Paul Lavender

Allergic diseases are among the most prevalent chronic conditions in Europe, yet undergraduate medical curricula lack structured Allergy and Clinical Immunology (ACI) teaching. Moreover, desite advances in specialist education, postgraduate university training varies due to differences in specialty recognition, regulatory frameworks, and the implementation of the European Training Requirements. These disparities contribute to inconsistent physician competencies, limited academic visibility of the specialty, and unequal access to high‐quality allergy care. This Position Paper, developed within the framework of the Declaration of Salamanca, analyses the current educational landscape, identifies the main barriers to integrating ACI into medical education, and proposes a strategic roadmap for future development. Evidence from an EAACI‐led European survey, published studies, and expert consensus demonstrates substantial variability in undergraduate curricula, limited academic representation of allergists, fragmented integration of basic immunology and clinical allergy, and challenges in educational innovation, including digital learning and artificial intelligence. The Declaration of Salamanca advocates a coordinated European strategy focused on strengthening undergraduate curricula, increasing ACI's academic presence, promoting closer integration between basic immunology and clinical practice, fostering educational innovation, and enhancing collaboration among universities, scientific societies, accreditation bodies, policymakers, and patient organizations. While responsibility for university curricula and specialty recognition remains with national authorities, the EAACI and National Allergy and Immunology Societies, in partnership with patient organizations, can provide scientific leadership, develop educational standards, and advocate for harmonised approaches. The Declaration of Salamanca offers a practical framework to improve the quality, consistency, and sustainability of ACI education across Europe.

During human B cell maturation, immature transitional (T1) cells transit from bone marrow into the blood. At the subsequent immature T2 stage, a separation into IgM^hi (T2M^hi) and IgM^lo (T2M^lo) developmental trajectories has been proposed. Here, we isolate T1, T2M^hi and T2M^lo cells from human adult and cord blood for bulk and single-cell ATAC-seq, CUT&RUN, RNA-seq and CITE-seq to profile their transcriptomic and epigenetic differences. We identify accessible chromatin domains discriminating between T2M^hi and T2M^lo cells in peripheral B cell development, with signatures persisting during the differentiation of T2M^lo to naïve B cells. Similarly, memory and marginal zone B cells retain epigenetic hallmarks of their T2M^lo and T2M^hi precursors, coupled with transcriptional diversity. Imaging mass cytometry with RNAscope of spleen, appendix and tonsil further validates the spatial relationships of expressed genes. Our study thus provides insights into B lineage T2 bifurcation and describes epigenetic signatures of B cell developmental pathways.

Cortical neurons are specified during embryonic development but often only acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV+) interneurons, which play critical roles in regulating the function of the cerebral cortex. We found that the maturation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α). Developmental loss of PGC-1α prevents PV+ interneurons from acquiring unique structural, electrophysiological, synaptic, and metabolic features and disrupts their diversification into distinct subtypes. PGC-1α exerts its function as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERRγ and Mef2c. Our results uncover a molecular switch that translates neural activity into a specific transcriptional program promoting the maturation of PV+ interneurons at the appropriate developmental stage.

Kelly A, et al. Allergy Asthma Immunol Res. 2024 Mar;16(2):130-141. https://doi.org/10.4168/aair.2024.16.2.130

The PML::RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML::RARA binding on gene expression and regulation in an inducible PML::RARA cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML::RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a computational machine learning implementation called Regulatory Element Behavior Extraction Learning to deconvolute the complex, local transcription factor binding site environment at PML::RARA bound positions to reveal distinct signatures that modulate how PML::RARA directs the transcriptional response.

Granulomatosis with polyangiitis (GPA) is a potentially fatal small vessel vasculitis of unknown etiology, characterized by anti-neutrophil cytoplasmic autoantibodies, chronic inflammation, and granulomatous tissue damage. T cell dysregulation, comprising decreased regulatory T cell function and increased circulating effector memory follicular Th cells (TFH), is strongly associated with disease pathogenesis, but the mechanisms driving these observations are unknown. We undertook transcriptomic and functional analysis of naive CD4 T cells from patients with GPA to identify underlying functional defects that could manifest in the pathogenic profiles observed in GPA. Gene expression studies revealed a dysregulation of the IL-2 receptor β/JAK-STAT signaling pathway and higher expression of BCL6 and BCL6-regulated genes in GPA naive CD4 T cells. IL-2–induced STAT5 activation in GPA naive CD4 T cells was decreased, whereas STAT3 activation by IL-6 and IL-2 was unperturbed. Consistently, BCL6 expression was sustained following T cell activation of GPA naive CD4 T cells and in vitro TFH differentiation of these cells resulted in significant increases in the production TFH-related cytokines IL-21 and IL-6. Thus, naive CD4 T cells are dysregulated in patients with GPA, resulting from an imbalance in signaling equilibrium and transcriptional changes that drives the skewed pathogenic CD4 effector immune response in GPA. Key Points BCL6 expression is increased in TCR-activated naive CD4 T cells from patients with GPA. IL-2/STAT5 signaling is dysregulated in GPA naive CD4 T cells. GPA naive CD4 T cells show increased TFH cell differentiation and IL-21 expression.

Background: Asthma is a chronic airway disease driven by complex genetic–environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood.Methods: We piloted genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma (n = 4) and healthy controls (n = 3).Results: We identified n = 4,321 (FDR < 0.05) regions exhibiting differential H3K27ac enrichment between asthma and health, clustering at genes associated predominately with epithelial processes (EMT). We identified initial evidence of asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (PTGS1). We integrated published datasets to identify epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and identify initial relationships between asthma-associated changes in H3K27ac and transcriptional profiles. Finally, we investigated the potential of CRISPR-based approaches to functionally evaluate H3K27ac-asthma landscape in vitro by identifying guide-RNAs capable of targeting acetylation to asthma DERs and inducing gene expression (TLR3).Conclusion: Our small pilot study validates genome-wide approaches for deciphering epigenetic mechanisms underlying asthma pathogenesis in the airways.

Innate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Various subsets exist resembling T cell lineages defined by the expression of specific transcription factors. Thus, T-bet is expressed in ILC1 and Th1 cells. In order to further understand the functional roles of T-bet in ILC, we generated a fate-mapping mouse model that permanently marks cells and their progeny that are expressing, or have ever expressed T-bet. Here we have identified and characterised a novel ILC with characteristics of ILC1 and ILC2 that are “fate-mapped” for T-bet expression and arise early in neonatal life prior to establishment of a mature microbiome. These ILC1-ILC2 cells are critically dependent on T-bet and are able to express type 1 and type 2 cytokines at steady state, but not in the context of inflammation. These findings refine our understanding of ILC lineage regulation and stability and have important implications for the understanding of ILC biology at mucosal surfaces. SUMMARY: Innate lymphoid cells (ILC) play a critical role in regulating immune responses at mucosal surfaces. Three distinct ILC groups have been described according to expression of subset defining transcription factors and other markers. In this study we characterize a novel ILC subset with characteristics of group 1 and group 2 ILC in vivo .

Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner ^1,2 . Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis ³ and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection ⁴ . The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-γ producing CD4 ⁺ T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-γ ⁺ Th1 cells to suppressive IL-10 ⁺ Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4 ⁺ T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor ^5–7 . Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4 ⁺ T cells were defective in IL-10 production. As proof-of-concept, we show that CD4 ⁺ T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4 ⁺ BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyperinflammation in severe COVID-19.