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      A Novel Mouse with B Cells but Lacking Serum Antibody Reveals an Antibody-independent Role for B Cells in Murine Lupus

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          Abstract

          The precise role of B cells in systemic autoimmunity is incompletely understood. Although B cells are necessary for expression of disease (Chan, O., and M.J. Shlomchik. 1998. J. Immunol. 160:51–59, and Shlomchik, M.J., M.P. Madaio, D. Ni, M. Trounstine, and D. Huszar. 1994. J. Exp. Med. 180:1295–1306), it is unclear whether autoantibody production, antigen presentation, and/or other B cell functions are required for the complete pathologic phenotype. To address this issue, two experimental approaches were used. In the first, the individual contributions of circulating antibodies and B cells were analyzed using MRL/MpJ- Fas lpr (MRL/ lpr) mice that expressed a mutant transgene encoding surface immunoglobulin (Ig), but which did not permit the secretion of circulating Ig. These mice developed nephritis, characterized by cellular infiltration within the kidney, indicating that B cells themselves, without soluble autoantibody production, exert a pathogenic role. The results indicate that, independent of serum autoantibody, functional B cells expressing surface Ig are essential for disease expression, either by serving as antigen-presenting cells for antigen-specific, autoreactive T cells, or by contributing directly to local inflammation.

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          Tubulointerstitial changes as a major determinant in the progression of renal damage.

          Tubulointerstitial injury is an invariant finding in the chronically diseased kidney, irrespective of the type of disease or the compartment in which the disease originates. Such histologic changes are functionally significant in that scores for such damage, rather than glomerular injury, correlate with decline of renal function. This review summarizes (1) clinical evidence attesting to tubulointerstitial changes as an index of functional impairment, (2) mechanisms by which tubulointerstitial injury impairs renal function, and (3) interactions of pathologic processes in the vascular, glomerular, tubular, and interstitial compartments that culminate in tubulointerstitial injury. This report concludes with a review of interstitial fibrosis, a pathologic process regarded as an irreversible outcome from tubulointerstitial injury.
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            Antigen-specific interaction between T and B cells.

            It is well known that B cells require T-cell help to produce specific antibody. Classic experiments suggested that antigen-specific helper T cells interact with antigen-specific B cells via an antigen 'bridge', the B cells binding to one determinant on an antigen molecule (the 'hapten'), while the T cells at the same time recognize another determinant (the 'carrier'). T-helper cells bind specifically to antigen-presenting cells (APC), which have picked up and processed the appropriate antigen, and this interaction, like the interaction of T-helper cells with specific B cells, is restricted by products encoded by the major histocompatibility complex (MHC). Whereas conventional APC such as macrophages display no binding specificity for antigen, B cells have clonally distributed antigen-specific surface immunoglobulin receptors which would be expected to enhance their capacity to present antigen to T cells. These findings are difficult to reconcile with the simple 'antigen bridge' mechanism of interaction, because it is hard to visualize how the bimolecular complex (processed antigen plus MHC molecule) on the APC surface can resemble the trimolecular complex (antigen bound to surface immunoglobulin plus MHC molecule) on the B-cell surface. To address this problem, we have cloned and immortalized human antigen-specific B cells with Epstein-Barr virus (EBV) and analysed their interaction with T-cell clones specific for the same antigen. We report here that surface immunoglobulin is indeed involved in the uptake and concentration of antigen, allowing specific B cells to present antigen to T cells with very high efficiency. However, the antigen must first be internalized and processed by specific B cells and it is then presented to T cells in an MHC-restricted manner indistinguishable from that characteristic of conventional APC.
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              B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new "speed congenic" stock of NOD.Ig mu null mice

              The T lymphocytes mediating autoimmune destruction of pancreatic beta cells in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes mellitus (IDDM) may be generated due to functional defects in hematopoietically derived antigen-presenting cells (APC). However, it has not been clear which particular subpopulations of APC (B lymphocytes, macrophages, and dendritic cells) contribute to the development and activation of diabetogenic T cells in NOD mice. In the current study we utilized a functionally inactivated immunoglobulin (Ig) mu allele (Ig mu null) to generate a "speed congenic" stock of B lymphocyte-deficient NOD mice that are fixed for linkage markers delineating previously identified diabetes susceptibility (Idd) genes. These B lymphocyte NOD.Ig mu null mice had normal numbers of T cells but were free of overt IDDM and insulitis resistant, while the frequency of disease in the B lymphocyte intact segregants was equivalent to that of standard NOD mice in our colony. Thus, B lymphocytes play a heretofore unrecognized role that is essential for the initial development and/or activation of beta cell autoreactive T cells in NOD mice.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                17 May 1999
                : 189
                : 10
                : 1639-1648
                Affiliations
                From the [* ]Section of Immunobiology and the []Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06510; and the [§ ]Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
                Author notes

                Address correspondence to Mark J. Shlomchik, CB462, Department of Laboratory Medicine, 333 Cedar St., Box 208035, Yale University School of Medicine, New Haven, CT 06510-8035. Phone: 203-688-2089; Fax: 203-688-2748; E-mail: mark.shlomchik@ 123456yale.edu

                Article
                10.1084/jem.189.10.1639
                2193634
                10330443
                c4aaa892-9b0a-4fd6-930e-92da2c91680e
                Copyright @ 1999
                History
                : 21 December 1998
                : 16 February 1999
                Categories
                Articles

                Medicine
                nephritis,transgenic,t cell,vasculitis,antigen presentation
                Medicine
                nephritis, transgenic, t cell, vasculitis, antigen presentation

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