The Journal of Immunology, Vol 159, Issue 12 5810-5820, Copyright © 1997 by American Association of Immunologists

ARTICLES

Resting B cells from autoimmune lupus-prone New Zealand Black and (New Zealand Black x New Zealand White)F1 mice are hyper-responsive to T cell-derived stimuli

J Jongstra-Bilen, B Vukusic, K Boras and JE Wither
The Arthritis Center, The Toronto Hospital, University of Toronto, Ontario, Canada.

To determine whether B cells from New Zealand Black (NZB) and (New Zealand Black x New Zealand White)F1 (NZB/W) mice possess intrinsic defects that lead to altered immune responsiveness, we purified resting B cells from these mice and compared their surface phenotype and function with those of resting B cells isolated from BALB/c and DBA/2 nonautoimmune mouse strains. Flow cytometric analysis of freshly isolated resting B cells revealed that NZB and NZB/W resting B cells are conventional B2-type cells similar to their nonautoimmune counterparts. Despite this, resting B cells from young NZB and NZB/W mice express lower levels of CD23 on their surface and aberrant levels of intracellular IgM. Upon stimulation, resting B cells from young NZB and NZB/W mice demonstrate increased proliferation, IgM secretion, or enhanced expression of costimulatory molecules in response to a variety of different T cell-derived stimuli, including cytokines and signals generated through CD40. Therefore, B cell hyper-responsiveness to T cell stimuli is immunodominant or codominant in NZB/W mice. Taken together, our results suggest that intrinsic B cell hyper- responsiveness may play a role in the pathogenesis of autoimmune disease in NZB and NZB/W mice. The increased clonal expansion of these B cells together with increased Ig production and enhanced costimulatory capacity serve to amplify the immune response. In the context of normal but incomplete T cell tolerance, B cell hyperresponsiveness to the limited signals provided by partially tolerant T cells may be sufficient to yield an autoantibody response.

This article has been cited by other articles:

				C. M. Prazma, N. Yazawa, Y. Fujimoto, M. Fujimoto, and T. F. Tedder CD83 Expression Is a Sensitive Marker of Activation Required for B Cell and CD4+ T Cell Longevity In Vivo J. Immunol., October 1, 2007; 179(7): 4550 - 4562. [Abstract] [Full Text] [PDF]

				S. Smith-Berdan, D. Gille, I. L. Weissman, and J. L. Christensen Reversal of autoimmune disease in lupus-prone New Zealand black/New Zealand white mice by nonmyeloablative transplantation of purified allogeneic hematopoietic stem cells Blood, August 15, 2007; 110(4): 1370 - 1378. [Abstract] [Full Text] [PDF]

				C. Loh, Y.-C. Cai, G. Bonventi, G. Lajoie, R. MacLeod, and J. E. Wither Dissociation of the Genetic Loci Leading to B1a and NKT Cell Expansions from Autoantibody Production and Renal Disease in B6 Mice with an Introgressed New Zealand Black Chromosome 4 Interval J. Immunol., February 1, 2007; 178(3): 1608 - 1617. [Abstract] [Full Text] [PDF]

				J. William, C. Euler, N. Primarolo, and M. J. Shlomchik B Cell Tolerance Checkpoints That Restrict Pathways of Antigen-Driven Differentiation J. Immunol., February 15, 2006; 176(4): 2142 - 2151. [Abstract] [Full Text] [PDF]

				V. Roy, N.-H. Chang, Y. Cai, G. Bonventi, and J. Wither Aberrant IgM Signaling Promotes Survival of Transitional T1 B Cells and Prevents Tolerance Induction in Lupus-Prone New Zealand Black Mice J. Immunol., December 1, 2005; 175(11): 7363 - 7371. [Abstract] [Full Text] [PDF]

				M. K. Haraldsson, N. G. dela Paz, J. G. Kuan, G. S. Gilkeson, A. N. Theofilopoulos, and D. H. Kono Autoimmune Alterations Induced by the New Zealand Black Lbw2 Locus in BWF1 Mice J. Immunol., April 15, 2005; 174(8): 5065 - 5073. [Abstract] [Full Text] [PDF]

				S. Atencio, H. Amano, S. Izui, and B. L. Kotzin 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., April 1, 2004; 172(7): 4159 - 4166. [Abstract] [Full Text] [PDF]

				N.-H. Chang, R. MacLeod, and J. E. Wither Autoreactive B Cells in Lupus-Prone New Zealand Black Mice Exhibit Aberrant Survival and Proliferation in the Presence of Self-Antigen In Vivo J. Immunol., February 1, 2004; 172(3): 1553 - 1560. [Abstract] [Full Text] [PDF]

				C. Wang, M. Khalil, J. Ravetch, and B. Diamond The Naive B Cell Repertoire Predisposes to Antigen-Induced Systemic Lupus Erythematosus J. Immunol., May 1, 2003; 170(9): 4826 - 4832. [Abstract] [Full Text] [PDF]

				C. Wang, H. Hayashi, R. Harrison, B. Chiu, J. R. Chan, H. L. Ostergaard, R. D. Inman, J. Jongstra, M. I. Cybulsky, and J. Jongstra-Bilen Modulation of Mac-1 (CD11b/CD18)-Mediated Adhesion by the Leukocyte-Specific Protein 1 Is Key to Its Role in Neutrophil Polarization and Chemotaxis J. Immunol., July 1, 2002; 169(1): 415 - 423. [Abstract] [Full Text] [PDF]

				G. S. Vratsanos, S. Jung, Y.-M. Park, and J. Craft CD4+ T Cells from Lupus-prone Mice Are Hyperresponsive to T Cell Receptor Engagement with Low and High Affinity Peptide Antigens: A Model to Explain Spontaneous T Cell Activation in Lupus J. Exp. Med., January 29, 2001; 193(3): 329 - 338. [Abstract] [Full Text] [PDF]

				H. Lettesjo, G. P. Burd, and R. A. Mageed CD4+ T Lymphocytes with Constitutive CD40 Ligand in Preautoimmune (NZB NZW)F1 Lupus-Prone Mice: Phenotype and Possible Role in Autoreactivity J. Immunol., October 1, 2000; 165(7): 4095 - 4104. [Abstract] [Full Text] [PDF]

				J. Jongstra-Bilen, V. L. Misener, C. Wang, H. Ginzberg, A. Auerbach, A. L. Joyner, G. P. Downey, and J. Jongstra LSP1 modulates leukocyte populations in resting and inflamed peritoneum Blood, September 1, 2000; 96(5): 1827 - 1835. [Abstract] [Full Text] [PDF]

				Y. Hashimoto, K. Dorshkind, E. Montecino-Rodriguez, N. Taguchi, L. Shultz, and M. E. Gershwin NZB Mice Exhibit a Primary T Cell Defect in Fetal Thymic Organ Culture J. Immunol., February 1, 2000; 164(3): 1569 - 1575. [Abstract] [Full Text] [PDF]

				M. L. Stoll and J. Gavalchin Systemic lupus erythematosus--messages from experimental models Rheumatology, January 1, 2000; 39(1): 18 - 27. [Full Text] [PDF]

				A. Kaliyaperumal, M. A. Michaels, and S. K. Datta Antigen-Specific Therapy of Murine Lupus Nephritis Using Nucleosomal Peptides: Tolerance Spreading Impairs Pathogenic Function of Autoimmune T and B Cells J. Immunol., May 15, 1999; 162(10): 5775 - 5783. [Abstract] [Full Text] [PDF]

				S K Datta Production of pathogenic antibodies: Cognate interactions between autoimmune T and B cells Lupus, November 1, 1998; 7(9): 591 - 596. [Abstract] [PDF]

				J. Wither and B. Vukusic Autoimmunity Develops in Lupus-Prone NZB Mice Despite Normal T Cell Tolerance J. Immunol., November 1, 1998; 161(9): 4555 - 4562. [Abstract] [Full Text] [PDF]