Altered B Cell Signalling in Autoimmunity

Overview

Journal Nat Rev Immunol

Specialty Allergy & Immunology

Date 2017 Apr 11

PMID 28393923

Citations 145

Authors

David J Rawlings

Genita Metzler

Michelle Wray-Dutra

Shaun W Jackson

Affiliations

Soon will be listed here.

Abstract

Recent work has provided new insights into how altered B cell-intrinsic signals - through the B cell receptor (BCR) and key co-receptors - function together to promote the pathogenesis of autoimmunity. These combined signals affect B cells at two distinct stages: first, in the selection of the naive repertoire; and second, during extrafollicular or germinal centre activation responses. Thus, dysregulated signalling can lead to both an altered naive BCR repertoire and the generation of autoantibody-producing B cells. Strikingly, high-affinity autoantibodies predate and predict disease in several autoimmune disorders, including type 1 diabetes and systemic lupus erythematosus. This Review summarizes how, rather than being a downstream consequence of autoreactive T cell activation, dysregulated B cell signalling can function as a primary driver of many human autoimmune diseases.

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References

Soni C, Wong E, Domeier P, Khan T, Satoh T, Akira S . B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers. J Immunol. 2014; 193(9):4400-14. PMC: 4201954. DOI: 10.4049/jimmunol.1401720. View

Otipoby K, Waisman A, Derudder E, Srinivasan L, Franklin A, Rajewsky K . The B-cell antigen receptor integrates adaptive and innate immune signals. Proc Natl Acad Sci U S A. 2015; 112(39):12145-50. PMC: 4593120. DOI: 10.1073/pnas.1516428112. View

Begovich A, Carlton V, Honigberg L, Schrodi S, Chokkalingam A, Alexander H . A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004; 75(2):330-7. PMC: 1216068. DOI: 10.1086/422827. View

Martin F, Kearney J . Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity. 2000; 12(1):39-49. DOI: 10.1016/s1074-7613(00)80157-0. View

Poholek A, Hansen K, Hernandez S, Eto D, Chandele A, Weinstein J . In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol. 2010; 185(1):313-26. PMC: 2891136. DOI: 10.4049/jimmunol.0904023. View

Hom G, Graham R, Modrek B, Taylor K, Ortmann W, Garnier S . Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. 2008; 358(9):900-9. DOI: 10.1056/NEJMoa0707865. View

Goenka R, Matthews A, Zhang B, ONeill P, Scholz J, Migone T . Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation. J Exp Med. 2013; 211(1):45-56. PMC: 3892970. DOI: 10.1084/jem.20130505. View

Habib T, Funk A, Rieck M, Brahmandam A, Dai X, Panigrahi A . Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant. J Immunol. 2011; 188(1):487-96. PMC: 3670766. DOI: 10.4049/jimmunol.1102176. View

Richardson C, Chida A, Adlowitz D, Silver L, Fox E, Jenks S . Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. J Immunol. 2013; 191(10):4926-39. PMC: 3816606. DOI: 10.4049/jimmunol.1202263. View

10.

Pendergraft 3rd W, Cortazar F, Wenger J, Murphy A, Rhee E, Laliberte K . Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis. Clin J Am Soc Nephrol. 2014; 9(4):736-44. PMC: 3974359. DOI: 10.2215/CJN.07340713. View

11.

Karnowski A, Chevrier S, Belz G, Mount A, Emslie D, DCosta K . B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J Exp Med. 2012; 209(11):2049-64. PMC: 3478936. DOI: 10.1084/jem.20111504. View

12.

Vinuesa C, Cook M, Angelucci C, Athanasopoulos V, Rui L, Hill K . A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 2005; 435(7041):452-8. DOI: 10.1038/nature03555. View

13.

Cambridge G, Stohl W, Leandro M, Migone T, Hilbert D, Edwards J . Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum. 2006; 54(3):723-32. DOI: 10.1002/art.21650. View

14.

Parkes M, Cortes A, van Heel D, Brown M . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013; 14(9):661-73. DOI: 10.1038/nrg3502. View

15.

Illei G, Shirota Y, Yarboro C, Daruwalla J, Tackey E, Takada K . Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010; 62(2):542-52. PMC: 3057537. DOI: 10.1002/art.27221. View

16.

Nickerson K, Christensen S, Shupe J, Kashgarian M, Kim D, Elkon K . TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol. 2010; 184(4):1840-8. PMC: 4098568. DOI: 10.4049/jimmunol.0902592. View

17.

Raj T, Kuchroo M, Replogle J, Raychaudhuri S, Stranger B, De Jager P . Common risk alleles for inflammatory diseases are targets of recent positive selection. Am J Hum Genet. 2013; 92(4):517-29. PMC: 3617371. DOI: 10.1016/j.ajhg.2013.03.001. View

18.

Yarwood A, Huizinga T, Worthington J . The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. Rheumatology (Oxford). 2014; 55(2):199-209. PMC: 4710800. DOI: 10.1093/rheumatology/keu323. View

19.

Aloisi F, Pujol-Borrell R . Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol. 2006; 6(3):205-17. DOI: 10.1038/nri1786. View

20.

Corneth O, de Bruijn M, Rip J, Asmawidjaja P, Kil L, Hendriks R . Enhanced Expression of Bruton's Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis. J Immunol. 2016; 197(1):58-67. DOI: 10.4049/jimmunol.1600208. View