Immunoglobulin E is the latest discovered of immunoglobulin family and has been long associated with anaphylaxis and worm expulsion. Immunoglobulin E, along with mast cells, basophils, and eosinophils, is also a hallmark of type 2 immunity which is dysregulated in numerous diseases such as asthma, rhinitis, atopic dermatitis, and eosinophilic esophagitis in addition to anaphylaxis as aforementioned. However, recent advances have shed light on IgE regulation and memory explaining the low level of free IgE, the scarcity of IgE plasma cells that are mainly short live and the absence of IgE memory B cells in homeostatic conditions. Furthermore, IgE was implicated in inflammatory conditions beyond allergic disorders where IgE‐mediated facilitated antigen presentation can enhance cellular and humoral response against autoantigens in systemic lupus or chronic urticaria leading to more severe disease and even against neoantigen facilitating tumor cell lysis. At last, IgE was unexpectedly associated with allograft rejection or atheromatous cardiovascular diseases where precise mechanisms remain to be deciphered. The purpose of this review is to summarize these recent advances in IgE regulation, biology, and physiopathology beyond allergic diseases opening whole new fields of IgE biology to explore.

Asthma, atopic dermatitis and chronic rhinoconjunctivitis are highly heterogeneous. However, epidemiologic associations exist between phenotypic groups of patients. Atopic march is one such association but is not the only common point. Indeed, beyond such phenotypes, hallmarks of type 2 immunity have been found in these diseases involving immune dysregulation as well as environmental triggers and epithelial dysfunction. From the canonical Th2 cytokines (IL‐4, IL‐5, IL‐13), new cellular and molecular actors arise, from the epithelium's alarmins to new innate immune cells. Their interactions are now better understood across the different environmental barriers, and slight differences appeared. In parallel, the development of type 2‐targeting biotherapies not only raised hope to treat those diseases but also raised new questions regarding their true pathophysiological involvement. Here, we review the place of type 2 immunity in the different phenotypes of asthma, chronic rhinitis, chronic rhinosinusitis and atopic dermatitis, highlighting nuances between them. New hypotheses rising from the use of biotherapies will be discussed along with the uncertainties and unmet needs of this field.

Host-microbiota interactions can modulate the immune system both at local and systemic levels, with potential consequences for organ transplantation outcomes. In this study, we hypothesized that differences in the urinary microbiome following kidney transplantation would be associated with posttransplantation status: stable, minimally immunosuppressed, or tolerant. One hundred thirteen urine samples from stable (n = 51), minimally immunosuppressed (n = 19), and spontaneously tolerant (n = 16) patients, paired with age-matched controls (n = 27) were profiled and compared to each other at a taxonomic level with special interest in the immunosuppressive regimen. All comparisons and correlations were adjusted on sex and time posttransplantation. Our results highlighted a unique and specific urinary microbiota associated with spontaneous tolerance characterized by a high diversity and a clear Proteobacteria profile. Finally, we report that this profile is (1) impacted by gender, (2) inversely correlated with immunosuppressive drugs (calcineurin inhibitors and mammalian target of rapamycin inhibitors), and (3) stable in time.

Operational tolerance is the holy grail in solid organ transplantation. Previous reports showed that the urinary compartment of operationally tolerant recipients harbor a specific and unique profile. We hypothesized that spontaneous tolerant kidney transplanted recipients (KTR) would have a specific urinary metabolomic profile associated to operational tolerance. We performed metabolomic profiling on urine samples from healthy volunteers, stable KTR under standard and minimal immunosuppression and spontaneous tolerant KTR using liquid chromatography in tandem with mass spectrometry. Supervised and unsupervised multivariate computational analyses were used to highlight urinary metabolomic profile and metabolite identification thanks to workflow4metabolomic platform. The urinary metabolome was composed of approximately 2700 metabolites. Raw unsupervised clustering allowed us to separate healthy volunteers and tolerant KTR from others. We confirmed by two methods a specific urinary metabolomic signature in tolerant KTR mainly driven by kynurenic acid independent of immunosuppressive drugs, serum creatinine and gender. Kynurenic acid and tryptamine enrichment allowed the identification of putative pathways and metabolites associated with operational tolerance like IDO, GRP35 and AhR and indole alkaloids. This study was supported by the ANR, IRSRPL and CHU de Nantes.

The microbiota plays a major role in the regulation of the host immune functions thus establishing a symbiotic relationship that maintains immune homeostasis. Among immune cells, regulatory B cells (Bregs), which can inhibit effector T cell responses, may be involved in the intestinal homeostasis. Recent works suggest that the interaction between the microbiota and Bregs appears to be important to limit autoimmune diseases and help to maintain tolerance in transplantation. Short‐chain fatty acids, recognized as major metabolites of the microbiota, seem to be involved in the generation of a pro‐tolerogenic environment in the gut, particularly through the regulation of B cell differentiation, limiting mature B cells and promoting the function of Bregs. In this review, we show that this B cells‐microbiota interaction may open a path towards new potential therapeutic applications not only for patients with autoimmune diseases but also in transplantation.

The aim of our study was to determine whether granzyme B-expressing regulatory B cells (GZMB⁺ B cells) are enriched in the blood of transplant patients with renal graft tolerance. To achieve this goal, we analysed two single-cell RNA sequencing (scRNAseq) datasets: (1) peripheral blood mononuclear cells (PBMCs), including GZMB⁺ B cells from renal transplant patients, i.e., patients with stable graft function on conventional immunosuppressive treatment (STA, n = 3), drug-free tolerant patients (TOL, n = 3), and patients with antibody-mediated rejection (ABMR, n = 3), and (2) ex-vivo-induced GZMB⁺ B cells from these groups. In the patient PBMCs, we first showed that natural GZMB⁺ B cells were enriched in genes specific to Natural Killer (NK) cells (such as NKG7 and KLRD1) and regulatory B cells (such as GZMB, IL10, and CCL4). We performed a pseudotemporal trajectory analysis of natural GZMB⁺ B cells and showed that they were highly differentiated B cells with a trajectory that is very different from that of conventional memory B cells and linked to the transcription factor KLF13. By specifically analysing GZMB⁺ natural B cells in TOLs, we found that these cells had a very specific transcriptomic profile associated with a reduction in the expression of HLA molecules, apoptosis, and the inflammatory response (in general) in the blood and that this signature was conserved after ex vivo induction, with the induction of genes associated with migration processes, such as CCR7, CCL3, or CCL4. An analysis of receptor/ligand interactions between these GZMB^+/− natural B cells and all of the immune cells present in PBMCs also demonstrated that GZMB⁺ B cells were the B cells that carried the most ligands and had the most interactions with other immune cells, particularly in tolerant patients. Finally, we showed that these GZMB⁺ B cells were able to infiltrate the graft under inflammatory conditions, thus suggesting that they can act in locations where immune events occur.