Title: Notch4, uncovering an immunomodulator in allergic asthmaAuthors: Beatriz Moyaa,b, Manali Mukherjeec and Parameswaran Nairca. Department of Allergy, Hospital Universitario 12 de Octubre, Madrid, Spainb. Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spainc. Division of Respirology, Department of Medicine, McMaster University, Hamilton & Firestone Institute for Respiratory Health, St Joseph’s Healthcare, Hamilton, ON, CanadaCorrespondence to : Beatriz Moya. Allergy Department. Hospital Universitario 12 de Octubre, Madrid, SpainEmail:firstname.lastname@example.orgAcknowledgements : Dr. Mukherjee is supported by investigator award from Canadian Institutes of Health Research and Canadian Allergy, Asthma, and Immunology Foundation. She has received honorarium from AZ, GSK and her university has received grants from Methapharm Speciality Pharmaceuticals. Dr. Nair is supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases. He has received honoraria from AZ, Sanofi, Teva, Merck, Novartis and Equillium and his university has received research grants from AZ, Teva, Sanofi, Novartis, BI and Methapharm. The authors recognize Dr. Anna Globinska for graphical abstract design and Dr. Rodrigo Jiménez-Saiz for critical review of the manuscript.Keywords: Allergic asthma; Airway inflammation; Th2 cell; Th17 cell; Treg cell; Notch4 receptorAbbreviations: Th, T helper; UFPs, pollutant ultrafine particles; AMs, alveolar macrophages; Treg cells, regulatory T cells; ILC2s, type 2 innate lymphoid cells; GDF15, cytokine growth and differentiation factor 15; IL, interleukin; IL-6R, interleukin-6 receptor; IL-4R, interleukin-4 receptorWord count: 918/1000
Methods: Twenty-two French nursing homes were included. COVID-19 had been diagnosed with real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2. Blood S-protein IgG and nucleocapsid (N) IgG protein (N-protein IgG) were measured 21-24 days after the first jab (1,004 residents) and 6 weeks after the second (820 residents). Results: Among the 735 residents without prior COVID-19, 41.7% remained seronegative for S-protein IgG after the first jab vs 2.1% of the 270 residents with a previous positive RT-PCR (p<0.001). After the second jab, only 3% of the 586 residents without prior COVID-19 remained seronegative. However, 26.5% of them had low S-protein IgG levels (50-1050 UA/mL) vs 6.4% of the 222 residents with prior COVID-19. Residents with old infection (first wave), or seropositive for N-protein IgG at the time of vaccination, had the highest S-protein IgG levels. Residents with a prior COVID-19 infection had higher S-protein IgG levels after one dose than those without two jabs. Interpretation: A single vaccine jab is sufficient to reach immunity in residents with prior COVID-19. Most residents without prior COVID-19 are seropositive for S-protein IgG after the second jab, but around 30% have low levels of S-protein IgG. Whether residents with no or low post-vaccine immunity are at higher risk of symptomatic COVID-19 requires further analysis.
Background: Several new variants of SARS-CoV-2 have emerged since fall 2020 which have multiple mutations in the receptor binding domain (RBD) of the spike protein. It is unclear which mutations affect receptor affinity versus immune recognition. Methods: We produced RBD with single mutations (E484K, K417N or N501Y) or with all three mutations combined and tested their binding to ACE2 by biolayer interferometry (BLI). The ability of convalescent sera to recognize RBDs and block their interaction with ACE2 was tested as well. Results: We demonstrated that single mutation N501Y increased binding affinity to ACE2 but did not significantly affect its recognition by convalescent sera. In contrast, single mutation E484K had almost no impact on the binding kinetics, but essentially abolished recognition of RBD by convalescent sera. Interestingly, combining mutations E484K, K417N and N501Y resulted in a RBD with both features: enhanced receptor binding and abolished immune recognition. Conclusion: Our data demonstrate that single mutations either affect receptor affinity or immune recognition while triple mutant RBDs combine both features.
Metagenomic analysis of the conjunctival bacterial and fungal microbiome in vernal keratoconjunctivitisShort title: Microbiome in VKCText Word Count: 597To the Editor,there is increasing interest in the role of conjunctival microbiome in the healthy ocular surface (1) and in different ocular diseases. There is also enough evidence that dysregulation of resident microbial communities (dysbiosis) might be associated with allergy risk(2). Vernal keratoconjunctivitis (VKC) is a severe form of ocular allergy affecting mostly male children and young adults with typical seasonal recurrences and potentially visual impairment. We recently found and overexpression of multiple pattern recognition receptors (PRRs) in VKC suggesting the role of host-microbe interaction in VKC pathogenesis(3). To investigate the VKC-associated ocular microbiome, we applied 16S and ITS2 amplicon sequencing (online supplementary MM) in conjunctival swabs obtained from 22 VKC patients and 20 age, sex and ethnicity-matched healthy controls (HC) (Table 1S). Written informed consent was obtained from all parent/subjects enrolled. Type of VKC, allergen sensitization, disease-specific ongoing treatment and results of the Quality of Life in Children with VKC (QUICK) questionnaire were recorded. A 10-items questionnaire investigating the presence of the principal factors related to allergy development was administered to all included subjects.16S rRNA amplification was successfully carried out in 12/22 VKC and 4/20 HC samples. High-throughput amplicon sequencing produced a total of 734.157 high-quality reads (average of 45.885 reads/sample), which were clustered into 1.241 OTUs (97% sequence identity) and classified according to the Greengenes database. Compared with HC, α-diversity was significantly higher in all VKC (p=0.05), in IgE-negative patients (p=0.03), in tarsal VKC (p=0.03), in formula-fed versus breastfed children (p=0.03) and in children with history of atopic dermatitis (AD) (p=0.01). β-diversity highlighted differences in microbiota composition (Figure 1S) suggesting clusters of subjects with different conjunctival microbiomes. At the phylum level, conjunctival microbiome was dominated by Proteobacteria , Firmicutes , Actinobacteria andBacteriodetes that accounted for >90% of all reads (Figure 1). Of the 132 observed families, Moraxellaceae (W=15) showed a higher abundance in VKC than HC (Figure 2S). At the genus level, Pseudomonas , Staphylococcus , Streptococcus ,Acinetobacter , Neisseria , Haemophilus ,Prevotella , Corynebacterium , Propionibacterium andRothia accounted for >70% of sequences (Figure 3S). In VKC, Bacteroidetes and Fusobacteria met the core microbiome’s definition criteria (Table 2S), which includes different species of gram-negative bacteria able to potentially induce an LPS-driven inflammatory response as shown in experimental models(4).For the fungal microbiome, 10/22 VKC samples produced a detectable ITS2 amplicon. A total of 677,115 high-quality reads (average of 48,365 reads/sample) were clustered into 933 OTUs and taxonomically classified against the UNITE ver. 7.0 database. At the family level,Saccharomycetaceae , Malasseziaceae , Pleosporaceaeand Cladosporiaceae accounted for the majority of sequences (Figure 2). OTUs referred to Malasseziaceae were significantly increased in VKC compared with HC (W=42). Malassezia have been associated with AD inducing a mixed Th2/Th17 response(5) interacting with several PRRs and activating multiple signaling pathways. Since multiple PRRs are over-expressed in VKC(3), we suggest that glycan, phospholipid carbohydrate residues of allergens and microbes may engage innate receptors on conjunctival cells priming a type-2 response in VKC.14/22 VKC children were under topical treatments at the time of swabbing, creating a potential bias (Table 1S). However, only 5/10 patients whose swabs were not sequenced because of absence of amplicons, were under topical medication. In addition, β-diversity didn’t show differences in microbial communities considering the use and type of medications suggesting that factors other than topical eyedrops may alter the conjunctival microbiota. The main limitation was the higher difficulty to obtain amplicon products from HC, which has been already described and attributed to the physiological antimicrobial activity and to the lower microbial load of healthy subjects(6).In conclusion, the described dysbiosis in VKC highlights the role of the host-microbes interaction in VKC pathogenesis.Andrea Leonardi1Rocco Luigi Modugno1Fabiano Cavarzeran1Umberto Rosani21 Department of Neuroscience, Ophthalmology Unit, University of Padova, Padova, Italy2 Department of Biology, University of Padova, Padova, ItalyKeywords: ocular surface microbiome, vernal keratoconjunctivitis, 16S rRNA gene amplicon sequencing, ITS2 rRNA gene amplicon sequencing, core microbiomeCorresponding author:Andrea Leonardi, MDDepartment of Neuroscience, Ophthalmology Unit, University of Paduavia Giustiniani 235128 Padua, ItalyFax: +39-049-875 5168Email: email@example.comAcknowledgmentsa. Funding/Support: Supported by MIUR DOR1952345/19 and DOR2092417/20 from Italian Institute of Health.b. Conflicts of Interest:Andrea Leonardi: No Conflicts of Interest.Rocco Luigi Modugno: No Conflicts of InterestFabiano Cavarzeran: No Conflicts of InterestUmberto Rosani: No Conflicts of Interestc. Contributions to Authors in each of these areas: Andrea Leonardi (AL), Rocco Luigi Modugno (RLM), Fabiano Cavarzeran (FC), Umberto Rosani (UR)Conception and Design: AL, URAnalysis and interpretation: AL, RLM, URWriting the article: AL, RLMCritical revision of the article: URFinal approval of the article: AL, RLM, URData Collection: RLM, UR, FCProvision of materials, patients, or resources: AL, URStatistical expertise: FCObtaining funding: ALLiterature search: RLM, AL, URAdministrative, technical or logistic support: AL, FCd. Statement about Conformity with Author Information: nonee. Other Acknowledgments: none
Long Term Disruption of Cytokine Signalling Networks are Evident Following SARS-CoV-2 InfectionSinead Ahearn-Ford1, Nonhlanhla Lunjani1, Brian McSharry1,2, John MacSharry1,2,3, Liam Fanning1,3, Gerard Murphy4, Cormac Everard4, Aoife Barry4, Aimee McGreal4, Sultan Mohamed al Lawati4, Susan Lapthorne4, Colin Sherlock4, Anna McKeogh4, Arthur Jackson4, Eamonn Faller4, Mary Horgan3,4, Corinna Sadlier4, Liam O’Mahony1,2,3*1APC Microbiome Ireland, University College Cork, Cork, Ireland2School of Microbiology, University College Cork, Cork, Ireland3Department of Medicine, University College Cork, Cork, Ireland4 Department of Infectious Diseases, Cork University Hospital, Cork, Ireland*Corresponding author – firstname.lastname@example.orgTo the Editor,The current pandemic caused by the SARS-CoV-2 virus has so far infected more than 130 million people worldwide, resulting in approximately 3 million deaths. While the current clinical and public health priorities are designed to limit severe acute and fatal episodes of the disease, and to quickly roll out vaccines to the general population, it has become apparent that there may also be significant detrimental long-term effects following SARS-CoV-2 infection that impact daily functioning and quality of life1. The mechanisms underpinning the post-acute sequelae of SARS-CoV-2 infection’s long-lasting symptoms can include direct effects of the infection (e.g. endothelial damage, lung fibrosis) or indirect effects associated with changes in the microbiome or abnormalities in inflammatory and immune signalling pathways stimulated by the infection2,3.In order to examine the potential long-term immune changes that occur following elimination of the primary infection, we examined the levels of 52 cytokines and growth factors (using MSD multiplex kits) in the serum of patients that attended follow-up post-COVID infection clinics at Cork University Hospital, Cork, Ireland (The Clinical Research Ethics Committee of the Cork Teaching Hospitals approved this study and all patients provided informed consent). All patients had been hospitalised for PCR-proven SARS-CoV-2 infection (median in-patient stay of 5.5 days, range 1 day to 24 days) during the first wave of the pandemic in Ireland (March-May 2020). 38 serum samples were obtained from 24 patients (median age 53.5 years, 11 female) at 3-9 months following hospital discharge. Clinical severity ranged from mild to critical during hospitalisation and the most common symptoms at follow-up clinics were fatigue and/or dyspnoea (supplementary Table S1). Sera obtained prior to the pandemic from 29 healthy volunteers (median age 43.2 years, 14 female) were analysed in parallel.Of the 52 analytes measured, 19 were significantly elevated in post-COVID patient sera compared to healthy controls (supplementary Table S2). These 19 mediators are illustrated as dot plots in Figure 1 and Figure 2. One group of mediators, c-reactive protein (CRP), serum amyloid A (SAA), Interleukin-1 receptor antagonist (IL-1RA), IL-6, IL-8, IL-15, IL-16, monocyte chemotactic protein (MCP)-1 and MCP-4, can be broadly categorised as being associated with ongoing inflammatory responses (Figure 1a)4. These mediators remained as elevated in samples taken 6-9 months following hospital discharge as those levels observed 3-6 months following discharge (p<0.05 versus controls, ANOVA). A second group of mediators, vascular endothelial growth factor (VEGF-A), soluble tyrosine-protein kinase receptor Tie-2 (Tie-2), soluble intercellular adhesion molecule (ICAM-1) and basic fibroblast growth factor (bFGF), can be generally associated with endothelial dysfunction, remodelling and angiogenesis (Figure 1b)5. The remaining elevated mediators are associated with patterns of lymphocyte polarisation. Elevated IL-4, macrophage-derived chemokine (MDC) and thymic stromal lymphopoietin (TSLP) sera levels indicate activation of TH2 responses (Figure 2a), while IL-17A, macrophage inflammatory protein (MIP)-3α and IL-12/23p40 indicate ongoing TH17 activity (Figure 2b). Other indicators of TH2-associated activities are just outside statistical significance (IL-5, p=0.06; supplementary Table S2). While TH1 responses are well described to be upregulated during acute infection6, the levels of these mediators (e.g. IFN-γ, IP-10) decrease following elimination of the virus and are at control levels in our cohort of post-COVID patients (supplementary Table S2).Our data suggests that there are long term immunological consequences following SARS-CoV-2 infection, at least in those that had acute symptoms severe enough to require hospitalisation. While the relatively low number of patients included in our study at this stage does not allow us to perform subgroup analysis, it is possible that these immune mediators may associate with clinically meaningful disease variables and ultimately may be of therapeutic value, if findings are replicated in future studies. Of particular interest is the elevation in TH2-associated mediators. Could this response be a component of the mucosal repair mechanisms that occur following viral damage, or does this indicate new TH2-associated pathological immune activity that might underpin an increased risk of developing allergy or asthma? Clearly the potential immune mechanisms underpinning the emerging post-COVID clinical entities will become increasingly more important to understand as the health care systems adapt to caring for large numbers of COVID-19 survivors during the coming months and years.
Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decissions.
Advances in molecular biology alongside the accelerated development of gene and cell engineering have contributed to the development of several endotype-targeted biological therapies against chronic immune-mediated allergic diseases. Conventional therapies for asthma, chronic rhinosinusitis with polyposis (CRSwNP), chronic spontaneous urticaria and atopic dermatitis (AD) are not without limitations, and as such the advent of biological therapies have provided a promising alternative treatment option. Biologicals have proven efficacious in the treatment of refractory chronic spontaneous urticaria, asthma, AD, CRSwNP and there is increasing evidence for their utility in treating food allergy. Biologicals are applied and investigated for the most urgent need: acute treatment, symptom control and reduction of steroid usage. Currently there are five approved biologicals for allergic disease management, targeted against IgE (omalizumab), type 2 (T2) cytokines and cytokine receptors (IL-4Ra; dupilumab, IL-5; mepolizumab/reslizumab, IL-5Ra; benralizumab).
Because of their selectivity, biologicals are crucial therapeutic agents in oncological, immunological, and inflammatory diseases and their use in clinical practice is broadening. Biologicals are among the most common drugs that can cause hypersensitivity reactions (HSRs), and this is primarily attributed to an explosion in new treatment options that has developed through personalized and precision medicine. Patients can develop HSRs to these agents during the first lifetime exposure or after repeated exposure. Despite its relatively high prevalence, the underlying mechanisms and optimal management of HSRs to biologicals remain incompletely explained. In this position paper, the authors provided evidence-based recommendations for the diagnosis and management of HSRs to biologicals. Additionally, the document defines unmet needs, which should be topics of future studies.
The TGF-β-Th2 axis: a new target for cancer therapy?García de Durango C1, Escribese MM2, Rosace D3.1: DKTK Research Group, Oncogenic Signalling Pathways of Colorectal Cancer, Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany.2: Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660 Boadilla del Monte, Madrid, Spain.3: Centro De Investigación Del Cáncer and Instituto De Biología Molecular Y Celular Del Cáncer, Consejo Superior De Investigaciones Científicas (CSIC) - Universidad de Salamanca, Salamanca, Spain.Correspondence :Domenico Rosace, Centro De Investigación Del Cáncer and Instituto De Biología Molecular Y Celular Del Cáncer, Consejo Superior De Investigaciones Científicas (CSIC) - University of Salamanca, Salamanca, Spain. email@example.com
Immunoglobulin E (IgE)-mediated allergy is the most common hypersensitivity disease affecting more than 30% of the population. In genetically-predisposed subjects exposure to minute quantities of allergens leads to the production of IgE antibodies which is termed allergic sensitization and mainly occurs in early childhood. Allergen-specific IgE then binds to the high (FcRI) and low affinity receptors (FcRII, also called CD23) for IgE on effector cells and antigen-presenting cells, respectively. Subsequent and repeated allergen exposure increases allergen-specific IgE levels and, by receptor cross-linking, triggers immediate release of inflammatory mediators from mast cells and basophils whereas IgE-facilitated allergen presentation perpetuates T cell-mediated allergic inflammation. Due to engagement of receptors which are highly selective for IgE even tiny amounts of allergens can induce massive inflammation. Naturally occurring allergen-specific IgG and IgA antibodies usually recognize different epitopes on allergens compared to IgE, and do not efficiently interfere with allergen-induced inflammation. However IgG and IgA antibodies to these important IgE epitopes can be induced by allergen-specific immunotherapy or by passive immunization. These will lead to competition with IgE for binding with the allergen and prevent allergic responses. Similarly, anti-IgE treatment does the same by preventing IgE from binding to its receptor on mastcells and basophils. Here we review the complex interplay of allergen-specific IgE, IgG and IgA and the corresponding cell receptors in allergic diseases and its relevance for diagnosis, treatment and prevention of allergy.
Increase of allergic conditions has occurred at the same pace with the Great Accleration, which stands for the rapid growth rate of human activities upon Earth from 1950s. Changes of environment and lifestyle along with escalating urbanization, are acknowledged as the main underlying causes. Secondary (tertiary) prevention for better disease control has advanced considerably with innovations for oral immunotherapy and effective treatment of inflammation with corticosteroids, calcineurin inhibitors and biologic medications. Patients are less disabled than before. However, primary prevention has remained a dilemma. Factors predicting allergy and asthma risk have proven complex: risk factors increase the risk while protective factors counteract them. Interaction of human body with environmental biodiversity with micro-organisms and biogenic compounds as well as the central role of epigenetic adaptation in immune homeostasis have given new insight. Allergic diseases are good indicators of the twisted relation to environment. In various non-communicable diseases, the protective mode of the immune system indicates low-grade inflammation without apparent cause. Giving microbes, pro- and prebiotics, has shown some promise in prevention and treatment. The real-world public health programme in Finland (2008-2018) emphasized nature relatedness and protective factors for immunological resilience, instead of avoidance. The nationwide action mitigated the allergy burden, but in the lack of controls, primary preventive effect remains to be proven. The first results of controlled biodiversity interventions are promising. In the fastly urbanizing world, new approaches are called for allergy prevention, which also has a major cost saving potential.
Background: It is unclear if asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2. Methods: All patients testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms. Results: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4·15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1·12 [95% CI 0·86, 1·45], p=0·40). Among SARS-CoV-2 positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared to non-allergic asthma (OR 0·52 (0·28, 0·91), p=0·026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared to patients with mild or asymptomatic disease, independent of asthma status (p=0.0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms. Conclusions: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.
José M. Carballido1 and Hergen Spits21Novartis Institutes for Biomedical Research, Translational Medicine, Preclinical Safety, Switzerland2Department of Experimental Immunology, UMC, University of Amsterdam, Amsterdam, The Netherlands.Jan Egbert de Vries (Figure 1) is a cosmopolitan immunologist and an enthralling mentor with a large track record of innovative achievements in the fields of allergy and immunology. Jan was born in Strijen (NL), a small town located in the Hollands Diep estuary in the South of The Netherlands. He spent his youth in the NL combining his studies with his passion for sports; he became Dutch champion in decathlon. Shortly after his PhD, and like his fellow countryman Erasmus of Rotterdam, he started a long journey that brought him to France, California, Austria and Switzerland, although never settling in any of the cities he worked. Like Erasmus, he has been since an insatiable scholar (“Non est ulla studiorum satietas ”) and an inspiring mentor for a large number of students and collaborators.Jan studied at the University of Utrecht (NL) and graduated from the University of Amsterdam (NL) with a PhD in Immunology in 1976. After his graduation, he spent two years in the lab of John Mendelsohn at the University of California, San Diego (US), as a recipient of an Eleanor Roosevelt fellowship. Thereafter, he returned to Amsterdam, where he became the Head of the Department of Immunology at the National Cancer Research Institute. His groundbreaking observations on the cytotoxic activity of T lymphocytes isolated from melanoma patients (1) motivated the search for tumor-specific antigens, which could be used for the development of cancer vaccines.In 1985, Jan took on the position of Director of Immunology at the UNICET- Laboratoires for Immunological Research in Dardilly, a small village near Lyon (FR). UNICET was part of Schering Plough and collaborated closely with the DNAX Research Institute of Molecular and Cellular Biology in Palo Alto (US). It was during that time when Jan became interested in allergy, gaining a notable reputation in the field. Jan made a key contribution to the elucidation of the mechanisms controlling human IgE and IgG4 switching (Figure 2), implicating IL-4 as a key regulator of these processes (2). These were the early days when mouse helper T (Th) cells were segregated as either Th1 or Th2 subsets, following the seminal work of Tim Mossman and Bob Coffman at DNAX. Jan’s team observed these distinct phenotypes in human lymphocyte populations isolated from healthy and atopic individuals. However, against the dogma, he also described additional cytokine production profiles aside of the canonical and mutually exclusive IFN-γ or IL-4 secreting types. Now, several decades later, we appreciate the diversity and plasticity of these Th cell responses. Three years in France seemed too long time for this Dutch globetrotter and thus, in 1988, he and his research team moved to DNAX to continue their work in allergy and extend their research to regulatory responses with human T cells. Jan joined DNAX as the Head of Human Immunology and his work was key in elucidating the biology of IL-10 and IL-13 following their DNA cloning at DNAX. He showed that IL-4 and IL-13 were the triggers for allergic diseases (3) such as asthma, rhinitis and atopic dermatitis, and that IL-10 was a major factor dampening immune responses (4). His team also cloned the signaling lymphocyte activation molecule (SLAM/CD150) (5), which gave name to a new family of immune receptors involved in lymphocyte activation. The in vitr o work was expanded to in vivoexperimentation using severe combined immunodeficient (SCID) mice that were reconstituted with human tissues and cells (SCID-hu mice). These studies supported many drug development projects aiming to interfere with allergic responses and/or prevent transplant rejection.In 1997, Jan was recruited by Novartis as Global Head autoimmune and inflammatory diseases and Head of the Novartis Research Institute (NFI, from its abbreviation in German) in Vienna (AT). Jan led the transition of NFI to the Novartis Institutes for Biomedical Research (NIBR), expanding its original focus on dermatology to autoimmunity and inflammation. Jan was the founder of the Novartis Immunology Platform, a multidisciplinary group focused on the discovery and early development of both therapeutic antibodies and low molecular weight drugs targeting immune checkpoints, cytokines and cytokine receptors, G-protein-coupled receptors and other targets controlling T cell activation and tolerance induction. In 2008, he became Head of NIBR Europe. During his time in Vienna and Basel, Jan was instrumental for the advancement of many projects, particularly the development of the sphingosine 1 phosphate receptor antagonists FTY720 (Fingolimod/Gilenya®) and BAF312 (Siponimod/Mayzent®) for multiple sclerosis and in championing the clinical testing of immunotherapeutics in psoriasis as early proof of concept, which led to the approval of the anti-IL-17A monoclonal antibody AIN457 (Secukinumab/Cosentyx®). Jan also nurtured the path to initiate antigen-specific immune tolerance projects at Novartis, enabling many collaborations with scientists outside of Novartis.Jan’s remarkable ability to identify transformative opportunities, together with the experience he gained in academic and industrial settings, facilitated his transition from the big pharma industry to biotech. In this new setting, he has been acting as CEO and Chairman of AIMM Therapeutics, Chairman of Cassiopea and CEO of Tr1X, where he is developing cell and gene therapies to cure autoimmune diseases.The authors of this short biography had the privilege of working with Jan for many years during different steps of his career. We, like many other colleagues who worked side by side with Jan, learned to appreciate Jan’s extraordinary scientific insights and people skills. We had the opportunity to witness his passion for science and to learn his innovative way to approach immunology challenges and we remain honored to count on him as a source for inspiration and as a good friend.Major contributionsDiscovery of cytotoxic tumor-specific cytotoxic T cell clones from melanoma patientsCloning of human IL-4 and IL-13 and elucidation of their roles in the regulation of IgE production by human B cellsCloning and characterization of human IL-10 and demonstration of its profound immune-suppressive effectsDevelopment of Gilenya® and Mayzent®, and of Cosentyx® for the treatment of multiple sclerosis and psoriasis, respectivelyReferences1. de Vries JE, Spits H. Cloned human cytotoxic T lymphocyte (CTL) lines reactive with autologous melanoma cells. I. In vitro generation, isolation, and analysis to phenotype and specificity. J Immunol1984;132 :510–519.2. Pène J, Rousset F, Briere F, Chrétien I, Bonnefoy JY, Spits H et al. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2.Proc Natl Acad Sci USA 1988;85 :6880–6884.3. Punnonen J, Aversa G, Cocks BG, McKenzie AN, Menon S, Zurawski G et al. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 1993;90 :3730–3734.4. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med1991;174 :1209–1220.5. Cocks BG, Chang C-CJ, Carballido JM, Yssel H, de Vries JE, Aversa G. A novel receptor involved in T-cell activation. Nature1995;376 :260–263.
Research data derived from observational studies are accumulating quickly in the field of allergy and immunology and a large amount of observational studies are published every year. The aim of the present study was to evaluate the adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist by papers published in the three European Academy of Allergy and Clinical Immunology journals, during the period 2009-2018. To this end, we conducted a bibliographic study of up to eight randomly selected papers per year per Journal. Our literature search resulted in 223 papers. Among those, 80, 80 and 63 records were from Pediatric Allergy and Immunology, Allergy and Clinical and Translational Allergy, respectively; the latter was published only from 2011 on. Prospective, case-control, and cross-sectional designs were described in 88, 43, and 92 papers, respectively. Full reporting of all STROBE items was present in 47.4%, 45.6%, and 41.2% for the cohort, cross-sectional, and case-control studies, respectively. Generally, no time trend in adherence of reporting STROBE items was observed, apart from reporting funding, which increased from 60% in 2009/2010 to more than 90% in 2018. We identified a cluster of STROBE items with low proportions of full reporting constituted by the items on reporting study design in the title and methods, variables types along with their measurement/assessment, bias and confounding, study size, and grouping of variables. It appears that the STROBE checklist is a suitable tool in observational allergy epidemiology. However, adherence to the STROBE checklist appeared suboptimal.
Sweet syndrome induced by SARS-CoV-2 Pfizer-BioNTech mRNA vaccineAS Darrigade, MD1, H Théophile, MD2, P Sanchez-Pena, MD2, B Milpied, MD1, M Colbert4, MD, S Pedeboscq5, MD, T Pistone6, MD, ML Jullié, MD7, J Seneschal, MD, PhD1,31 : Department of Adult and Pediatric Dermatology, Bordeaux University Hospitals, France2 : Department of pharmacovigilancy, Bordeaux University Hospitals, France3 : Research Unit INSERM U10354 : Department of geriatry, Clinic Bordeaux Nord, Bordeaux, France5 : Department of pharmacology, Bordeaux University Hospitals, France6: Department of infectious disease, Bordeaux University Hospitals, France7: Department of anatomopathology, Bordeaux University Hospitals, FranceManuscript word count: 607Key words : sweet syndrome, SARS-CoV-2, Pfizer-BioNTech mRNA vaccine, delayed hypersensitivity, IDRCorresponding author: A.S. Darrigade, Dermatology Department, Saint-André Hospital, 1, rue Jean Burguet 33000 Bordeaux, FrancePhone: +33556794705Fax: +firstname.lastname@example.orgFunding source: No financial disclosuresFinancial Disclosure: No external funding for this manuscriptTo the editor,A 45-year-old woman, without any past medical history or allergy presented in our clinic with a rapid onset of diffuse skin eruptions. Five days earlier, she received the first injection of the SARS-CoV-2 Pfizer-BioNTech mRNA. Concomitantly she took 1000mg paracetamol to prevent any post-vaccination syndrome. She well tolerated the preceding vaccines (influenza every year) before this one.The eruption started 24h after vaccine injection and was composed at time of the clinical exam of erythematous infiltrated papulosis located all over the body, without face involvement (Figure 1). No other extracutaneous symptoms were noted. Blood exams showed increased blood count levels with increased neutrophils count (8.77G/l), hepatic cytolysis (AST 67UI/L and ALT 116UI/l) with high level of PCR (115mg/l). SARS-CoV-2 PCR test and serology were negative. Viral tests for EBV, CMV, parvovirus B19, and Herpes simplex/Herpes zoster showed only a slight EBV reactivation. Histopathological examination of the skin biopsy showed a hyperplastic epidermis with an edematous papillary dermis. A superficial and deep dermal perivascular, periadnexal and interstitial dense infiltrate composed of neutrophils, eosinophils and lymphocytes was also a feature. Leukocytoclastic vasculitis was also seen (Figure 2A-2B). Clinical and pathological exams were compatible with the diagnosis of SS induced by SARS-CoV-2 Pfizer-BioNTech mRNA vaccine. Systemic steroid therapy (prednisone 0.5mg/kg/d) for five days was started and led to rapid improvement of the skin condition without any recurrence after treatment discontinuation. She did not receive the second vaccine injection.Patch-tests performed (14 days after steroid treatment stop, one month after SS) on both on healed and normal skin with pur SARS-CoV-2 Pfizer-BioNTech mRNA vaccine prepared less than 4 hours before were negative (Figure 1C 2-3). Then, intradermoreaction (IDR) with vaccine diluted at 1/10 on normal skin was positive in delayed reading (Figure 1C 1). Cutaneous biopsy was realized on the positive IDR reaction, showing an abundant inflammatory infiltrate predominantly with lymphocytes (Figure 2C).Cutaneous reactions after vaccine injection are rare, and heterogenous1. They could be related to the vaccine or the adjuvant. In addition, vaccine could trigger flares of chronic inflammatory conditions as it was previously reported1. At that time, minor local side effects are reported with SARS-CoV-2 vaccines such as pain, swelling or redness; hypersensitivity reactions were anaphylactic reaction but no severe delayed hypersensitivity are reported2-3. Three cases of acute febrile neutrophilic dermatosis are reported in the international bank of WHO, one in United Kingdom, one in United States of America and our case. Under SARS-CoV-2 Pfizer-BioNTech mRNA vaccine four cases of vasculitis had been reported after injection. In France one case of relapse of neutrophilic disorder was reported one day after SARS-CoV-2 Pfizer-BioNTech mRNA vaccine. The adjuvant associated with the SARS-CoV-2 Pfizer-BioNTech mRNA vaccine is polyethylene glycol (PEG) 20003. However our patient never received infusion containing PEG or polysorbate before. Patch-tests with PEG or polysorbate alone were not performed because of the negativity of the patch-test with the SARS-CoV-2 Pfizer-BioNTech mRNA vaccine. Only 10 cases of SS induced by vaccine are published so far including: 3 with seasonal influenza, 1 with influenza A, 2 with pneumococcal, 2 tuberculosis, 2 small pox4. SS is an acute inflammatory skin disease associated with important infiltration of neutrophils. Leukocytoclastic vasculitis could be present in SS5. One case of SS in a patient receiving pneumococcal vaccine showed the presence of dermal vasculitis associated with infiltration of neutrophils6. In case of anaphylactic reaction under SARS-CoV-2 Pfizer-BioNTech mRNA vaccine, the risk of relapse with the Moderna SARS-CoV-2 mRNA vaccine or SARS-CoV-2 vaccines with an adenovirus carrier and protein subunit remains unknown3, in case of SS even more.To conclude we report the first case of SS induce by SARS-CoV-2 Pfizer-BioNTech mRNA vaccine confirmed by positive IDR.