Background/Purpose: Systemic lupus erythematosus (SLE) is characterized by an interferon-stimulated gene (ISG) signature typically attributed to interferon (IFN)-α. However, ISGs can be induced by other innate type I interferons (such as β) as well as type III IFN (λ). Type I IFNs may contribute to disease pathogenesis through immune dysregulation, including activation of the B cell compartment. One recently described B cell abnormality associated with lupus in mouse models is the presence of age-associated B cells (ABCs), a population expanded by self-antigen and type II adaptive IFNs (γ), enriched for autoreactivty, and poised for plasma cells differentiation. ABCs have been characterized as CD11c+, CD21- and T-bet+ B cells. The precise frequency and triggers of ABCs in human lupus remain unclear. The purpose of this study was to characterize the ABC population in SLE patients and relationship with disease activity and innate IFN serum levels.

Methods: Peripheral blood leukocytes from 26 lupus patients with a range of disease activity as well as 6 normal healthy donors (ND) were analyzed by flow cytometry using a panel which included CD3, CD11c, CD19, CD20, CD21, CD24, CD27, CD38, CD95, CXCR3, IgD, and T-bet. All lupus patients met ACR criteria. Lupus patients were divided into groups based upon SLEDAI score. IFN-α, IFN-β, and IFN-λ1 (IL-29) levels were quantitated by ELISA from sera drawn on the same day.

Results: CD11c+ CD21- identified a distinct B cell population. The majority of these putative ABCs (CD3- CD19+ CD11c+ CD21-) were distributed in the IgD- CD27- double negative B cell compartment (mean±SEM% of ABC; 61.5±2.8 in SLE, 66.8±4.3% ND) followed by IgD+CD27- total naïve (23.0±3.0% SLE, 17.9±3.4% ND), then switched memory IgD-CD27+ (12.2±1.4% SLE, 11.0±1.2% ND). ABC were primarily CD24- (84.4±1.9% SLE, 78.3±8.3% ND). Thus, activated naïve represented the majority ABC in the total naïve compartment. Putative ABCs comprised a greater percentage of total B cells in lupus patients (4.7±1.1%) compared to ND (0.99±0.1%, unpaired T test with Welch’s correction p-value = 0.0026 with significant difference in variances). Within this CD11c+CD21- B cell population, a subset of cells expressed T-bet (46.2±4.3% SLE, 58.1±5.4% ND). IFN-λ1 serum level positively correlated with CD11c+CD21- (Spearman r=+0.415, p=0.018), double negative IgD-CD27-CD24-CD21- (Spearman r=+0.454, p=0.009) and T bet+ (Spearman r=+0.304, p=0.09) expressing B cells. IFN-β serum level positively correlated with the percentage of transitional B cells (Spearman r=+0.428, p=0.015). ABCs made up a statistitically significant greater percentage of total B cells in patients with a SLEDAI >8 compared to patients grouped by lower disease activity scores (p=0.01, 2-tailed unpaired T test). No correlation between B cell subsets or SLEDAI was found with serum IFN-α level as measured by an all alpha subtype ELISA.

Conclusion:

Our data highlights the importance of innate IFNs other than IFN-α (such as IFN-λ1 and IFN-β) in B cell abnormalities in SLE, including the expansion of ABCs and transitional B cells. Functional characterization of the ABC subset is needed to better understand how it contributes to disease pathogenesis and further define therapeutic target potential.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/peripheral-blood-cd11c-cd21-age-associated-b-cells-abcs-in-human-systemic-lupus-erythematosus-are-associated-with-innate-type-iii-interferon-and-disease-activity/