Date: Sunday, November 8, 2020
Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by antinuclear autoantibodies produced by plasma cells. Type I interferon (IFN) are cytokines which promote plasma cell development and are important to lupus pathogenesis. Type III IFN (IFN lambda, IFN-λ) are more recently discovered and not as well-studied with unclear roles in human lupus pathogenesis and the immune system. Because type III IFN utilize a unique receptor from type I IFN, they are not targeted by type I IFN blocking therapies. We have previously shown an expansion of IgD- CD27- CD24- CD21- (DN2) B cells within lupus disease activity. This compartment contains age/autoimmunity-associated B cells (ABC) defined as either CD11c+ T-bet+ or CD11c+CD21-, which are poised for plasma cell differentiation. SLE is associated with an IFN gene signature in many cell types historically attributed to IFN-α. In epithelial cells, IFN-λ generates the same gene transcription profile as IFN-α. Since IFN-α and IFN-λ might induce a similar transcription program in B cells and IFN-α enhances plasma cell formation, we hypothesize that IFN-λ drives plasma cell differentiation.
Methods: Human peripheral blood B cells from healthy donors or SLE patients meeting 1997 ACR classification criteria were isolated for culture and phenotyping by flow cytometry. Dose response to IFN-λ in terms of RNA expression of interferon stimulated genes (ISG) at 4 hours was measured by RT-qPCR via the 2∆∆CT method. B cells were also stimulated with TLR7/8 agonist R848 in the presence of BAFF and IL-21 +/- IFN-λ for flow cytometric analysis on day 7. IgG and IgM levels in culture supernatants at 7 days were quantitated by ELISA.
Results: DN2, T-bet+, and CD11c+CD21- peripheral blood B cells positively correlated with IFN-λ1 serum levels in SLE patients (n=26). IFN-λ1 directly induced IFIT1, IRF7, ISG15 expression at 4 hours in vitro confirming IFN-λ receptor functionality in human B cells. A dose response relationship between these ISG and IFN-λ stimulation was observed. When IFN-λ was included with R848 stimulation, CD27+ CD38+ plasmablast percentage increased amongst healthy (n=10, p = 0.002) and lupus B cell (n = 6, p= 0.2) cultures. In TLR7 activated lupus B cells, a higher IgG:IgM ratio was observed compared to cultures from age, sex, and race matched healthy donors. In TLR7 activated healthy B cell culture supernatants with IFN-λ included, IgM was significantly increased at day 7 (n=8, p=0.02), but not IgG level.
Conclusion: IFN-λ1 stimulation of human B cells induces a gene signature historically attributed to type I IFN. IFN-λ significantly enhances the differentiation of plasmablasts and IgM levels in TLR7-activated B cell cultures from healthy donors with a lesser effect observed among lupus B cells, which may already have been exposed to interferon in vivo. IFN-λ could provide explanation for poor clinical response of subsets of patients to type I interferon blockade given type III interferon utilize a different receptor. Studies are ongoing to determine if IFN-λ1 has differential effects on B cell and plasma cell subsets in lupus versus healthy donors.
To cite this abstract in AMA style:Barnas J, Albrecht J, Anolik J. Interferon Lambda Promotes Human Plasma Cell Differentiation in Lupus and Healthy Donors [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/interferon-lambda-promotes-human-plasma-cell-differentiation-in-lupus-and-healthy-donors/. Accessed August 1, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-lambda-promotes-human-plasma-cell-differentiation-in-lupus-and-healthy-donors/