Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus
Open accessAbstract
Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.
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ABCs are characterized in mice by the surface phenotype CD19+, CD11c+, T-bet+, CD11b+, CD21-, CD23-, CD86+, MHCII+, and in humans by CD11c+, T-bet+, CD27-, IgD-, CD38-, CD21-.
“They are charac terized in mice by the surface phenotype CD19 + , CD11c + , T-bet + , CD11b + , CD21 , CD23 , CD86 + , MHCII + , and in humans by CD11c + , Tbet + , CD27 , IgD , CD38 , CD21 [69 -72].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [70]
The Results sections on DN2 cells describe the human phenotype: CD11c+, T-bet+, CD27−, IgD−, CD21−, and low or absent CD38. The Discussion says human DN2 cells share a T-bet+ CD11c-bright phenotype with mouse ABCs, but our copy does not establish the rest of the claimed mouse marker panel (CD19, CD11b, CD21, CD23, CD86, and MHCII). Page numbers are unavailable in our copy. (LLM, conf=0.88)
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- Authors
- Jenks, S. A., Cashman, K. S., Zumaquero, E., Marigorta, U. M., Patel, A. V., Wang, X., Tomar, D., Woodruff, M. C., Simon, Z., Bugrovsky, R., Blalock, E. L., Scharer, C. D., Tipton, C. M., Wei, C., Lim, S. S., Petri, M., Niewold, T. B., Anolik, J. H., Gibson, G., Lee, F. E.-H., Boss, J. M., Lund, F. E., & Sanz, I.
- Affiliations
- Emory University (US)
- University of Alabama at Birmingham (US)
- Georgia Institute of Technology (US)
- Johns Hopkins University (US)
- NYU Langone Health (US)
- University of Rochester Medicine (US)
- ORCID
- Jenks, Scott A.
- Cashman, Kevin S.
- Zumaquero, Esther
- Marigorta, Urko M.
- Patel, Aakash V.
- Wang, Xiaoqian
- Tomar, Deepak
- Woodruff, Matthew C.
- Bugrovsky, Regina
- Blalock, Emily L.
- Scharer, Christopher D.
- Tipton, Christopher M.
- Wei, Chungwen
- Lim, S. Sam
- Petri, Michelle
- Niewold, Timothy B.
- Anolik, Jennifer H.
- Gibson, Greg
- Lee, F. Eun-Hyung
- Boss, Jeremy M.
- Lund, Frances E.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 49
- Issue
- 4
- Pages
- 725-739.e6
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC6217820
- OpenAlex
- W2897114391
- Cited by
- 1,078
- References
- 2
- Citations by year
- 2026: 166 · 2025: 156 · 2024: 161 · 2023: 149 · 2022: 147 · 2021: 152 · 2020: 84 · 2019: 60 · 2018: 1 · 2014: 1
- FWCI
- 63.62
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-01-14)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (T32-DK007656)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- systemic lupus erythematosus, TLR7, naive B cells, T-bet, TRAF5, autoantibody production, IL-21, B cell differentiation, nephritis, African American patients
- MeSH terms
- Adult, Aged, Aged, 80 and over, B-Lymphocytes, Female, Humans, Lupus Erythematosus, Systemic, Male, Middle Aged, Plasma Cells, B-Lymphocyte Subsets, Toll-Like Receptor 7, Gene Regulatory Networks, Young Adult, Transcriptome
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