Abstract
BackgroundAging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known.MethodsSplenic B cells and the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs), were isolated from the spleens of young and old mice and left unstimulated. The RNA was collected to measure the expression of markers associated with intrinsic inflammation and autoimmune antibody production by qPCR. B cells and B cell subsets were also stimulated with CpG and supernatants collected after 7 days to measure autoimmune IgG secretion by ELISA. Metabolic measures (oxygen consumption rate, extracellular acidification rate and glucose uptake) were performed using a Seahorse XFp extracellular flux analyzer.ResultsResults have identified the subset of ABCs, whose frequencies and numbers increase with age and represent the most pro-inflammatory B cell subset, as the cell type mainly if not exclusively responsible for the expression of inflammatory markers and for the secretion of autoimmune antibodies in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic, as compared to those from young mice and to the subset of FO B cells, a feature needed not only to support their higher expression of RNA for inflammatory markers but also their higher autoimmune antibody secretion.ConclusionsThese results identify a relationship between intrinsic inflammation, metabolism and autoimmune B cells and suggest possible ways to understand cellular mechanisms that lead to the generation of pathogenic B cells, that are hyper-inflammatory and hyper-metabolic, and secrete IgG antibodies with autoimmune specificities.
Highlights
Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses
Results show that associated B cells (ABCs) frequency and number increase with age at the expense of FO, whereas no significant changes were observed in the MZ B cell subset as previously shown by us [20, 21] and by other groups [2, 22]
We compared intrinsic B cell inflammation in unstimulated total B cells isolated by magnetic sorting from the spleen of young and old mice, as well as in unstimulated FO and ABCs B cell subsets sorted from the spleen of the same mice
Summary
Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. Aging is associated with increased low-grade systemic inflammation, called inflammaging [1], that has been associated with decreased protective antibody responses against infections and vaccines. Inflammaging induces intrinsic inflammation in immune cells that leads to functional impairment. Data from our laboratory [2] have shown that unstimulated splenic B cells from old mice make more TNF-α than those from young mice. We pre-incubated splenic B cells with exogenous TNF-α before stimulation and found that this pre-treatment significantly decreases both young and old B cell responses. Blocking TNF-α by adding an anti-TNF-α antibody to B cells before stimulation significantly increases class switch in young and more significantly restores it to young levels in old cultured B cells and in vivo [2]
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