Breathe (in the air) : pulmonary immunology in multiple sclerosis

Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system, with etiology still unknown. MS is thought to arise from a complex interplay between genetic and environmental factors. One of the most well established environmental risk factor is smoking, which confers a striking increase in risk of developing MS and especially in interaction with the risk allele HLA-DRB1*15 and absence of the protective allele HLA-A*02. The major part of this thesis is focused on investigating the involvement of the pulmonary immune system in MS, and further to uncover underlying smoking associated changes that could elucidate on the role of smoking as a risk factor in MS. To characterize the lung immune cells, bronchoalveolar lavage (BAL) cells were obtained by bronchoscopy, from healthy volunteers and MS-patients, smokers and non-smokers. In project I we provide an initial characterization of our study cohort. We could observe that smokers carrying the MS specific risk allele HLA-DRB1*15 did not show a smoking-associated increase in macrophages defined in non-carriers. Smokers showed higher frequency of proliferating T-cells, while non-smoking MS-patients had increased levels of preformed CD40L in CD4+ T-cells. We could further provide a more in-depth characterization of pulmonary T-cells in MS-patients and smokers, in Project III. The majority of CD4+T-cells in both healthy and MS patients showed a tissue resident memory phenotype, characterized by expression of CD69 and CD44, while also expressing both CXCR3 and CCR6. Cells from healthy smokers showed an increased proliferative capacity and we also observed a significantly higher frequency of regulatory Tcells in the lungs of both healthy smokers and MS-patients compared to healthy non-smokers. When investigating the migratory profile of lung T-cells based on integrins VLA-4 and LFA- 1, both implicated in MS pathogenesis, we found no upregulation of these in MS patients compared to healthy. In recent years, it has been suggested that dysbiosis of the commensal microbiome in the gut is involved in the pathogenies of MS. The lungs also host a unique commensal microbiota, which recently was shown to be dysregulated in the autoimmune disease Rheumatoid Arthritis and pulmonary Sarcoidosis. In Project IV we investigated if the microbiota in the lungs of MS patients also show dysbiosis. We found that the microbial composition in the lungs of MS patients differed considerably compared to healthy controls, with increased richness and diversity. We could further report that MS patients also had altered expression and presence of the antimicrobial peptide human beta defensin-1 (hBD1) in the lungs. In Project II we developed a novel method, called Small-seq, to study small RNAs, such as microRNAs (miRNA) from a scarce source of starting material; a single cell. Previously methods required large quantities of sample material in order to investigate small RNAs, which often can be a limitation to obtain in clinical samples, as well as average out biological variability and heterogeneity within populations. With Small-seq we are were able to capture different types of small RNAs from single cells, such as miRNA, snoRNA and tsRNA. Captured miRNAs revealed cellular heterogeneity in primed hESC, as well as being able to cluster and separate different cell types. The method implemented a masking strategy to efficiently limit capture of the highly abundant 5.8S rRNA, and incorporation of a unique molecular identifier allowed for molecular quantification of the detected small RNAs. The work provided in this thesis concludes that the pulmonary immune milieu is altered in MS patients, thereby presenting the lungs as an organ of interest for further investigation into the pathology and potential therapeutic opportunities in MS. The described changes in immune cell composition between smokers carrying the MS risk allele HLA-DRB1*15 and noncarriers, could further shed light upon the mechanisms behind the impact of smoking as a risk factor for disease and in exacerbating MS. Herein we further provide the development of a novel technique to capture and investigate small RNA, such as miRNAs in single cell

Structural and dynamic studies of Pr(11^{11}BH4_{4})3_{3}

Rare earth borohydrides RE (BH4)(3) are studied in the context of energy storage, lumines-cence and magnetic applications. We have investigated the structural behavior of pra-seodymium borohydride Pr ((BH4)-B-11)(3) containing B-11 isotope because of the previously reported negative thermal expansion. Differential scanning calorimetry (DSC), in-situ var-iable temperature synchrotron radiation powder X-ray diffraction (SR-PXD) and infrared studies reveal that Pr ((BH4)-B-11)(3) undergoes to a volume contraction during the phase tran-sition from alpha alpha-Pr ((BH4)-B-11)(3) to rhombohedral r-Pr ((BH4)-B-11)(3) phase upon heating to 493 K. Surprisingly, the phase transition persists upon cooling at room temperature. Vibrational analysis also shows that the stretching frequency of BH4-3; anion does not change upon heating which indicates that the B-H bond length remains constant during the structural phase transition from alpha-Pr ((BH4)-B-11)(3) to r-Pr ((BH4)-B-11)(3) phase. Additionally, the energy barrier of reorientation motion of the BH4- anion in the alpha-phase was estimated to be ca 23 kJ/mol by quasi-elastic neutron scattering (QENS) and Raman spectroscopy. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of Hydrogen Energy Publications LLC

Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells

Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for more rapid blood replenishment from stem cells, established models of hematopoiesis implicate only one mandatory differentiation pathway for each blood cell lineage. Here, we establish a nonhierarchical relationship between distinct stem cells that replenish all blood cell lineages and stem cells that replenish almost exclusively platelets, a lineage essential for hemostasis and with important roles in both the innate and adaptive immune systems. These distinct stem cells use cellularly, molecularly and functionally separate pathways for the replenishment of molecularly distinct megakaryocyte-restricted progenitors: a slower steady-state multipotent pathway and a fast-track emergency-activated platelet-restricted pathway. These findings provide a framework for enhancing platelet replenishment in settings in which slow recovery of platelets remains a major clinical challenge

The ARIA-MASK-air® approach

Funding Information: The authors thank Ms Véronique Pretschner for submitting the paper. MASK‐air has been supported by Charité Universitätsmedizin Berlin, EU grants (EU Structural and Development Funds Languedoc Roussillon and Region PACA; POLLAR: EIT Health; Twinning: EIP on AHA; Twinning DHE: H2020; Catalyse: Horizon Europe) and educational grants from Mylan‐Viatris, ALK, GSK, Novartis, Stallergènes‐Greer and Uriach. None for the study. ® Publisher Copyright: © 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.MASK-air®, a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK-air® is a Good Practice of DG Santé on digitally-enabled, patient-centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co-operation and Development). MASK-air® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK-air® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as-needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom-medication score (ARIA-EAACI-CSMS) has been validated for clinical practice and trials. The implications of the novel MASK-air® results should lead to change management in rhinitis and asthma.publishersversionpublishe

Rhinitis associated with asthma is distinct from rhinitis alone: TARIA‐MeDALL hypothesis

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of “one-airway-one-disease,” coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the “Epithelial Barrier Hypothesis.” This review determined that the “one-airway-one-disease” concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme “allergic” (asthma) phenotype combining asthma, rhinitis, and conjunctivitis.info:eu-repo/semantics/publishedVersio

The selenium metabolite methylselenol regulates the expression of ligands that trigger immune activation through the lymphocyte receptor NKG2D

For decades, selenium research has been focused on the identification of active metabolites, which are crucial for selenium chemoprevention of cancer. In this context, the metabolite methylselenol (CH(3)SeH) is known for its action to selectively kill transformed cells through mechanisms that include increased formation of reactive oxygen species, induction of DNA damage, triggering of apoptosis, and inhibition of angiogenesis. Here we reveal that CH(3)SeH modulates the cell surface expression of NKG2D ligands. The expression of NKG2D ligands is induced by stress-associated pathways that occur early during malignant transformation and enable the recognition and elimination of tumors by activating the lymphocyte receptor NKG2D. CH(3)SeH regulated NKG2D ligands both on the transcriptional and the posttranscriptional levels. CH(3)SeH induced the transcription of MHC class I polypeptide-related sequence MICA/B and ULBP2 mRNA. However, the induction of cell surface expression was restricted to the ligands MICA/B. Remarkably, our studies showed that CH(3)SeH inhibited ULBP2 surface transport through inhibition of the autophagic transport pathway. Finally, we identified extracellular calcium as being essential for CH(3)SeH regulation of NKG2D ligands. A balanced cell surface expression of NKG2D ligands is considered to be an innate barrier against tumor development. Therefore, our work indicates that the application of selenium compounds that are metabolized to CH(3)SeH could improve NKG2D-based immune therapy