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Abstract Number: 1905

CD11c+ Expression Associates with IFN-λ Responsiveness in Human B Cells with Clinical Implications for SLE

Jennifer Barnas1, Jennifer Barnard2, Cameron Baker2, Nida Meednu2, Andrew McDavid1, R. John Looney1 and Jennifer Anolik2, 1University of Rochester, Rochester, NY, 2University of Rochester Medical Center, Rochester, NY

Meeting: ACR Convergence 2021

Keywords: B-Cell Targets, B-Lymphocyte, cytokines, interferon, Systemic lupus erythematosus (SLE)

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Session Information

Date: Tuesday, November 9, 2021

Session Title: Abstracts: B Cell Biology & Targets in Autoimmune & Inflammatory Disease (1905–1908)

Session Type: Abstract Session

Session Time: 2:00PM-2:15PM

Background/Purpose: Type I interferon (IFN), namely IFN- α, and B cell aberrations are long recognized in systemic lupus erythematosus (SLE) pathogenesis. Type I IFN receptor blockade has undergone clinical trials in SLE with varying degrees of success. Type III IFN (IFN-λ) produce a gene signature currently indistinguishable from that of type I in responsive cell types. IFN-λ are not blocked by type I IFN receptor blockade as they utilize a unique receptor (IFNLR1). Type III IFN are appreciated to have an important role in viral infection at epithelial barriers where IFNLR1 is strongly expressed. The effects of IFN-λ on immune cells remain understudied and are different between human and murine models. We have previously shown that human B cells can transcribe type I IFN genes after IFN-λ treatment including those associated with SLE. We have found that IFN-λ is detected in the serum of human SLE patients and correlates with IgD- CD27- CD21- CD24- (DN2) B cells, a compartment which contains CD11c+ age/autoimmunity B cells (ABC). ABC are a target of interest as recent studies suggest they are poised for plasma cell differentiation and enriched in autoreactivity and thus have the potential to contribute to SLE pathogenesis.

Methods: Patients meeting 1997 ACR systemic lupus erythematosus classification criteria (n = 8) and healthy donors (HD, n = 5) had blood drawn under IRB-approved protocol. The transcriptome of sorted IgD+ CD27- naïve and IgD- CD27- (DN) B cells was measured by bulk RNA sequencing for differential expression and gene set enrichment analysis. Cell phenotype and STAT1 phosphorylation (pSTAT1) in IFN-α2 and IFN-λ1 treated PBMC was measured by flow cytometry (n =10).

Results: Naïve and DN cells display a prominent type I IFN gene expression profile in SLE. Transcript for type I, type II, and type III IFN receptors (IFNAR1, IFNAR2, IFNGR1, IFNGR2, IFNLR1, and IL10RB) are detected in HD and SLE B cells. CD11c+ CD21- frequency increased in DN compared to naïve B cells for SLE and HD (both p< 0.001). The mean and range of CD11c+ CD21- frequency was higher in SLE DN (30.7± 9.5%, mean±SEM; range 4.8-74.7%) compared to HD DN (7.6%±1.0%,3.6-9.4%). Increased IFNLR1 transcript correlated with CD11c+ CD21- B cell expansion (r2=0.922, p< 0.0001). Increased pSTAT1 after IFN-α2 treatment is found in monocytes, T cells, and B cells but only in the B cells after IFN-λ1 treatment. Naïve, DN, switched, and unswitched memory HD B cells are responsive to type I and type III IFN, but demonstrated a higher pSTAT1 fold change with type I IFN treatment compared to type III IFN. In all B cell subsets, CD11c+ cells had a higher pSTAT1 fold change after IFN-λ1 stimulation than did CD11c- B cells. In HD with well-defined populations of CD11c+ CD21- DN cells, pSTAT1 fold change for IFN-λ approached that of IFN-α2.

Conclusion: All human B cell subsets defined by CD27 and IgD respond to IFN-α and IFN-λ, but those expressing CD11c+ have increased responsiveness to IFN-λ. CD11c+ cells expand in SLE and associate with autoreactive plasma cell development. Thus, the role of IFN-λ may take on increased clinical significance in the setting type I IFN receptor blockade. These results suggest IFN-λ is an underappreciated driver of the IFN signature and B cell aberrations in SLE.


Disclosures: J. Barnas, None; J. Barnard, None; C. Baker, None; N. Meednu, None; A. McDavid, None; R. Looney, None; J. Anolik, None.

To cite this abstract in AMA style:

Barnas J, Barnard J, Baker C, Meednu N, McDavid A, Looney R, Anolik J. CD11c+ Expression Associates with IFN-λ Responsiveness in Human B Cells with Clinical Implications for SLE [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/cd11c-expression-associates-with-ifn-%ce%bb-responsiveness-in-human-b-cells-with-clinical-implications-for-sle/. Accessed January 28, 2023.
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