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B Cell Activation and Plasma Cell Differentiation Are Promoted by IFN-λ in Systemic Lupus Erythematosus

Jennifer L. Barnas, Jennifer Albrecht, Nida Meednu, Diana F. Alzamareh, Cameron Baker, Andrew McDavid, R. John Looney and Jennifer H. Anolik
J Immunol October 27, 2021, ji2100339; DOI: https://doi.org/10.4049/jimmunol.2100339
Jennifer L. Barnas
*Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY;
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Jennifer Albrecht
*Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY;
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Nida Meednu
*Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY;
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Diana F. Alzamareh
*Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY;
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Cameron Baker
†University of Rochester Genomics Research Center, University of Rochester Medical Center, Rochester, NY; and
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Andrew McDavid
‡Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY
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R. John Looney
*Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY;
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Jennifer H. Anolik
*Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY;
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Key Points

  • A type I IFN transcriptional profile is upregulated in SLE B cells.

  • Human B cells express type I IFN genes in response to IFN-λ (type III IFN).

  • IFN-λ may enhance TLR7-mediated B cell activation and PC differentiation in SLE.

Abstract

Type I IFN is essential for viral clearance but also contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), via aberrant nucleic acid–sensing pathways, leading to autoantibody production. Type III IFN (IFN-λ) is now appreciated to have a nonredundant role in viral infection, but few studies have addressed the effects of IFN-λ on immune cells given the more restricted expression of its receptor primarily to the epithelium. In this study, we demonstrate that B cells display a prominent IFN gene expression profile in patients with lupus. Serum levels of IFN-λ are elevated in SLE and positively correlate with B cell subsets associated with autoimmune plasma cell development, including CD11c+T-bet+CD21− B cells. Although B cell subsets express all IFN receptors, IFNLR1 strongly correlates with the CD11c+CD21− B cell expansion, suggesting that IFN-λ may be an unappreciated driver of the SLE IFN signature and B cell abnormalities. We show that IFN-λ potentiates gene transcription in human B cells typically attributed to type I IFN as well as expansion of T-bet–expressing B cells after BCR and TLR7/8 stimulation. Further, IFN-λ promotes TLR7/8-mediated plasmablast differentiation and increased IgM production. CD11c+ B cells demonstrate IFN-λ hyperresponsive signaling compared with other B cell subsets, suggesting that IFN-λ accelerates plasma cell differentiation through this putative extrafollicular pathway. In summary, our data support type III IFN-λ as a cytokine promoting the Ab-secreting cell pool in human viral and autoimmune disease.

Footnotes

  • This work was supported by the Rheumatology Research Foundation (Scientist Development Award 060631-02 to J.L.B.), National Institute of Arthritis and Musculoskeletal and Skin Diseases (Accelerated Medicines Partnership Grant 1UH2-AR-067690 to J.H.A.), and the Bertha and Louis Weinstein Research Fund (to J.H.A.).

  • The gene expression profiles and reads presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE175913.

  • The online version of this article contains supplemental material.

  • Received April 7, 2021.
  • Accepted September 17, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.

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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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B Cell Activation and Plasma Cell Differentiation Are Promoted by IFN-λ in Systemic Lupus Erythematosus
Jennifer L. Barnas, Jennifer Albrecht, Nida Meednu, Diana F. Alzamareh, Cameron Baker, Andrew McDavid, R. John Looney, Jennifer H. Anolik
The Journal of Immunology October 27, 2021, ji2100339; DOI: 10.4049/jimmunol.2100339

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B Cell Activation and Plasma Cell Differentiation Are Promoted by IFN-λ in Systemic Lupus Erythematosus
Jennifer L. Barnas, Jennifer Albrecht, Nida Meednu, Diana F. Alzamareh, Cameron Baker, Andrew McDavid, R. John Looney, Jennifer H. Anolik
The Journal of Immunology October 27, 2021, ji2100339; DOI: 10.4049/jimmunol.2100339
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Print ISSN 0022-1767        Online ISSN 1550-6606