAD4) and calpain activity in neutrophils resulting in nuclear decondensation typical of NETs. Interestingly, PAD4 relies on proteolysis by calpain to achieve efficient nuclear lamina breakdown and chromatin decondensation. Pharmacological or genetic inhibition of PAD4 and calpain strongly inhibit chromatin decondensation of human and murine neutrophils in response to calcium ionophores as well as the proteolysis of nuclear proteins like lamin B1 and high mobility group box protein 1 (HMGB1). Taken together, the concerted action of PAD4 and calpain induces nuclear decondensation in the course of calcium-mediated NET formation.
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http://dx.doi.org/10.3389/fimmu.2019.02481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817590PMC
September 2020

Live cell imaging of macrophage/bacterium interaction demonstrates cell lysis induced by Corynebacterium diphtheriae and Corynebacterium ulcerans.

BMC Res Notes 2019 Oct 25;12(1):695. Epub 2019 Oct 25.

Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.

Objectives: In frame of a study to characterize the interaction of human macrophage-like cells with pathogenic corynebacteria, Corynebacterium diphtheriae and Corynebacterium ulcerans, live cell imaging experiments were carried out and time lapse fluorescence microscopy videos were generated, which are presented here.

Data Description: The time lapse fluorescence microscopy data revealed new insights in the interaction of corynebacteria with human macrophage-like THP-1 cells. In contrast to uninfected cells and infections with non-pathogenic C. glutamicum used as a control, pathogenic C. diphtheriae and C. ulcerans showed highly detrimental effects towards human cells and induction of cell death of macrophages.
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http://dx.doi.org/10.1186/s13104-019-4733-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815039PMC
October 2019

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).

Eur J Immunol 2019 Oct;49(10):1457-1973

Flow Cytometry Laboratory, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany.

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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http://dx.doi.org/10.1002/eji.201970107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350392PMC
October 2019

Autoantibodies Activating the β2-Adrenergic Receptor Characterize Patients With Primary and Secondary Glaucoma.

Front Immunol 2019 1;10:2112. Epub 2019 Oct 1.

Department of Internal Medicine III, Institute of Clinical Immunology and Rheumatology, University of Erlangen-Nürnberg, Erlangen, Germany.

Recently, agonistic autoantibodies (agAAb) activating the β2-adrenergic receptor were detected in primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients and were linked to intraocular pressure (IOP) (1). The aim of the present study was to quantify β2-agAAb in the sera of glaucoma suspects and patients with primary and secondary glaucoma. Patients with OHT ( = 33), pre-perimetric POAG (pre-POAG; = 11), POAG ( = 28), and 11 secondary OAG (SOAG) underwent ophthalmological examinations including examinations with Octopus G1 perimetry and morphometry. Twenty-five healthy individuals served as controls. Serum-derived IgG samples were analyzed for β2-agAAb using a functional bioassay. The beat-rate-increase of spontaneously beating cultured neonatal rat cardiomyocytes was monitored with 1.6 beats/15 s as cut-off. None of the sera of normal subjects showed β2-agAAb. In POAG or OHT patients increased beating rates of 4.1 ± 2.2 beats/15 s, and 3.7 ± 2.8 beats/15 s were detected ( > 0.05). Glaucoma patients with (POAG) and without perimetric (pre-POAG) defects did not differ (pre-POAG 4.4 ± 2.6 beats/15 s, POAG 4.1 ± 2.0 beats/15 s, > 0.05). Patients with SOAG yielded mean beating rates of 4.7 ± 1.7 beats/15 s ( > 0.05). β2-agAAb were seen in 73% of OHT, 82% of pre-POAG, 82% of POAG, and 91% SOAG patients ( < 0.001). Clinical data did not correlate with beating rate ( > 0.05). The robust β2-agAAb seropositivity in patients with OHT, pre-POAG, POAG, and SOAG suggest a primary common role for β2-agAAb starting early in glaucoma pathophysiology and turned out to be a novel marker identifying all patients with increased IOP independent of glaucoma stage and entity.
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http://dx.doi.org/10.3389/fimmu.2019.02112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779694PMC
October 2020

A network of trans-cortical capillaries as mainstay for blood circulation in long bones.

Nat Metab 2019 02 21;1(2):236-250. Epub 2019 Jan 21.

Bioinformatics and Computational Biophysics, Faculty of Biology, University Duisburg-Essen, Essen, Germany.

Closed circulatory systems (CCS) underlie the function of vertebrate organs, but in long bones their structure is unclear, although they constitute the exit route for bone marrow (BM) leukocytes. To understand neutrophil emigration from BM, we studied the vascular system of murine long bones. Here we show that hundreds of capillaries originate in BM, cross murine cortical bone perpendicularly along the shaft and connect to the periosteal circulation. Structures similar to these trans-cortical-vessels (TCVs) also exist in human limb bones. TCVs express arterial or venous markers and transport neutrophils. Furthermore, over 80% arterial and 59% venous blood passes through TCVs. Genetic and drug-mediated modulation of osteoclast count and activity leads to substantial changes in TCV numbers. In a murine model of chronic arthritic bone inflammation, new TCVs develop within weeks. Our data indicate that TCVs are a central component of the CCS in long bones and may represent an important route for immune cell export from the BM.
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http://dx.doi.org/10.1038/s42255-018-0016-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795552PMC
February 2019