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BMC Immunology
Published in: BMC Immunology 1/2011

Open Access 01-12-2011 | Research article

Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice

Authors: Zhenhai Zhou, Haitao Niu, Ying-Yi Zheng, Laurence Morel

Published in: BMC Immunology | Issue 1/2011

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Abstract

Backgound

Marginal zone B cells have been implicated in the production of autoantibodies in murine models of lupus. It has been suggested that they contribute to lupus immunopathogenesis through their enhanced effector functions and their repertoire that is biased toward autoreactive specificities. In the B6.NZM2410.Sle.Sle2.Sle3 (B6.TC) model of lupus, the majority of marginal zone B cells are located outside the marginal zone and inside the follicles. Genetic alterations of this strain have shown a correlation between autoimmune pathogenesis and the presence of intrafollicular marginal zone B cells. This study was designed first to strengthen our original observations and to determine how the marginal zone B cells from the lupus-prone mice respond to stimulations and interact with T cells.

Results

The intrafollicular location of B6.TC MZB cells starts before disease manifestations and puts MZB cells in direct contact with CD4+ T cells. Two different autoreactive B cell receptor (BCR) transgenic models showed that the expression of the Sle susceptibility loci enhances the presence of MZB cells inside the follicles. In vitro, B6.TC MZB cells were better effectors than B6 MZB cells with enhanced proliferation and antibody (Ab) production, including anti-DNA Ab, in response to stimulation with TLR ligands, immune complexes or anti-CD40. Furthermore, B6.TC MZB and CD4+ T cells showed a reciprocally enhanced activation, which indicated that their contacts inside B6.TC follicles have functional consequences that suggest an amplification loop between these two cell types.

Conclusions

These results showed that the NZM2410 susceptibility loci induce MZB cells to locate into the follicles, and that this breach of follicular exclusion occurs early in the development of the autoimmune pathogenesis. The enhanced responses to stimulation and increased effector functions of MZB cells from lupus-prone mice as compare to non-autoimmune MZB cells provide a mechanism by which the failure of MZB cell follicular exclusion contributes to the autoimmune process.
Appendix
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Literature
1.
Lipsky PE: Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001, 2: 764-766. 10.1038/ni0901-764.PubMedCrossRef
2.
Bendelac A, Bonneville M, Kearney JF: Autoreactivity by design: innate B and T lymphocytes. Nat Rev Immunol. 2001, 1: 177-186. 10.1038/35105052.PubMedCrossRef
3.
Cinamon G, Zachariah MA, Lam OM, Foss FW, Cyster JG: Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol. 2008, 9: 54-62. 10.1038/ni1542.PubMedPubMedCentralCrossRef
4.
Attanavanich K, Kearney JF: Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J Immunol. 2004, 172: 803-811.PubMedCrossRef
5.
Snapper CM, Yamada H, Smoot D, Sneed R, Lees A, Mond JJ: Comparative in vitro analysis of proliferation, Ig secretion, and Ig class switching by murine marginal zone and follicular B cells. J Immunol. 1993, 150: 2737-2745.PubMed
6.
Oliver AM, Martin F, Gartland GL, Carter RH, Kearney JF: Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses. Eur J Immunol. 1997, 27: 2366-2374. 10.1002/eji.1830270935.PubMedCrossRef
7.
Oliver AM, Martin F, Kearney JF: IgMhigh CD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J Immunol. 1999, 162: 7198-7207.PubMed
8.
Gunn KE, Brewer JW: Evidence that marginal zone B cells possess an enhanced secretory apparatus and exhibit superior secretory activity. J Immunol. 2006, 177: 3791-3798.PubMedCrossRef
9.
Mandik-Nayak L, Racz J, Sleckman BP, Allen PM: Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help. J Exp Med. 2006, 203: 1985-1998. 10.1084/jem.20060701.PubMedPubMedCentralCrossRef
10.
Phan TG, Gardam S, Basten A, Brink R: Altered migration, recruitment, and somatic hypermutation in the early response of marginal zone B cells to T cell-dependent antigen. J Immunol. 2005, 174: 4567-4578.PubMedCrossRef
11.
Martin F, Kearney JF: B-cell subsets and the mature preimmune repertoire. Marginal zone and B1B cells as part of a "natural immune memory". Immunol Rev. 2000, 175: 70-79. 10.1111/j.1600-065X.2000.imr017515.x.PubMedCrossRef
12.
Dunn-Walters DK, Isaacson PG, Spencer J: Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J Exp Med. 1995, 182: 559-566. 10.1084/jem.182.2.559.PubMedCrossRef
13.
Tangye SG, Liu YJ, Aversa G, Phillips JH, de Vries JE: Identification of functional human splenic memory B cells by expression of CD148 and CD27. J Exp Med. 1998, 188: 1691-10.1084/jem.188.9.1691.PubMedPubMedCentralCrossRef
14.
Tsuiji M, Yurasov S, Velinzon K, Thomas S, Nussenzweig MC, Wardemann H: A checkpoint for autoreactivity in human IgM+ memory B cell development. J Exp Med. 2006, 203: 393-400. 10.1084/jem.20052033.PubMedPubMedCentralCrossRef
15.
Grimaldi CM, Michael DJ, Diamond B: Cutting Edge: Expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J Immunol. 2001, 167: 1886-1890.PubMedCrossRef
16.
Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL: Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999, 190: 1697-1710. 10.1084/jem.190.11.1697.PubMedPubMedCentralCrossRef
17.
Wither JE, Loh C, Lajoie G, Heinrichs S, Cai YC, Bonventi G, MacLeod R: Colocalization of expansion of the splenic marginal zone population with abnormal B cell activation and autoantibody production in B6 mice with an introgressed New Zealand Black chromosome 13 interval. J Immunol. 2005, 175: 4309-4319.PubMedCrossRef
18.
Amano H, Amano E, Moll T, Marinkovic D, Ibnou-Zekri N, Martinez-Soria E, Semac I, Wirth T, Nitschke L, Izui S: The Yaa mutation promoting murine lupus causes defective development of marginal zone B cells. J Immunol. 2003, 170: 2293-2301.PubMedCrossRef
19.
Atencio S, Amano H, Izui S, Kotzin BL: Separation of the New Zealand Black genetic contribution to lupus from New Zealand Black determined expansions of marginal zone B and B1a cells. J Immunol. 2004, 172: 4159-4166.PubMedCrossRef
20.
Morel L, Croker BP, Blenman KR, Mohan C, Huang G, Gilkeson G, Wakeland EK: Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc Natl Acad Sci USA. 2000, 97: 6670-6675. 10.1073/pnas.97.12.6670.PubMedPubMedCentralCrossRef
21.
Duan B, Niu H, Xu Z, Sharpe AH, Croker BP, Sobel ES, Morel L: Intrafollicular location of marginal zone/CD1dhi B cells is associated with autoimmune pathology in a mouse model of lupus. Lab Invest. 2008, 88: 1008-1019. 10.1038/labinvest.2008.62.PubMedPubMedCentralCrossRef
22.
Duan B, Croker BP, Morel L: Lupus resistance is associated with marginal zone abnormalities in an NZM murine model. Lab Invest. 2007, 87: 14-28. 10.1038/labinvest.3700497.PubMedCrossRef
23.
Li H, Jiang Y, Prak EL, Radic M, Weigert M: Editors and editing of anti-DNA receptors. Immunity. 2001, 15: 947-957. 10.1016/S1074-7613(01)00251-5.PubMedCrossRef
24.
Shlomchik MJ, Zharhary D, Saunders T, Camper SA, Weigert MG: A rheumatoid-factor transgenic mouse model of autoantibody regulation. Int Immunol. 1993, 5: 1329-1341. 10.1093/intimm/5.10.1329.PubMedCrossRef
25.
Fields ML, Erikson J: The regulation of lupus-associated autoantibodies: immunoglobulin transgenic models. Curr Opin Immunol. 2003, 15: 709-717. 10.1016/j.coi.2003.09.016.PubMedCrossRef
26.
Liu Y, Li L, Kumar KR, Xie C, Lightfoot S, Zhou XJ, Kearney JF, Weigert M, Mohan C: Lupus susceptibility genes may breach tolerance to DNA by impairing receptor editing of nuclear antigen-reactive B cells. J Immunol. 2007, 179: 1340-1352.PubMedCrossRef
27.
Pereira JP, Kelly LM, Cyster JG: Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int Immunol. 2010, 22: 413-419. 10.1093/intimm/dxq047.PubMedPubMedCentralCrossRef
28.
Chen Y, Cuda C, Morel L: Genetic determination of T cell help in loss of tolerance to nuclear antigens. J Immunol. 2005, 174: 7692-7702.PubMedCrossRef
29.
Wither JE, Roy V, Brennan LA: Activated B cells express increased levels of costimulatory molecules in young autoimmune NZB and (NZB × NZW)F-1 mice. Clin Immunol. 2000, 94: 51-63. 10.1006/clim.1999.4806.PubMedCrossRef
30.
Rolf J, Motta V, Duarte N, Lundholm M, Berntman E, Bergman ML, Sorokin L, Cardell SL, Holmberg D: The enlarged population of marginal zone/CD1dhigh B lymphocytes in Nonobese Diabetic Mice maps to diabetes susceptibility region Idd11. J Immunol. 2005, 174: 4821-4827.PubMedCrossRef
31.
Marino E, Batten M, Groom J, Walters S, Liuwantara D, Mackay F, Grey ST: Marginal zone B cells of Non-obese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes and present auto-antigen to diabetogenic T cells. Diabetes. 2007, 57: 395-404. 10.2337/db07-0589.PubMedCrossRef
32.
Erickson LD, Lin LL, Duan B, Morel L, Noelle RJ: A genetic lesion that arrests plasma cell homing to the bone marrow. Proc Natl Acad Sci USA. 2003, 100: 12905-12910. 10.1073/pnas.2131686100.PubMedPubMedCentralCrossRef
33.
Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002, 416: 603-607. 10.1038/416603a.PubMedCrossRef
34.
Wu T, Qin X, Kurepa Z, Kumar KR, Liu K, Kanta H, Zhou XJ, Satterthwaite AB, Davis LS, Mohan C: Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J Clin Invest. 2007, 117: 2186-2196. 10.1172/JCI30398.PubMedPubMedCentralCrossRef
35.
Rubtsov AV, Swanson CL, Troy S, Strauch P, Pelanda R, Torres RM: TLR agonists promote marginal zone B cell activation and facilitate T-dependent IgM responses. J Immunol. 2008, 180: 3882-3888.PubMedCrossRef
36.
Genestier L, Taillardet M, Mondiere P, Gheit H, Bella C, Defrance T: TLR agonists selectively promote terminal plasma cell differentiation of B cell subsets specialized in thymus-independent responses. J Immunol. 2007, 178: 7779-7786.PubMedCrossRef
37.
Rahman ZSM, Manser T: Failed up-regulation of the inhibitory IgG Fc receptor FcgRIIB on germinal center B cells in autoimmune-prone mice is not associated with deletion polymorphisms in the promoter region of the FcgRIIB gene. J Immunol. 2005, 175: 1440-1449.PubMedCrossRef
38.
Burlingame RW, Rubin RL: Autoantibody to the nucleosome subunit (H2A-H2B)-DNA is an early and ubiquitous feature of lupus-like conditions. Mol Biol Rep. 1996, 23: 159-166. 10.1007/BF00351164.PubMedCrossRef
39.
Herlands RA, William J, Hershberg U, Shlomchik MJ: Anti-chromatin antibodies drive in vivo antigen-specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites. Eur J Immunol. 2007, 37: 3339-3351. 10.1002/eji.200737752.PubMedPubMedCentralCrossRef
40.
Boackle SA, Holers VM, Chen XJ, Szakonyi G, Karp DR, Wakeland EK, Morel L: Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity. 2001, 15: 775-785. 10.1016/S1074-7613(01)00228-X.PubMedCrossRef
41.
Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR: Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J Exp Med. 2004, 199: 1631-1640. 10.1084/jem.20031942.PubMedPubMedCentralCrossRef
42.
Mohan C, Adams S, Stanik V, Datta SK: Nucleosome - A major immunogen for pathogenic autoantibody-inducing T-cells of lupus. J Exp Med. 1993, 177: 1367-1381. 10.1084/jem.177.5.1367.PubMedCrossRef
Metadata
Title
Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice
Authors
Zhenhai Zhou
Haitao Niu
Ying-Yi Zheng
Laurence Morel
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2011
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/1471-2172-12-7

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