© The Rockefeller University Press, 0022-1007/1997/10/1257/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 8, October 20, 1997 1257-1267
Regulation of Anti–double-stranded DNA B Cells in Nonautoimmune Mice: Localization to the T–B Interface of the Splenic Follicle
Laura Mandik-Nayak,
Anh Bui,
Hooman Noorchashm,
Ashlyn Eaton, and
Jan Erikson
From The Wistar Institute, Philadelphia, Pennsylvania 19104
Systemic lupus erythematosus (SLE) and the MRL-lpr/lpr murine model for SLE are characterized by the presence of serum anti–double-stranded (ds)DNA antibodies (Abs), whereas nonautoimmune individuals have negligible levels of these Abs. To increase the frequency of anti-DNA B cells and identify the mechanisms involved in their regulation in nonautoimmune mice, we have used Ig transgenes (tgs). In the present study, we used the VH3H9 heavy (H) chain tg which expresses an H chain that was repeatedly isolated from anti-dsDNA Abs from MRL-lpr/lpr mice. Because the VH3H9 H chain can pair with endogenous L chains to generate anti–single-stranded DNA, anti-dsDNA, and non-DNA B cells, this allowed us to study the regulation of anti-dsDNA B cells in the context of a diverse B cell repertoire. We have identified anti-dsDNA B cells that are located at the T–B interface in the splenic follicle where they have an increased in vivo turnover rate. These anti-dsDNA B cells exhibit a unique surface phenotype suggesting developmental arrest due to antigen exposure.
Address correspondence to Dr. Jan Erikson, The Wistar Institute, Rm 273, 3601 Spruce St., Philadelphia, PA 19104. Phone: 215-898-3823; FAX: 215-573-9053; E-mail: jan{at}wista.wistar.upenn.edu
Services provided by the Wistar Institute staff were supported by the Core grant No. CA10815 and by grants from the National Institutes of Health (5R01 AI32137-06), the Arthritis Foundation, and the Pew Charitable Trust to J. Erikson. L. Mandik-Nayak is supported by the Wistar Training grant CA-09171. H. Noorchashm and A. Eaton are supported by the National Cancer Institute Training grant 2T32CA09140.
1 Abbreviations used in this paper: AP, alkaline phosphatase; BrdU, bromodeoxyuridine; ds, double-stranded; HEL, hen egg lysozyme; HRP, horseradish peroxidase; HSA, heat-stable antigen; MFI, mean fluorescence intensity; PALS, periarteriolar lymphoid sheath; ss, single-stranded; tg, transgene; V, variable.

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-
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-
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-
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-
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-
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[Abstract]
[Full Text]
-
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-
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-
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[Abstract]
[Full Text]
-
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[Abstract]
[Full Text]
-
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[Abstract]
-
Yan, J., Mamula, M. J.
(2002). B and T cell tolerance and autoimmunity in autoantibody transgenic mice. Int Immunol
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[Abstract]
[Full Text]
-
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(2002). Level of B Cell Antigen Receptor Surface Expression Influences Both Positive and Negative Selection of B Cells During Primary Development. J. Immunol.
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[Abstract]
[Full Text]
-
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(2002). Induction of Autoantibody Production Is Limited in Nonautoimmune Mice. J. Immunol.
169: 587-594
[Abstract]
[Full Text]
-
Rudolph, E. H., Congdon, K. L., Sackey, F. N. A., Fitzsimons, M. M., Foster, M. H.
(2002). Humoral Autoimmunity to Basement Membrane Antigens Is Regulated in C57BL/6 and MRL/MpJ Mice Transgenic for Anti-Laminin Ig Receptors. J. Immunol.
168: 5943-5953
[Abstract]
[Full Text]
-
Sekiguchi, D. R., Jainandunsing, S. M., Fields, M. L., Maldonado, M. A., Madaio, M. P., Erikson, J., Weigert, M., Eisenberg, R. A.
(2002). Chronic Graft-Versus-Host in Ig Knockin Transgenic Mice Abrogates B Cell Tolerance in Anti-Double-Stranded DNA B Cells. J. Immunol.
168: 4142-4153
[Abstract]
[Full Text]
-
Chu, Y.-P., Taylor, D., Yan, H.-G., Diamond, B., Spatz, L.
(2002). Persistence of partially functional double-stranded (ds) DNA binding B cells in mice transgenic for the IgM heavy chain of an anti-dsDNA antibody. Int Immunol
14: 45-54
[Abstract]
[Full Text]
-
Borrero, M., Clarke, S. H.
(2002). Low-Affinity Anti-Smith Antigen B Cells Are Regulated by Anergy as Opposed to Developmental Arrest or Differentiation to B-1. J. Immunol.
168: 13-21
[Abstract]
[Full Text]
-
Mandik-Nayak, L., Huang, G., Sheehan, K. C. F., Erikson, J., Chaplin, D. D.
(2001). Signaling Through TNF Receptor p55 in TNF-{alpha}-Deficient Mice Alters the CXCL13/CCL19/CCL21 Ratio in the Spleen and Induces Maturation and Migration of Anergic B Cells into the B Cell Follicle. J. Immunol.
167: 1920-1928
[Abstract]
[Full Text]
-
Fields, M. L., Sokol, C. L., Eaton-Bassiri, A., Seo, S.-j., Madaio, M. P., Erikson, J.
(2001). Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells. J. Immunol.
167: 2370-2378
[Abstract]
[Full Text]
-
Seo, S.-j., Buckler, J., Erikson, J.
(2001). Novel Roles for Lyn in B Cell Migration and Lipopolysaccharide Responsiveness Revealed Using Anti-Double-Stranded DNA Ig Transgenic Mice. J. Immunol.
166: 3710-3716
[Abstract]
[Full Text]
-
Lentz, V. M., Manser, T.
(2000). Self-limiting systemic autoimmune disease during reconstitution of T cell-deficient mice with syngeneic T cells: support for a multifaceted role of T cells in the maintenance of peripheral B cell tolerance. Int Immunol
12: 1483-1497
[Abstract]
[Full Text]
-
Desai, D. D., Marion, T. N.
(2000). Induction of anti-DNA antibody with DNA-peptide complexes. Int Immunol
12: 1569-1578
[Abstract]
[Full Text]
-
Eaton-Bassiri, A. S., Mandik-Nayak, L., Seo, S.-j., Madaio, M. P., Cancro, M. P., Erikson, J.
(2000). Alterations in splenic architecture and the localization of anti-double-stranded DNA B cells in aged mice. Int Immunol
12: 915-926
[Abstract]
[Full Text]
-
Mandik-Nayak, L., Nayak, S., Sokol, C., Eaton-Bassiri, A., Madaio, M. P., Caton, A. J., Erikson, J.
(2000). The origin of anti-nuclear antibodies in bcl-2 transgenic mice. Int Immunol
12: 353-364
[Abstract]
[Full Text]
-
Boes, M., Schmidt, T., Linkemann, K., Beaudette, B. C., Marshak-Rothstein, A., Chen, J.
(2000). Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc. Natl. Acad. Sci. USA
97: 1184-1189
[Abstract]
[Full Text]
-
Mandik-Nayak, L., Seo, S.-j., Eaton-Bassiri, A., Allman, D., Hardy, R. R., Erikson, J.
(2000). Functional Consequences of the Developmental Arrest and Follicular Exclusion of Anti-Double-Stranded DNA B Cells. J. Immunol.
164: 1161-1168
[Abstract]
[Full Text]
-
Wang, H., Shlomchik, M. J.
(1999). Autoantigen-Specific B Cell Activation in FAS-Deficient Rheumatoid Factor Immunoglobulin Transgenic Mice. JEM
190: 639-650
[Abstract]
[Full Text]
-
Mandik-Nayak, L., Seo, S.-j., Sokol, C., Potts, K. M., Bui, A., Erikson, J.
(1999). MRL-lpr/lpr Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti-double-stranded DNA B Cells. JEM
189: 1799-1814
[Abstract]
[Full Text]
-
Noorchashm, H., Bui, A., Li, H.-L., Eaton, A., Mandik-Nayak, L., Sokol, C., Potts, K. M., Pure, E., Erikson, J.
(1999). Characterization of anergic anti-DNA B cells: B cell anergy is a T cell-independent and potentially reversible process. Int Immunol
11: 765-776
[Abstract]
[Full Text]
-
Clark, L., Otvos, L. Jr., Stein, P. L., Zhang, X.-M., Skorupa, A. F., Lesh, G. E., McMorris, F. A., Heber-Katz, E.
(1999). Golli-Induced Paralysis: A Study in Anergy and Disease. J. Immunol.
162: 4300-4310
[Abstract]
[Full Text]
-
Schmidt, K. N., Cyster, J. G.
(1999). Follicular Exclusion and Rapid Elimination of Hen Egg Lysozyme Autoantigen-Binding B Cells Are Dependent on Competitor B Cells, But Not on T Cells. J. Immunol.
162: 284-291
[Abstract]
[Full Text]
-
Townsend, S. E., Goodnow, C. C.
(1998). Abortive Proliferation of Rare T Cells Induced by Direct or Indirect Antigen Presentation by Rare B Cells In Vivo. JEM
187: 1611-1621
[Abstract]
[Full Text]
-
Schmidt, K. N., Hsu, C. W., Griffin, C. T., Goodnow, C. C., Cyster, J. G.
(1998). Spontaneous Follicular Exclusion of SHP1-deficient B Cells Is Conditional on the Presence of Competitor Wild-type B Cells. JEM
187: 929-937
[Abstract]
[Full Text]