Single-cell profiling of CD11c+ B cells in atherosclerosis

Abstract

Circulating CD11c+ B cells, a novel subset of activated B cells, have been linked to autoimmunity and shown to expand with age. Atherosclerosis is an age-associated disease that involves innate and adaptive immune responses to modified self-antigens. Yet, the expression of CD11c on specific B-cell subtypes and its link to atherosclerosis are poorly understood. In this study, we characterized the frequency of CD11c+ B cells in tissues in mice with aging. We observed an age-associated increase in CD11c+ B cells in the spleen and bone marrow of ApoE−/− mice, and this was associated with an increase in aortic plaque. In addition, we also utilized single-cell multi-omics profiling of 60 human subjects undergoing advanced imaging for coronary artery disease (CAD) to subtype CD11c+ B cells and determine their frequency in subjects with high and low severity of CAD. Using unsupervised clustering, we identified four distinct clusters of CD11c+ B cells, which include CD27 and IgD double negative 2 (DN2), age-associated (ABC), CD11c+ unswitched memory (USWM), and activated Naïve (aNav) B cells. We observed an increase in the frequency of both ABC B cells and DN2 B cells in patients with high CAD severity. Pathway analysis further demonstrated augmentation of autophagy, IFNg signaling, and TLR signaling in DN2 cells in high-severity CAD patients. On the other hand, an increase in the negative regulator of BCR signaling through CD72 was found in ABC cells in low-severity CAD patients. Through investigating scRNAseq of atheroma, these DN2 cells were also found to infiltrate human coronary atheroma.

Adaptive immunity and atherosclerosis: aging at its crossroads

“…In line with these research findings, Pattarabanjird et al. describe an age-associated increase of CD11c expressing B cells, containing ABCs, in the spleen and bone marrow of ApoE -/- mice concomitant with an increase in aortic plaque size ( 167 ). Furthermore, ABCs have been demonstrated as highly potent antigen presenting cells in vivo through transcriptome analysis of aorta-enriched ABCs from Ldlr -/- mice ( 15 ), as well as in vitro by antigen-specific T cell proliferation assays and through the use of multiphoton microscopy in which ABCs display an increased stability of antigen specific B-T cell interactions ( 15 , 168 ).…”

“…There have been indications of ABCs being able to skew T cell differentiation towards a Th17 phenotype through their antigen presenting capability, but whether this also occurs in atherosclerosis context remains to be investigated ( 15 , 169 ). Interestingly, the frequency of CD11c expressing B cells positively correlated to plaque severity in cardiac catheterization patients assessed through coronary angiography ( 167 ).…”

Therapeutic Avenues to Modulate B-Cell Function in Patients With Cardiovascular Disease

“…For instance, single-cell sequencing was used to identify and better characterize several subsets of B cells, including B1 cells, 102 MZBs, 103 or age-associated (ABC) B cells. 104 , 105 Single B-cell RNA sequencing paired with BCR sequencing allows paired observations of B-cell subset phenotypes with their antigen specificities. The use of paired BCR sequencing can generate a better understanding of antigen-specific responses and guide therapeutic designs such as immunizations or the development of antibodies directed to specific BCR sequences.…”