Characterisation of human pericardial adipose tissue B cells and natural antibody production during obesity and ageing
Creators: name: Smith, Peter
Publisher: name: The University of Edinburgh
Year: 2023
Subjects: B1 cells
natural antibody
Ox-LDL
FALCs
B1 cell function
ageing
obesity
mouse model
pericardial adipose tissue
cardiovascular disease

description: Antibody production by B cells is a critical part of the adaptive immune response to infection, however a population of B cells termed B1 cells links the adaptive and innate immune system. B1 cells produce a type of antibody called natural antibody (Nab) that is present without prior foreign antigen encounter. An important fraction of these recognises phospholipid and oxidised lipids present on bacteria and viruses as well as on apoptotic cells and oxidised LDL (Ox-LDL). In mouse, B1 cells are located in the serous cavities and in visceral adipose tissue like the omentum and pericardium in structures called fat associated lymphoid clusters (FALCs). In addition to producing Nab, B1 cells also play important immunomodulatory functions through secretion of anti-inflammatory IL-10 and inflammatory GM-CSF. Our group and others have previously shown that a population of B1 cells in the pericardium is critical in regulating healing of the heart in response to myocardial infarction (MI) through IL-10 secretion. In cardiovascular disease (CVD) levels of IgM against Ox-LDL are negatively correlated with cardiovascular risk, while levels of IgG positively correlate. Ageing and obesity are both risk factors for cardiovascular disease however how this affects B1 cell function and Nab production are currently unknown. In addition, a human equivalent of murine B1 cells remains to be characterised in adipose tissue. Here I hypothesise that (1) human Nab levels are decreased by obesity and ageing through dysfunction of B1 cell IgM secretion in FALCs and (2) the human pericardium contains a population of B1 cells that are activated during obesity. During my PhD I aimed to: Aim 1: Determine the effect of ageing and obesity on Nab levels in human serum; Aim 2: Characterise B cells present in the human pericardium and assess their suitability as a human equivalent of murine B1 cells; Aim3: Analyse the effect of MI on pericardial B1 cell activation and Nab secretion. I found that in human, obesity significantly reduced serum Nab levels in males but that females were protected. Age did not significantly alter levels of Nab in males or females; however, in lean males levels trended towards an age-related decline. Using biopsies of omental adipose tissues obtained during surgery for hernia or biliary cholic (non-inflammatory conditions) or appendicitis, I found that in lean patients with appendicitis adipose tissue B cells produced higher amounts of Nab against phosphorylcholine (PC) and phosphatidylserine (PtdSer) than patients undergoing surgeries for non-inflammatory conditions, this however was lost in obese patients, suggesting that adipose tissue B cells are dysfunctional in obesity. I confirmed using mouse models that B1 cells in FALCs had reduced IgM production during ageing and obesity. Using single cell RNA sequencing I discovered a novel population of B cells in human pericardial adipose tissue that display characteristics of murine B1 cells including expression of NUR77, a transcription factor shown to negatively regulate murine B1 cells, keeping these autoreactive cells in a quiescent state. In addition, I transcriptionally identified new markers including CD69 and CD83 and confirmed protein expression in these cells by flow cytometry. In patients with a recent MI, pericardial B cells were activated to secrete Nab and increased their expression of HSP70. Collectively this work points to a role for human B1 cells in cardiovascular disease and highlights their potential to be targeted for therapeutic intervention in response to MI.