Abstract
CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation. In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM). In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p < 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. P < 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2 = 0.76; p < 0.01), which was subsequently lost over sequential cycles of proliferation. There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells. In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood. CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.
Highlights
CD24 is one of the earliest expressed proteins during human B cell maturation, being present at the late pro-B cell stages alongside surface markers such as CD21 and cytoplasmic μ heavy chains [1, 2]
We recently described significantly increased frequency and expression of CD24 on subsets of IgD+IgM+ B cells from patients suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) [16], a multisystem disorder characterized by fatigue, post-exertional malaise and cognitive impairment [17, 18]
CD24 expression of transitional B cells newly exited from the bone marrow through to antibody-producing plasmablasts is shown for CD19 gated B cells (Figure 1D) in healthy controls (HC)
Summary
CD24 is one of the earliest expressed proteins during human B cell maturation, being present at the late pro-B cell stages alongside surface markers such as CD21 and cytoplasmic μ heavy chains [1, 2]. The dynamic regulation of CD24 on immature bone marrow B cells and its role in apoptosis has been confirmed in in vitro cell cultures of mouse and human cell lines and was suggested to be involved in determining the fate of B lymphoid progenitor cells [6,7,8]. The selection process that results in apoptosis of many autoreactive B cells in the bone marrow is complex but involves both the specificity of the B cell receptor (BCR) and other signaling molecules, including CD24 [1, 9, 10]. Crosslinking or engagement of CD24 may regulate BCR-mediated B cell selection in the bone marrow, the generation and emigration of transitional B cells to the periphery
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