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Development of a glucocorticoid exposure signature for SLE

ABSTRACT: We performed RNA-seq on peripheral blood mononuclear cells (PBMC) from healthy human donors treated with interferon alpha 2a (1000IU/mL) +/- dexamethasone 10^-7M, with the aims of studying interactions between IFN and glucocorticoid induced gene expression, as well as identifying potential transcripts that may be used as a glucocorticoid exposure signature in clinical practice in patients with SLE. Transcripts identified from RNA-seq data were analysed in SLE patient data sets to validate clinical utility. We found that dexamethasone minimally impacts on interferon stimulated gene expression however IFN altered gene transcription of many previously reported glucocorticoid induced genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159094 | GEO | 2021/03/31

REPOSITORIES: GEO

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Project description: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. 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. Conclusions: 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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Development of a glucocorticoid exposure signature for SLE

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