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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd11c-expression-associates-with-ifn-%ce%bb-responsiveness-in-human-b-cells-with-clinical-implications-for-sle/