Innate and Adaptive Signals Enhance Differentiation and Expansion of Dual-antibody Autoreactive B Cells in Lupus

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Sep 30

PMID 30266981

Citations 9

Authors

Allison Sang

Thomas Danhorn

Jacob N Peterson

Andrew L Rankin

Brian P OConnor

Sonia M Leach

Raul M Torres

Roberta Pelanda

Affiliations

Soon will be listed here.

Abstract

Autoreactive B cells have a major function in autoimmunity. A small subset of B cells expressing two distinct B-cell-antigen-receptors (B cells) is elevated in many patients with systematic lupus erythematosus (SLE) and in the MRL(/lpr) mouse model of lupus, and is often autoreactive. Here we show, using RNAseq and in vitro and in vivo analyses, signals that are required for promoting B cell numbers and effector function in autoimmune mice. Compared with conventional B cells, B cells are more responsive to Toll-like receptor 7/9 and type I/II interferon treatment, display higher levels of MHCII and co-receptors, and depend on IL-21 for their homeostasis; moreover they expand better upon T cell-dependent antigen stimulation, and mount a more robust memory response, which are characteristics essential for enhanced (auto)immune responses. Our findings thus provide insights on the stimuli for the expansion of an autoreactive B cell subset that may contribute to the etiology of SLE.

Citing Articles

Organ-based characterization of B cells in patients with systemic lupus erythematosus.

Wang Y, Zhao R, Liang Q, Ni S, Yang M, Qiu L Front Immunol. 2025; 16:1509033.

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scRNA + BCR-seq identifies proportions and characteristics of dual BCR B cells in the peritoneal cavity of mice and peripheral blood of healthy human donors across different ages.

Wang H, Li J, Xu Y, Yao X Immun Ageing. 2024; 21(1):90.

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Correlations of baseline neutrophil-lymphocyte ratio with prognosis of patients with lupus nephritis: A single-center experience.

Chen Y, Wu X, Chen X, Li M, Luo C, Shi Y Rheumatol Immunol Res. 2023; 4(4):196-203.

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scBCR-seq revealed a special and novel IG H&L V(D)J allelic inclusion rearrangement and the high proportion dual BCR expressing B cells.

Zhu L, Peng Q, Wu Y, Yao X Cell Mol Life Sci. 2023; 80(11):319.

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NCAE: data-driven representations using a deep network-coherent DNA methylation autoencoder identify robust disease and risk factor signatures.

Martinez-Enguita D, Dwivedi S, Jornsten R, Gustafsson M Brief Bioinform. 2023; 24(5).

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References

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Thibault D, Graham K, Lee L, Balboni I, Hertzog P, Utz P . Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus. Arthritis Res Ther. 2009; 11(4):R112. PMC: 2745794. DOI: 10.1186/ar2771. View

Simard N, Konforte D, Tran A, Esufali J, Leonard W, Paige C . Analysis of the role of IL-21 in development of murine B cell progenitors in the bone marrow. J Immunol. 2011; 186(9):5244-53. PMC: 3080450. DOI: 10.4049/jimmunol.1004040. View

Grandien A, Fucs R, Nobrega A, Andersson J, Coutinho A . Negative selection of multireactive B cell clones in normal adult mice. Eur J Immunol. 1994; 24(6):1345-52. DOI: 10.1002/eji.1830240616. View

Leider N, Melamed D . Differential c-Myc responsiveness to B cell receptor ligation in B cell-negative selection. J Immunol. 2003; 171(5):2446-52. DOI: 10.4049/jimmunol.171.5.2446. View

Casellas R, Shih T, Kleinewietfeld M, Rakonjac J, Nemazee D, Rajewsky K . Contribution of receptor editing to the antibody repertoire. Science. 2001; 291(5508):1541-4. DOI: 10.1126/science.1056600. View

Herber D, Brown T, Liang S, Young D, Collins M, Dunussi-Joannopoulos K . IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J Immunol. 2007; 178(6):3822-30. DOI: 10.4049/jimmunol.178.6.3822. View

Velez M, Kane M, Liu S, Gauld S, Cambier J, Torres R . Ig allotypic inclusion does not prevent B cell development or response. J Immunol. 2007; 179(2):1049-57. DOI: 10.4049/jimmunol.179.2.1049. View

Pauza M, Rehmann J, LeBien T . Unusual patterns of immunoglobulin gene rearrangement and expression during human B cell ontogeny: human B cells can simultaneously express cell surface kappa and lambda light chains. J Exp Med. 1993; 178(1):139-49. PMC: 2191066. DOI: 10.1084/jem.178.1.139. View

10.

Domeier P, Chodisetti S, Soni C, Schell S, Elias M, Wong E . IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J Exp Med. 2016; 213(5):715-32. PMC: 4854731. DOI: 10.1084/jem.20151722. View

11.

Rookhuizen D, DeFranco A . Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses. Proc Natl Acad Sci U S A. 2014; 111(31):E3224-33. PMC: 4128120. DOI: 10.1073/pnas.1323985111. View

12.

Goodnow C, Sprent J, Fazekas de St. Groth B, Vinuesa C . Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005; 435(7042):590-7. DOI: 10.1038/nature03724. View

13.

Zotos D, Tarlinton D . Determining germinal centre B cell fate. Trends Immunol. 2012; 33(6):281-8. DOI: 10.1016/j.it.2012.04.003. View

14.

KENNY J, Rezanka L, Lustig A, Fischer R, Yoder J, Marshall S . Autoreactive B cells escape clonal deletion by expressing multiple antigen receptors. J Immunol. 2001; 164(8):4111-9. DOI: 10.4049/jimmunol.164.8.4111. View

15.

Fraser L, Zhao Y, Lutalo P, DCruz D, Cason J, Silva J . Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus. Eur J Immunol. 2015; 45(8):2409-19. PMC: 5102633. DOI: 10.1002/eji.201545599. View

16.

Nemazee D, Weigert M . Revising B cell receptors. J Exp Med. 2000; 191(11):1813-7. PMC: 2213535. DOI: 10.1084/jem.191.11.1813. View

17.

Gerdes T, Wabl M . Autoreactivity and allelic inclusion in a B cell nuclear transfer mouse. Nat Immunol. 2004; 5(12):1282-7. DOI: 10.1038/ni1133. View

18.

Parker Harp C, Archambault A, Sim J, Ferris S, Mikesell R, Koni P . B cell antigen presentation is sufficient to drive neuroinflammation in an animal model of multiple sclerosis. J Immunol. 2015; 194(11):5077-84. PMC: 4433779. DOI: 10.4049/jimmunol.1402236. View

19.

Rees F, Doherty M, Grainge M, Lanyon P, Zhang W . The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford). 2017; 56(11):1945-1961. DOI: 10.1093/rheumatology/kex260. View

20.

Zhang W, Shi Q, Xu X, Chen H, Lin W, Zhang F . Aberrant CD40-induced NF-κB activation in human lupus B lymphocytes. PLoS One. 2012; 7(8):e41644. PMC: 3428310. DOI: 10.1371/journal.pone.0041644. View