Complement Receptor 2/CD21- Human Naive B Cells Contain Mostly Autoreactive Unresponsive Clones

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2010 Mar 17

PMID 20231422

Citations 228

Authors

Isabelle Isnardi

Yen-Shing Ng

Laurence Menard

Greta Meyers

David Saadoun

Iva Srdanovic

Jonathan Samuels

Jessica Berman

Jane H Buckner

Charlotte Cunningham-Rundles

Eric Meffre

Affiliations

Soon will be listed here.

Abstract

Complement receptor 2-negative (CR2/CD21(-)) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21(-/lo) B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21(-/lo) B cells in their blood. A majority of CD21(-/lo) B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21(-/lo) B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21(-/lo) B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans.

Citing Articles

CD21 B cells reveal a unique glycosylation pattern with hypersialylation and hyperfucosylation.

Felixberger P, Andrieux G, Maul-Pavicic A, Goldacker S, Harder I, Gutenberger S Front Immunol. 2025; 16:1512279.

PMID: 40013136 PMC: 11861550. DOI: 10.3389/fimmu.2025.1512279.

Aberrant B cell receptor signaling responses in circulating double-negative 2 B cells from radiographic axial spondyloarthritis patients.

Wilbrink R, Neys S, Hendriks R, Spoorenberg A, Kroese F, Corneth O J Transl Autoimmun. 2025; 10:100270.

PMID: 39974741 PMC: 11835616. DOI: 10.1016/j.jtauto.2025.100270.

Functional validation of a novel STAT3 'variant of unknown significance' identifies a new case of STAT3 GOF syndrome and reveals broad immune cell defects.

Mackie J, Suan D, McNaughton P, Haerynck F, OSullivan M, Guerin A Clin Exp Immunol. 2025; 219(1).

PMID: 39836489 PMC: 11791529. DOI: 10.1093/cei/uxaf005.

Metabolically activated and highly polyfunctional intratumoral VISTA regulatory B cells are associated with tumor recurrence in early-stage NSCLC.

Lo Tartaro D, Aramini B, Masciale V, Paschalidis N, Lofaro F, Neroni A Mol Cancer. 2025; 24(1):16.

PMID: 39810191 PMC: 11730485. DOI: 10.1186/s12943-024-02209-2.

Longevity of antibody responses is associated with distinct antigen-specific B cell subsets early after infection.

Kuijper L, Kreher C, Elias G, Claireaux M, Kerster G, Bos A Front Immunol. 2025; 15:1505719.

PMID: 39742271 PMC: 11686410. DOI: 10.3389/fimmu.2024.1505719.

References

Allen C, Ansel K, Low C, Lesley R, Tamamura H, Fujii N . Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol. 2004; 5(9):943-52. DOI: 10.1038/ni1100. View

Halverson R, Torres R, Pelanda R . Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. Nat Immunol. 2004; 5(6):645-50. DOI: 10.1038/ni1076. View

Goodnow C, Crosbie J, Adelstein S, Lavoie T, Brink R, Wotherspoon J . Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 1988; 334(6184):676-82. DOI: 10.1038/334676a0. View

Nemazee D, Burki K . Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature. 1989; 337(6207):562-6. DOI: 10.1038/337562a0. View

Erikson J, Radic M, Camper S, Hardy R, Carmack C, Weigert M . Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature. 1991; 349(6307):331-4. DOI: 10.1038/349331a0. View

Goodnow C, Brink R, Adams E . Breakdown of self-tolerance in anergic B lymphocytes. Nature. 1991; 352(6335):532-6. DOI: 10.1038/352532a0. View

Hartley S, Crosbie J, Brink R, Kantor A, Basten A, Goodnow C . Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature. 1991; 353(6346):765-9. DOI: 10.1038/353765a0. View

Hartley S, Cooke M, Fulcher D, Harris A, Cory S, Basten A . Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell. 1993; 72(3):325-35. DOI: 10.1016/0092-8674(93)90111-3. View

Radic M, Mackle J, Erikson J, Mol C, Anderson W, Weigert M . Residues that mediate DNA binding of autoimmune antibodies. J Immunol. 1993; 150(11):4966-77. View

10.

Tsao B, Chow A, Cheroutre H, Song Y, McGrath M, Kronenberg M . B cells are anergic in transgenic mice that express IgM anti-DNA antibodies. Eur J Immunol. 1993; 23(9):2332-9. DOI: 10.1002/eji.1830230942. View

11.

Fulcher D, Basten A . Reduced life span of anergic self-reactive B cells in a double-transgenic model. J Exp Med. 1994; 179(1):125-34. PMC: 2191321. DOI: 10.1084/jem.179.1.125. View

12.

Cooke M, Heath A, Shokat K, Zeng Y, Finkelman F, Linsley P . Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J Exp Med. 1994; 179(2):425-38. PMC: 2191355. DOI: 10.1084/jem.179.2.425. View

13.

Cyster J, Hartley S, Goodnow C . Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature. 1994; 371(6496):389-95. DOI: 10.1038/371389a0. View

14.

Radic M, Weigert M . Origins of anti-DNA antibodies and their implications for B-cell tolerance. Ann N Y Acad Sci. 1995; 764:384-96. DOI: 10.1111/j.1749-6632.1995.tb55853.x. View

15.

Nemazee D . Does immunological tolerance explain the waste in the B-lymphocyte immune system? Experiment and theory. Ann N Y Acad Sci. 1995; 764:397-401. DOI: 10.1111/j.1749-6632.1995.tb55854.x. View

16.

Cyster J, Goodnow C . Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate. Immunity. 1995; 3(6):691-701. DOI: 10.1016/1074-7613(95)90059-4. View

17.

Healy J, Dolmetsch R, Timmerman L, Cyster J, Thomas M, Crabtree G . Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity. 1997; 6(4):419-28. DOI: 10.1016/s1074-7613(00)80285-x. View

18.

Nguyen K, Mandik L, Bui A, Kavaler J, Norvell A, Monroe J . Characterization of anti-single-stranded DNA B cells in a non-autoimmune background. J Immunol. 1997; 159(6):2633-44. View

19.

Mandik-Nayak L, Bui A, Noorchashm H, Eaton A, Erikson J . Regulation of anti-double-stranded DNA B cells in nonautoimmune mice: localization to the T-B interface of the splenic follicle. J Exp Med. 1997; 186(8):1257-67. PMC: 2199093. DOI: 10.1084/jem.186.8.1257. View

20.

Cunningham-Rundles C, Bodian C . Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999; 92(1):34-48. DOI: 10.1006/clim.1999.4725. View