Though memory B cells (MBCs) and long-lived plasma cells (LLPCs) are both thought to derive from the germinal center (GC) reaction, there is little insight into or agreement about the signals that control differentiation to one cell type or another. By performing BrdU pulse-labeling studies, GC disruption experiments and V gene sequencing, we found that the generation of these cell types is actually temporally controlled and separated during the immune response. We report that MBCs mainly derive from early GCs (much before GC peak size), while more affinity matured LLPCs are predominantly formed during late GCs - long after its peak in size. Based on these findings, we propose a new model that the GC response undergoes a temporal switch, functioning quite differently at early and late stages. Therefore the generation of MBCs and LLPCs is the consequence of a general shift in GC output over time rather than the result of specific instructive signals that are selectively delivered to GC B cells at any given time during the response. We also present direct evidence that a large fraction of long-lived IgM+ MBC, and even some IgG+ MBC, are formed at very early time points, prior to the existence of detectable GCs. The knowledge of when specific long-lived immune-effector cells are generated during an immune response has strong implications for vaccine design and understanding long-term pathogen immunity.

A temporal switch in the germinal center determines differential output of memory B and plasma cells (IRC3P.468)

Modern health care requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping, and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long-lasting therapies. Escalating healthcare costs together with questions about the efficacy of the current management of allergic diseases require further development of a biomarker-driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen immunotherapy with a special emphasis on specific IgE, the microbiome and the epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/all.14582

Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date, it has resulted in ~9 million confirmed cases and caused almost 500 000 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socioeconomic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a "cytokine storm" leading to acute respiratory distress syndrome, endothelitis, thromboembolic complications, and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19, and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development, and epidemiology. A total of 150 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/all.14449

A compendium answering 150 questions on COVID-19 and SARS-CoV-2.

The achievement of long-lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component-resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests such as the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food-allergic individuals with distinct mechanistic features. Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continues to inform the understanding of natural tolerance development. Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, and the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit. More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL-4 and IL-13, or IgE may help to achieve that.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/all.14082

Recent developments and highlights in food allergy.

Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (TFH ) cells, rather than type 2 T-helper (TH 2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (TFR ) cells, a specialized subset of regulatory T (TREG ) cells resident in B-cell follicles, restricts TFH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5+ TFH cells, not CXCR5- conventional TH 2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5+ TFR cell deletion. Upregulation of TFH cell activities, including a skewing toward type 2 TFH (TFH 2) and IL-13 producing TFH (TFH 13) phenotypes, and defects in TFR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between TFH and TFR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of TFH and TFR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/all.14639

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy.

Background The generation of IgE-mediated food allergy in humans is silent and only diagnosed upon manifestation of clinical symptoms. While experimental models have been used to investigate some mechanisms of allergic sensitization, the generation of humoral immunity and memory remains to be elucidated. Here, we defined the evolution of allergen-specific B-cell responses during epicutaneous sensitization to foods. Methods Wild-type and genetic knockout animals, and drug or antibody strategies for cell depletion and immunoglobulin signaling blockade were used to investigate epicutaneous sensitization and disease progression; we analyzed allergen-specific germinal centers and IgG1+ memory B cells by flow cytometry, evaluated humoral responses, and determined clinical reactivity (anaphylaxis). Results Epicutaneous sensitization caused microscopic skin damage, inflammation, and recruitment of activated dendritic cells to the draining lymph nodes. This process generated allergen-specific IgG1+ germinal center B cells, serum IgG1, and anaphylaxis that was mediated by the alternative pathway. Whether we used peanut and/or ovalbumin from the egg white for sensitization, the allergen-specific IgG1+ memory compartment predominantly exhibited an immature, pro-germinal center phenotype (PDL-2- CD80- CD35+ CD73+ ). Subsequent subclinical exposures to the allergen induced IgE+ germinal center B cells, serum IgE, and likely activated the classical pathway of anaphylaxis. Conclusions Our data demonstrate that IgG1+ B-cell immunity against food allergens in epicutaneous sensitization precedes the generation of IgE responses. Therefore, the assessment of allergen-specific cellular and humoral IgG1+ immunity may help to identify individuals at risk of developing IgE-mediated food allergy and hence provide a window for therapeutic interventions.

IgG1+ B-cell immunity predates IgE responses in epicutaneous sensitization to foods

The impact of instructional guidance on learning outcomes in higher biomedical education is subject of intense debate. There is the teacher-centered or traditional way of teaching (TT) and, on the other side, the notion that students learn best under minimal guidance such as problem-based learning (PBL). Although the benefits of PBL are well-known, there are aspects susceptible to improvement. Hence, a format merging TT and PBL (hybrid-PBL, h-PBL) may advance education in biomedical sciences. Studies that employed h-PBL in higher biomedical education compared to TT and/or pure PBL were systematically reviewed. Specifically, this review addressed the following question: does h-PBL in biomedical sciences result in superior marks and a better student’s perception of the teaching and learning process? We found that the use of h-PBL in higher biomedical sciences was superior compared to TT and pure-PBL. This was evidenced by the higher performance of the students in h-PBL as well as the level of student’s satisfaction as compared to TT or pure PBL. These findings encourage more research on investigating the pedagogical benefits of h-PBL. In addition, these data support an eclectic system in which the pedagogical tools from TT and PBL are used cooperatively in the best interest of the education and satisfaction of the students.

/pdf/is-hybrid-pbl-advancing-teaching-in-biomedicine-a-systematic-3sx3x5wob9.pdf

Domenico Rosace

Papers

IgG1+ B-cell immunity predates IgE responses in epicutaneous sensitization to foods

Is hybrid-PBL advancing teaching in biomedicine? A systematic review.