Background/Purpose: CD11c+ age/autoimmunity-associated B cells (ABC) are associated with autoantibody producing cells and disease flare in systemic lupus erythematosus. ABC were initially identified in aged mice and later shown to accumulate in autoimmune disease. The developmental origin and trafficking of ABC or their association with aging is not well understood in healthy individuals. Here, we compare human ABC frequency and phenotype in younger and older individuals with paired blood and bone marrow. We then assess responsiveness of ABC to interferon (IFN) because this is a known driver of these cells in autoimmunity.

Methods: Paired peripheral blood (PB) and bone marrow (BM) were collected from younger (Y, aged 21-27 years, n=5) and older (O, aged 52-65 years, n=5) healthy donors. Mononuclear cells were isolated by density centrifugation. Cells were treated with IFN-α2 or IFN-λ1. Cells were stained with CD3, CD14, CD11c, CD19, CD20, CD27, CD38, IgA, IgD, IgG, IgM, pSTAT1, and T-Bet antibodies for flow cytometry. Fold change of pSTAT1 median fluorescent intensity was measured after IFN treatment.

Results: CD11c+ and CD11c+ T-Bet+ B cells were found at similar frequency amongst total B cells in both blood and bone marrow in younger and older healthy donors (mean±SEM, CD11c+% of B Cells: 3.3±0.8 Y PB, 3.8±1.3 O PB, 3.3±0.9 Y BM, 2.0±0.4 O BM; CD11c+T-Bet+% of B cells 1.6±0.4 Y PB, 1.5±0.4 O PB, 1.7±0.5 Y BM, 1.2±0.1 O BM). Within the IgD- CD27- (DN) B cell compartment, there was a greater frequency of CD11c+ cells in blood (9.8±2.1% of DN) compared to the bone marrow (5.0±1.2%, Wilcoxon Matched Pairs Signed Rank Test p=0.002, n=10). CD11c+ B cells (T-Bet MFI: PB 2234±336, n=10; BM 2513±333, n=10) had higher T-Bet expression than CD11c- B cells (T-Bet MFI: PB 659±81, n=10; BM 660±79, n=10) in both blood and bone marrow. T-Bet MFI of DN B cells was higher in the blood DN B cells (4417±718, n=10) compared to those of the bone marrow (3411±524, n=10). Overall, IFN-α2 was a more potent stimulus for pSTAT1 than IFN-λ. Blood B cells responded more robustly than bone marrow B cells to type I and type III IFN stimuli. Younger bone marrow B cells responded with greater pSTAT1 fold change (3.4±0.2, n=5) to IFN-α2 than older bone marrow B cells (2.3± 0.2, n=5). CD11c- B cells (PB 6.2±0.3, BM 3.0±0.2, n=10) had greater pSTAT1 fold change than CD11c+ B cells (PB 5.4±0.3, BM 2.4±0.2, n=10) in response to IFN-α2. This was reversed for type III IFN, where CD11c+ B cells (PB 2.8±0.1, BM 1.7±0.1, n=10) responded more robustly IFN-λ1 than did CD11c- B cells (PB 2.5±0.1, BM 1.6±. 0.09).

Conclusion: Our data supports the hypothesis that ABC are generated in the periphery and circulate to the bone marrow. Although the frequency of ABC was not higher in older individuals, there were differences in their responsiveness to type I IFN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd11c-t-bet-b-cells-traffic-to-human-bone-marrow/