Guesdon, W. | Search bioRxiv

bioRxiv2021

Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood

B cells generate antibodies that are essential for immune protection. Major events driving B cell responses occur in lymphoid tissues, which guide antigen acquisition and support cellular interactions, yet complexities of B cell subsets in human lymphoid tissues are poorly understood. Here we perform undirected, global profiling of B cells in matched human lymphoid tissues from deceased transplant organ donors and tracked dissemination of B cell clones. In addition to identifying unanticipated features of tissue-based B cell differentiation, we resolve two clonally independent subsets of marginal zone B cells that differ in cell surface and transcriptomic profiles, tendency to disseminate, distribution bias within splenic marginal zone microenvironment and immunoglobulin repertoire diversity and hypermutation frequency. Each subset is represented in spleen, gut-associated lymphoid tissue, mesenteric lymph node, and also blood. Thus, we provide clarity and diffuse controversy surrounding human MZB - the elephant in the room of human B cell biology.

immunology↗

bioRxiv2020

Human marginal zone B cell development from early T2 progenitors

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2 and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of 4{beta}7 integrin and lower expression of IL4 receptor (IL4R) compared to the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZB). Lineage progression from T1 cells to MZB via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut homing T2 cells is observed in severe SLE and is associated with reduction of MZB and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence and importance for maintaining health.

cell biology↗

bioRxiv2019

Targeting the resolvin E1 - eicosapentaenoic acid axis improves hyperinsulinemia and hyperglycemia in a host genetic dependent manner

ObjectiveEicosapentaenoic acid (EPA) has recently garnered strong attention given the success of the REDUCE-IT trial, which overturned previous conclusions on EPA and led to its FDA approval for lowering cardiovascular disease risk. Therefore, there is a need to study EPA for cardiometabolic risk factors. Here we focused on EPAs preventative role on hyperglycemia and hyperinsulinemia. MethodsC57BL/6J male mice were fed a high fat diet in the absence or presence of pure EPA. Mass spectrometry was used to identify how EPA prevents hyperinsulinemia and hyperglycemia that drove subsequent experiments with resolvin E1 (RvE1) across inbred and outbred models. ResultsAdministration of EPA to C57BL/6J mice prevented obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Supporting analyses of National Health and Nutrition Examination Survey data showed fasting glucose levels of obese adults were inversely related to EPA intake in a sex-specific manner. We next investigated how EPA improved murine hyperinsulinemia and hyperglycemia. Mass spectrometry revealed EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in white adipose tissue and liver. Treatment of obese mice with RvE1, the immunoresolvant metabolite of 18-HEPE, reversed hyperinsulinemia and hyperglycemia through the G-protein coupled receptor ERV1/ChemR23. RvE1s effects were not mediated by macrophage enrichment in white adipose tissue. Finally, we determined if the metabolic effects of RvE1 were dependent on host genetics. RvE1s effects on hyperinsulinemia and hyperglycemia were divergent in diversity outbred mice that model human genetic variation. Secondary SNP analyses further revealed extensive genetic variation in human RvE1- and EPA- metabolizing genes. ConclusionsThe data suggest EPA prevents hyperinsulinemia and hyperglycemia through the endogenous bioactive metabolite RvE1 that activates ERV1/ChemR23. Importantly, the studies reveal host genetics are an overlooked but critical factor in the metabolic response to RvE1. These results underscore the need for personalized administration of EPA-derived RvE1 based on genetic/metabolic enzyme profiles.

biochemistry↗