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Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is well known that B lymphocytes are not only involved in humoral immune responses but also have a determinative role as APCs in the generation of T cell-mediated immune responses (17, 18, 19). In particular, B lymphocytes are highly efficient APCs for the specific Ag that their surface Igs (sIgs) bind. Resting B cells cannot prime naive T cells, since necessary costimulatory signals such as the B7 molecule are lacking. However, once B cells receive appropriate Ag-specific T cell help through CD40-CD40 ligand, Ag-specific interaction, and cytokine signals (mainly IL-4 and IL-5), they shift to an activated state. Activated B cells express costimulatory signals and can internalize their specific Ag much more efficiently than can non-Ag-specific (professional) APCs such as dendritic cells and macrophages. B cells can receive help from T cell clones that are specific for a single epitope; however, once activated, B cells dramatically increase the uptake and processing of the whole Ag and diversify the T cell response by presenting a broader array of different peptides within the same protein (20).
The latter ability of B cells led to speculation about their importance in amplifying and diversifying T cell-mediated autoimmune responses, allowing the recruitment of diverse populations of self-reactive T cells. Presumably, these events follow the activation of B cells from a few Th clones primed by professional APCs (21). We investigated this hypothesis by analyzing the role of B lymphocytes as APCs in generating spontaneous autoreactive T cell responses to the major autoantigens identified in NOD mice. We tested the autoantigens glutamate decarboxylase (GAD65) and the 60-kDa heat shock protein (HSP60), because spontaneous responses to these Ags were integrally linked with IDDM in both humans and NOD mice. Significantly, the finding that tolerance to these autoantigens ameliorates autoimmune diabetes in NOD mice is the most significant evidence of the involvement of such autoantigens in the pathogenesis of the disease (22, 23, 24, 25). These responses in wild-type (wt) NOD mice with an intact population of B cells were compared with those in genetically B cell-deficient NOD mice, and it was determined that the lack of B cells dramatically affected the profile of spontaneous autoimmune T cell responses against GAD65 and HSP60. T cells from the two groups of mice were immunologically responsive and reacted similarly to a foreign Ag, purified protein derivative (PPD), and to the T cell mitogen Con A. We also found that splenocytes from B cell-deficient mice showed no proliferative response to the peptide determinants of GAD65 that are recognized by T cells from wt NOD mice (23). We believe that these results suggest that B cells have a critical role in vivo in the uptake and processing of the GAD65 protein Ag and in shaping the T cell repertoire to this critical autoantigen. The absence of B cell-mediated diversification of the autoimmune T cell response and the consequent lack of activated, autoreactive T cell clones specific for GAD65 and HSP60 may be the ultimate cause of the protection from autoimmune diabetes that was previously reported in B cell-deficient NOD mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NOD mice carrying in their genome a targeted disruption of the membrane exon of the Ig µ-chain gene (µMT) (26) were kindly provided by Dr. D. Mathis (Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France). The mice were bred in specific pathogen-free conditions at the Scripps Research Institute (La Jolla, CA). At the time of our experiments, the µMT mice were backcrossed onto the NOD background for eight generations, so that 90% of the negative and heterozygous individuals developed spontaneous diabetes. Homozygous, B cell-deficient NOD mice were screened by typing their PBLs with two-color flow cytometric analysis (FACScan, Becton Dickinson, San Jose, CA) using FITC-conjugated anti-B220 Ab and phycoerythrin-conjugated anti-CD3 Ab (PharMingen, La Jolla, CA). Negative and heterozygous littermates were used as controls in each experiment.
Ags and Abs
rGAD65 was expressed in a baculovirus expression system, and HSP60 was produced in Escherichia coli (24); both were generous gifts of R. Tisch (University of North Carolina, Chapel Hill, NC). Both were affinity-purified using a Ni2+/nitrilotriacetic acid resin (Quiagen, Chatsworth, CA). D. L. Kaufman (University of California, Los Angeles, CA) provided us with peptides 6, 15, 17, 34, 35, and 36 from a set of 38 peptides; each peptide was 20 to 23 aa long and spanned the human GAD65 with 5 aa overlaps (27). PPD, an highly immunogenic nonself Ag, was purified from Mycobacterium tuberculosis in the laboratory of B. R. Bloom (Albert Einstein College of Medicine, Bronx, NY). The T cell mitogen Con A was obtained from Sigma (St. Louis, MO).
Purified rabbit anti-murine IgG F(ab')2 Ab
(blocking Ab for sIg) was purchased from Accurate Chemical and
Scientific (Westbury, NY), and rat anti-murine CD16 (blocking for
the Fc
III/IIR) was obtained from PharMingen.
Purification of B cells
B lymphocytes were isolated from the splenocytes of NOD mice using the magnetic activated cell sorter (MACS) magnetic separation system (Miltenyi Biotec, Sunnyvale, CA). Briefly, spleens from 8-wk-old female NOD mice were sieved through mesh, depleted of RBCs by NH4Cl lysis buffer, and washed with PBS. Splenocytes were bound to magnetic bead-conjugated anti-B220 Abs and sorted through MACS separation columns according to the manufacturer’s instructions. Two populations were eluted: B lymphocytes and B cell-depleted splenocytes; their purity (98%) was assessed by FACS analysis using anti-B220 mAb (see above).
Proliferation assays
Spleens from female 8-wk-old B cell-deficient NOD and wt littermates were teased through nylon meshes. The single-cell suspensions of splenocytes were washed and plated at 8 to 10 x 105 cells per well in 96-well microtiter plates in HL-1 serum-free medium (Ventrex, Ventura, CA) supplemented with 100 U/ml penicillin/streptomycin, 2 mM glutamine, and 50 µM 2-ß-mercaptoethanol. Protein Ags were added at various concentrations: 2 to 50 µg/ml GAD65, 10 to 20 µg/ml HSP60, 10 µg/ml PPD, and 2.5 µg/ml Con A. Peptides were used at the optimal concentration of 7 µM. The primary cultures were kept at 37°C, 5% CO2 for 5 days, and 1 µCi of [3H]thymidine per well was added during the last 16 h of culture. Thymidine incorporation was measured by liquid scintillation counting.
Statistical analysis
Pooled data of proliferative indexes from each group of mice were computed as means and compared using the Student t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To test whether the reported protection from autoimmune diabetes
in B cell-deficient NOD mice correlates with an altered autoimmune
response against self Ags, we measured their spontaneous in vitro
responses to GAD65 and HSP60 and compared them with those seen in their
wt (B cell-positive) littermates. Splenocytes that had been isolated
from 6- to 8-wk-old mice were cultured and tested in primary cultures
for proliferative responses to the self Ags GAD65 and HSP60.
Splenocytes from B cell-deficient mice failed to respond to GAD65 at
any of the concentrations tested (p < 0.0001)
(Fig. 1
A). The response to
HSP60 was also significantly lower in B cell-deficient mice compared
with wt mice (p < 0.004). However, both groups of
mice responded positively and similarly to the highly immunogenic,
nonself Ag PPD and to the mitogen Con A (Fig. 1B).
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To determine whether the reduced spontaneous response to
self Ags in B-deficient mice was related to the lack of B cell
Ag-presenting function, we isolated B cells from the splenocytes of wt
NOD mice and tested the ability of these splenocytes to induce
GAD65-specific proliferative responses in vitro. As Figure 2 illustrates, no GAD65 or HSP60 response
occurred in the absence of B cells in the B-depleted splenocyte
cultures from wt mice. However, adding B cells as APCs to the B
cell-depleted splenocyte cultures completely restored the responses to
GAD65 (p < 0.005) and HSP60 (p
< 0.05). We also measured the ability of autoantigen-specific B cells
from wt mice to stimulate T cells from congenitally B cell-deficient
NOD mice. The presence of autoimmune B lymphocytes from wt NOD mice in
the splenocyte cultures was sufficient to induce the amplification of
GAD65- and HSP60-specific T cell responses in vitro. Interestingly, the
immune responses to the foreign Ag PPD (Fig. 2) as well as to the Con A
mitogen (data not shown) were not modified by the presence of B cells
in splenocyte cultures from both wt and B cell-deficient NOD mice. We
believe that these results exclude the possibility that the only
function of B cells is to facilitate the uptake of soluble Ags in
vitro. In addition, these findings support the hypothesis that
activated B cells, which are in vivo committed to recognize their
specific autoantigen in the wt NOD mice, are very efficient in vitro in
the uptake and presentation of self Ags through their sIg and,
consequently, are solely responsible for the amplification of
autoimmune T cell responses against GAD65 and HSP60.
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GAD65-specific Abs that are present in both patients
affected by IDDM and NOD mice may participate directly in the
pathogenesis of autoimmune diabetes. GAD65-specific Ag-Ab complexes are
thought to facilitate the uptake of Ag through FcRs on professional
APCs and to help induce autoimmune T cell responses (28, 29, 30).
Alternatively, GAD65-specific Abs may only represent an epiphenomenon,
while specific B lymphocytes directly activate T cell autoimmune
responses through their Ag-presenting function by efficiently binding
Ag to sIg for subsequent presentation (31). To distinguish between
these alternatives and determine how the humoral immune response is
involved in the T cell-mediated immune response to GAD65, we interfered
with the ability of the IgR of B cells to take up protein Ag by adding
anti-F(ab)2 Ab to the primary cultures of splenocytes.
As a result, the response of GAD65 was dramatically reduced
(p < 0.06). In contrast, using an anti-CD16 Ab
to inhibit the Fc-mediated capture of the Ag from the FcRs of
professional APCs had no effect on the primary response to GAD65 (Fig. 3).
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To exclude the possibility that the B cells were only required in
vitro to recall the response to protein autoantigens such as GAD65 and
HSP60, we looked at the responses to the immunodominant peptides of
GAD65. B cells are believed to be particularly efficient in the uptake
and processing of their specific protein Ag, while their uptake of
peptides and induction of peptide-specific T cell responses is less
critical (32). In NOD mice whose splenocytes were in vitro-depleted of
B cells, the responses to immunodominant GAD65 peptides 6, 15, and 35
(Fig. 4A) were comparable
with those of splenocytes from wt NOD mice, confirming that B cells
were not necessary to induce these immune responses in vitro.
Conversely, genetically B cell-deficient NOD mice did not have
measurable responses to these GAD65 peptides (p 
0.05) (Fig. 4B). Evidently, the B cells were important
in vivo to shape the T cell repertoire to the self Ag GAD65 and in
particular to develop and diversify the autoreactive T cell response to
peptide determinants of GAD65.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of B lymphocytes in T cell-mediated autoimmune diseases is still not fully elucidated. Although autoantibodies are detectable in the sera of NOD mice and patients affected by IDDM (33, 34) as well as other T cell-mediated autoimmune diseases (35, 36), their role in the pathogenesis of these diseases remains uncertain. One hypothesis holds that Ag-Ab complexes may facilitate the FcR-mediated capture of autoantigen by professional APCs (28, 30, 37) and increase the processing and presentation of autoantigens. It has also been proposed that autoantibodies may directly bind to pancreatic islets and mediate their destruction by an Ab-dependent cell-mediated cytotoxic response (38). However, there is already convincing evidence that B cells are not required during the effector phase of B cell destruction (39). This finding supports the alternative hypothesis that the secreted autoantibodies only represent an epiphenomenon in the pathogenesis of T cell-mediated autoimmune diseases, while B lymphocytes may play a major role during the induction phase of the disease by directly mediating the activation of autoreactive T cells through their Ag-presenting function (40, 41). Here, we provide evidence that B lymphocytes have a critical role as APCs with regard to the induction of spontaneous autoreactive T cell responses in NOD mice, so that splenocytes from B cell-deficient NOD mice, which have been shown previously to be protected from autoimmune diabetes, did not have any proliferative response to GAD65 and HSP60 in vitro. B cells are known to act very efficiently as APCs by uptaking specific Ag through sIg (18). Activated B cells assumed an Ag presenting function after the specific uptake of their Ag that was 10,000-fold more efficient than that of resting B lymphocytes and professional APCs (21). Our results show that the IgR-mediated uptake of GAD65 Ag by B cells was crucial for the activation of autoreactive T cells, suggesting that Ag-specific B cells have an important role as APCs in the autoimmune response to GAD65 Ag. The possibility that the FcR-mediated uptake of Ag-Ab complexes by professional APCs was responsible for the immune response to GAD65 in vitro was excluded when anti-FcR blocking Ab did not inhibit the response to the self Ag; however, we cannot exclude the possibility that this mechanism may play a role in the uptake of the autoantigen in vivo.
Theories about the necessity of B cells to prime T cell-mediated immune responses vary. Some theories propose that B cells are essential as APCs (42, 43, 44); others suggest that B cells have no involvement at all (45, 46), or even induce anergy in naive T cells (47). Resting B cells lack the costimulatory signals necessary to prime T cells, but they become very efficient in the processing and presentation of soluble protein Ags once they receive appropriate help from epitope-specific T cells; they become critical APCs with regard to the amplification of the immune response by priming an increased number of Ag-specific T cell precursors.
Moreover, Ag-specific B cells, owing to their highly efficient uptake of Ag and their processing of Ag-Ig complexes, have the ability to present an array of peptides that are usually not presented (cryptic determinants) by professional APCs (31). Low levels of self Ags may circulate to the thymus and be presented on professional APCs, allowing autoreactive T cells to be deleted. On the other hand, peptide determinants that depend upon prior T cell activation to GAD65 followed by B cell activation, uptake, and processing are not usually available in the thymus, so T cell clones with a high affinity for these peptides may not have been subject to negative selection. As a result, B lymphocytes, by generating these determinants, may allow high affinity autoreactive T cell clones to be activated in the periphery. This hypothesis was strongly supported by the study by Mamula et al., which showed that the Ag-presenting function of B cells is crucial for breaking T cell tolerance to self Ag (20). Particularly, the investigators demonstrated that B cells are responsible for amplifying the T cell response from reactivity with a single immunodominant peptide to reactivity with the entire self Ag (e.g., murine cytochrome c). The results presented here provide evidence that B cell-mediated presentation of self Ag represents a key mechanism to break the tolerance against autoantigens such as GAD65 and HSP60 and to generate autoimmune pathogenic T cell responses that ultimately lead to the outcome of autoimmune diabetes. We cannot exclude that the crucial Ag-presenting function of B cells in the autoimmune response to GAD65 and HSP60 may be exclusively due to an amplification of the response through the priming of an increased number of autoreactive T cell precursors, an effect that we were also able to see in vitro by stimulating splenocytes from B cell-deficient NOD mice with in vivo activated, autoimmune B cells from wt littermates. However, the results presented here suggest that B cells as APCs may be also able to amplify the autoimmune response by diversifying the T cell repertoire to the self Ag GAD65. Many studies have shown that B cells are more important for generating immune responses to whole protein Ag rather than to peptide Ag (32). Accordingly, we found that splenocytes taken from wt NOD mice and depleted of B cells in vitro showed a normal profile of immune responses to GAD65 peptides. Conversely, T cells from genetically B cell-deficient NOD mice did not respond to GAD65 peptides, suggesting that, in the absence of B cells, there is a lack of activation of self-reactive T cell clones that are specific for the immunodominant peptides of the GAD65 autoantigen.
To further demonstrate the crucial role of B cells as APCs in the generation of pathogenic autoimmune responses in the NOD mice, we also grafted B lymphocytes that had been purified from wt NOD mice to 3-wk-old B cell-deficient animals. We found that most of the B cell-grafted mice rejected the B lymphocytes; in few cases, we found circulating B cells after 18 h, and none of the grafted animals showed any circulating B cells at 4 wk of age (after 7 days). However, we found that the B cell-grafted mice had an increased insulitis index and most importantly an increased GAD65-specific autoimmune response compared with the B cell-deficient littermates (data not shown). In these mice, the spontaneous response to the GAD65 soluble Ag was still compromised in vitro due to the lack of B cells in their splenocytes at the time of the experiment (7 wk of age). However, the immune responses to GAD65 in the B cell-grafted mice were more similar to those of wt NOD mice rather than B cell-deficient mice. Taken together, these results led us to conclude that B cells were crucial in vivo to generate autoimmune responses to an array of GAD65 antigenic determinants. We can imagine an hypothetical scenario in which a first wave of T cells is primed by professional APCs presenting a self peptide (more likely a molecular mimic peptide) that binds to low avidity T cell clones. These primed autoimmune T cells would subsequently act as helpers for epitope-specific B cells, which in turn would play the crucial role of taking up the whole self protein. Ultimately, the activated self-specific B cells would amplify the autoimmune response by presenting a new set of epitopes to high affinity autoreactive T cell clones that consequently would be empowered to initiate autoimmune diabetes.
We believe that the Ag-presenting function of B cells is crucial only with respect to the generation of autoimmune T cell responses. That is, B cells process self protein Ag and prime high affinity autoreactive T cell clones with self determinants that are not usually expressed on professional APCs in the periphery as well as in the thymic compartment. We found that T cell clones specific for the foreign Ag PPD could be primed entirely without B cells. In that case, B cells were not needed, since APCs such as macrophages and dendritic cells were able to express these foreign determinants to high affinity T cell clones that, since they were nonself reactive, were not deleted in the thymus.
Recently, the Th1/Th2 paradigm applied to the pathogenesis of T cell-mediated autoimmune diseases has been strongly questioned. Several studies have shown that the cell populations and cytokines of the Th2 humoral immune response are deeply involved in autoimmune diseases (7, 8, 9). Our study has identified the mechanism by which the humoral immune response, in particular autoantigen-specific B cells, play a critical role in the pathogenesis of IDDM. The lack of amplification of the autoimmune response against a self Ag such as GAD65 by B lymphocytes via their Ig-specific Ag-presenting function can entirely account for the protection from autoimmune diabetes observed in B cell-deficient NOD mice.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nora Sarvetnick, Department of Immunology, IMM23, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
3 Abbreviations used in this paper: IDDM, insulin-dependent diabetes mellitus; NOD, nonobese diabetic; GAD65, 65-kDa glutamate decarboxylase; HSP60, 60-kDa heat shock protein; PPD, purified protein derivative; wt, wild-type; sIg, surface Ig; MACS, magnetic activated cell sorter.
Received for publication December 4, 1997. Accepted for publication March 31, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RII gene expression in macrophages of NOD mice. J. Immunol. 157:4707.[Abstract]
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S. Quaratino, J. Ruf, M. Osman, J. Guo, S. McLachlan, B. Rapoport, and M. Londei Human Autoantibodies Modulate the T Cell Epitope Repertoire but Fail to Unmask a Pathogenic Cryptic Epitope J. Immunol., January 1, 2005; 174(1): 557 - 563. [Abstract] [Full Text] [PDF]
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F. S. Wong, L. Wen, M. Tang, M. Ramanathan, I. Visintin, J. Daugherty, L. G. Hannum, C. A. Janeway Jr, and M. J. Shlomchik Investigation of the Role of B-Cells in Type 1 Diabetes in the NOD Mouse Diabetes, October 1, 2004; 53(10): 2581 - 2587. [Abstract] [Full Text] [PDF]
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S. Hussain, K. V. Salojin, and T. L. Delovitch Hyperresponsiveness, Resistance to B-Cell Receptor--Dependent Activation-Induced Cell Death, and Accumulation of Hyperactivated B-Cells in Islets Is Associated With the Onset of Insulitis but not Type 1 Diabetes Diabetes, August 1, 2004; 53(8): 2003 - 2011. [Abstract] [Full Text] [PDF]
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P. A. Silveira, J. Dombrowsky, E. Johnson, H. D. Chapman, D. Nemazee, and D. V. Serreze B Cell Selection Defects Underlie the Development of Diabetogenic APCs in Nonobese Diabetic Mice J. Immunol., April 15, 2004; 172(8): 5086 - 5094. [Abstract] [Full Text] [PDF]
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I. F. Robey, M. Peterson, M. S. Horwitz, D. H. Kono, T. Stratmann, A. N. Theofilopoulos, N. Sarvetnick, L. Teyton, and A. J. Feeney Terminal Deoxynucleotidyltransferase Deficiency Decreases Autoimmune Disease in Diabetes-Prone Nonobese Diabetic Mice and Lupus-Prone MRL-Faslpr Mice J. Immunol., April 1, 2004; 172(7): 4624 - 4629. [Abstract] [Full Text] [PDF]
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 S. Ugrinovic, N. Menager, N. Goh, and P. Mastroeni Characterization and Development of T-Cell Immune Responses in B-Cell-Deficient (Igh-6-/-) Mice with Salmonella enterica Serovar TyphimuriumInfection Infect. Immun., December 1, 2003; 71(12): 6808 - 6819. [Abstract] [Full Text] [PDF]
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S. Trembleau, G. Penna, S. Gregori, N. Giarratana, and L. Adorini IL-12 Administration Accelerates Autoimmune Diabetes in Both Wild-Type and IFN-{gamma}-Deficient Nonobese Diabetic Mice, Revealing Pathogenic and Protective Effects of IL-12-Induced IFN-{gamma} J. Immunol., June 1, 2003; 170(11): 5491 - 5501. [Abstract] [Full Text] [PDF]
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 R. F. Tsuji, M. Szczepanik, I. Kawikova, V. Paliwal, R. A. Campos, A. Itakura, M. Akahira-Azuma, N. Baumgarth, L. A. Herzenberg, and P. W. Askenase B Cell-dependent T Cell Responses: IgM Antibodies Are Required to Elicit Contact Sensitivity J. Exp. Med., November 18, 2002; 196(10): 1277 - 1290. [Abstract] [Full Text] [PDF]
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E. S. Sobel, M. Satoh, Y. Chen, E. K. Wakeland, and L. Morel The Major Murine Systemic Lupus Erythematosus Susceptibility Locus Sle1 Results in Abnormal Functions of Both B and T Cells J. Immunol., September 1, 2002; 169(5): 2694 - 2700. [Abstract] [Full Text] [PDF]
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C. H. Nielsen and R. G. Q. Leslie Complement's participation in acquired immunity J. Leukoc. Biol., August 1, 2002; 72(2): 249 - 261. [Abstract] [Full Text] [PDF]
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J. C. Jaume, S. L. Parry, A.-M. Madec, G. Sonderstrup, and S. Baekkeskov Suppressive Effect of Glutamic Acid Decarboxylase 65-Specific Autoimmune B Lymphocytes on Processing of T Cell Determinants Located Within the Antibody Epitope J. Immunol., July 15, 2002; 169(2): 665 - 672. [Abstract] [Full Text] [PDF]
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D. C. Tsitoura, V. P. Yeung, R. H. DeKruyff, and D. T. Umetsu Critical role of B cells in the development of T cell tolerance to aeroallergens Int. Immunol., June 1, 2002; 14(6): 659 - 667. [Abstract] [Full Text] [PDF]
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H. Kita, Z.-X. Lian, J. Van de Water, X.-S. He, S. Matsumura, M. Kaplan, V. Luketic, R. L. Coppel, A. A. Ansari, and M. E. Gershwin Identification of HLA-A2-restricted CD8+ Cytotoxic T Cell Responses in Primary Biliary Cirrhosis: T Cell Activation Is Augmented by Immune Complexes Cross-Presented by Dendritic Cells J. Exp. Med., January 7, 2002; 195(1): 113 - 123. [Abstract] [Full Text] [PDF]
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P. P. L. Chiu, A. M. Jevnikar, and J. S. Danska Genetic Control of T and B Lymphocyte Activation in Nonobese Diabetic Mice J. Immunol., December 15, 2001; 167(12): 7169 - 7179. [Abstract] [Full Text] [PDF]
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A. Rivera, C.-C. Chen, N. Ron, J. P. Dougherty, and Y. Ron Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations Int. Immunol., December 1, 2001; 13(12): 1583 - 1593. [Abstract] [Full Text] [PDF]
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Y. Yang, M. Bao, and J.-W. Yoon Intrinsic Defects in the T-Cell Lineage Results in Natural Killer T-Cell Deficiency and the Development of Diabetes in the Nonobese Diabetic Mouse Diabetes, December 1, 2001; 50(12): 2691 - 2699. [Abstract] [Full Text] [PDF]
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C. Hulbert, B. Riseili, M. Rojas, and J. W. Thomas Cutting Edge: B Cell Specificity Contributes to the Outcome of Diabetes in Nonobese Diabetic Mice J. Immunol., November 15, 2001; 167(10): 5535 - 5538. [Abstract] [Full Text] [PDF]
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S. A. W. Greeley, D. J. Moore, H. Noorchashm, L. E. Noto, S. Y. Rostami, A. Schlachterman, H. K. Song, B. Koeberlein, C. F. Barker, and A. Naji Impaired Activation of Islet-Reactive CD4 T Cells in Pancreatic Lymph Nodes of B Cell-Deficient Nonobese Diabetic Mice J. Immunol., October 15, 2001; 167(8): 4351 - 4357. [Abstract] [Full Text] [PDF]
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S. Takemura, P. A. Klimiuk, A. Braun, J. J. Goronzy, and C. M. Weyand T Cell Activation in Rheumatoid Synovium Is B Cell Dependent J. Immunol., October 15, 2001; 167(8): 4710 - 4718. [Abstract] [Full Text] [PDF]
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K. Jury, P. Sohnlein, M. Vogel, and W. Richter Isolation and Functional Characterization of Recombinant GAD65 Autoantibodies Derived by IgG Repertoire Cloning From Patients With Type 1 Diabetes Diabetes, September 1, 2001; 50(9): 1976 - 1982. [Abstract] [Full Text] [PDF]
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 M. P. Armengol, M. Juan, A. Lucas-Martin, M. T. Fernandez-Figueras, D. Jaraquemada, T. Gallart, and R. Pujol-Borrell Thyroid Autoimmune Disease : Demonstration of Thyroid Antigen-Specific B Cells and Recombination-Activating Gene Expression in Chemokine-Containing Active Intrathyroidal Germinal Centers Am. J. Pathol., September 1, 2001; 159(3): 861 - 873. [Abstract] [Full Text] [PDF]
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S. M. Liva and R. R. Voskuhl Testosterone Acts Directly on CD4+ T Lymphocytes to Increase IL-10 Production J. Immunol., August 15, 2001; 167(4): 2060 - 2067. [Abstract] [Full Text] [PDF]
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E. A. Johnson, P. Silveira, H. D. Chapman, E. H. Leiter, and D. V. Serreze Inhibition of Autoimmune Diabetes in Nonobese Diabetic Mice by Transgenic Restoration of H2-E MHC Class II Expression: Additive, But Unequal, Involvement of Multiple APC Subtypes J. Immunol., August 15, 2001; 167(4): 2404 - 2410. [Abstract] [Full Text] [PDF]
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J. Tian, D. Zekzer, L. Hanssen, Y. Lu, A. Olcott, and D. L. Kaufman Lipopolysaccharide-Activated B Cells Down-Regulate Th1 Immunity and Prevent Autoimmune Diabetes in Nonobese Diabetic Mice J. Immunol., July 15, 2001; 167(2): 1081 - 1089. [Abstract] [Full Text] [PDF]
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D. J. Weaver Jr., B. Liu, and R. Tisch Plasmid DNAs Encoding Insulin and Glutamic Acid Decarboxylase 65 Have Distinct Effects on the Progression of Autoimmune Diabetes in Nonobese Diabetic Mice J. Immunol., July 1, 2001; 167(1): 586 - 592. [Abstract] [Full Text] [PDF]
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R. Weissert, K. L. de Graaf, M. K. Storch, S. Barth, C. Linington, H. Lassmann, and T. Olsson MHC Class II-Regulated Central Nervous System Autoaggression and T Cell Responses in Peripheral Lymphoid Tissues Are Dissociated in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis J. Immunol., June 15, 2001; 166(12): 7588 - 7599. [Abstract] [Full Text] [PDF]
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S.-H. Im, D. Barchan, P. K. Maiti, S. Fuchs, and M. C. Souroujon Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4 J. Immunol., June 1, 2001; 166(11): 6893 - 6898. [Abstract] [Full Text] [PDF]
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P. P.L. Chiu, D. V. Serreze, and J. S. Danska Development and Function of Diabetogenic T-cells in B-cell-Deficient Nonobese Diabetic Mice Diabetes, April 1, 2001; 50(4): 763 - 770. [Abstract] [Full Text]
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A. Quinn, B. McInerney, E. P. Reich, O. Kim, K. P. Jensen, and E. E. Sercarz Regulatory and Effector CD4 T Cells in Nonobese Diabetic Mice Recognize Overlapping Determinants on Glutamic Acid Decarboxylase and Use Distinct V{{beta}} Genes J. Immunol., March 1, 2001; 166(5): 2982 - 2991. [Abstract] [Full Text] [PDF]
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H. Braley-Mullen and S. Yu Early Requirement for B Cells for Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice J. Immunol., December 15, 2000; 165(12): 7262 - 7269. [Abstract] [Full Text] [PDF]
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A. Holz, T. Dyrberg, W. Hagopian, D. Homann, M. v. Herrath, and M. B. A. Oldstone Neither B Lymphocytes Nor Antibodies Directed Against Self Antigens of the Islets of Langerhans Are Required for Development of Virus-Induced Autoimmune Diabetes J. Immunol., November 15, 2000; 165(10): 5945 - 5953. [Abstract] [Full Text] [PDF]
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H. Noorchashm, D. J. Moore, L. E. Noto, N. Noorchashm, A. J. Reed, A. L. Reed, H. K. Song, R. Mozaffari, A. M. Jevnikar, C. F. Barker, et al. Impaired CD4 T Cell Activation Due to Reliance Upon B Cell-Mediated Costimulation in Nonobese Diabetic (NOD) Mice J. Immunol., October 15, 2000; 165(8): 4685 - 4696. [Abstract] [Full Text] [PDF]
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S.-H. Im, D. Barchan, M. C. Souroujon, and S. Fuchs Role of Tolerogen Conformation in Induction of Oral Tolerance in Experimental Autoimmune Myasthenia Gravis J. Immunol., October 1, 2000; 165(7): 3599 - 3605. [Abstract] [Full Text] [PDF]
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S. Kondo, I. Iwata, K. Anzai, T. Akashi, S. Wakana, K. Ohkubo, H. Katsuta, J. Ono, T. Watanabe, Y. Niho, et al. Suppression of insulitis and diabetes in B cell-deficient mice treated with streptozocin: B cells are essential for the TCR clonotype spreading of islet-infiltrating T cells Int. Immunol., July 1, 2000; 12(7): 1075 - 1083. [Abstract] [Full Text] [PDF]
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J. D. Lich, J. F. Elliott, and J. S. Blum Cytoplasmic Processing Is a Prerequisite for Presentation of an Endogenous Antigen by Major Histocompatibility Complex Class II Proteins J. Exp. Med., May 1, 2000; 191(9): 1513 - 1524. [Abstract] [Full Text] [PDF]
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O. T. M. Chan and M. J. Shlomchik Cutting Edge: B Cells Promote CD8+ T Cell Activation in MRL-Faslpr Mice Independently of MHC Class I Antigen Presentation J. Immunol., February 15, 2000; 164(4): 1658 - 1662. [Abstract] [Full Text] [PDF]
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M. E. Ozaki, B. A. Coren, T. N. Huynh, D. J. Redondo, H. Kikutani, and S. R. Webb CD4+ T Cell Responses to CD40-Deficient APCs: Defects in Proliferation and Negative Selection Apply Only with B Cells as APCs J. Immunol., November 15, 1999; 163(10): 5250 - 5256. [Abstract] [Full Text] [PDF]
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S. Malkiel, S. Factor, and B. Diamond Autoimmune Myocarditis Does Not Require B Cells for Antigen Presentation J. Immunol., November 15, 1999; 163(10): 5265 - 5268. [Abstract] [Full Text] [PDF]
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X.-Z. Yu, S. Bidwell, P. J. Martin, and C. Anasetti Visualization, Fate, and Pathogenicity of Antigen-Specific CD8+ T Cells in the Graft-Versus-Host Reaction J. Immunol., November 1, 1999; 163(9): 4780 - 4787. [Abstract] [Full Text] [PDF]
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O. T. M. Chan, M. P. Madaio, and M. J. Shlomchik B Cells Are Required for Lupus Nephritis in the Polygenic, Fas-Intact MRL Model of Systemic Autoimmunity J. Immunol., October 1, 1999; 163(7): 3592 - 3596. [Abstract] [Full Text] [PDF]
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H. Noorchashm, Y. K. Lieu, N. Noorchashm, S. Y. Rostami, S. A. S. Greeley, A. Schlachterman, H. K. Song, L. E. Noto, A. M. Jevnikar, C. F. Barker, et al. I-Ag7-Mediated Antigen Presentation by B Lymphocytes Is Critical in Overcoming a Checkpoint in T Cell Tolerance to Islet {beta} Cells of Nonobese Diabetic Mice J. Immunol., July 15, 1999; 163(2): 743 - 750. [Abstract] [Full Text] [PDF]
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O. T.M. Chan, L. G. Hannum, A. M. Haberman, M. P. Madaio, and M. J. Shlomchik A Novel Mouse with B Cells but Lacking Serum Antibody Reveals an Antibody-independent Role for B Cells in Murine Lupus J. Exp. Med., May 17, 1999; 189(10): 1639 - 1648. [Abstract] [Full Text] [PDF]
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 S. Kim, S. M. Liva, M. A. Dalal, M. A. Verity, and R. R. Voskuhl Estriol ameliorates autoimmune demyelinating disease: Implications for multiple sclerosis Neurology, April 1, 1999; 52(6): 1230 - 1230. [Abstract] [Full Text] [PDF]
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B. Balasa, J. D. Davies, J. Lee, A. Good, B. T. Yeung, and N. Sarvetnick IL-10 Impacts Autoimmune Diabetes Via a CD8+ T Cell Pathway Circumventing the Requirement for CD4+ T and B Lymphocytes J. Immunol., October 15, 1998; 161(8): 4420 - 4427. [Abstract] [Full Text] [PDF]
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) and µMT (
) NOD mice were cultured for 5 days in
the presence of graded doses of rGAD65 Ag. [3H]thymidine
(1 µCi/well) was added in the last 16 h of culture, and the
incorporation of label was measured by liquid scintillation
counting. Data from one representative experiment are expressed as
stimulation indexes plus the SD of the means calculated from two to
three mice that had been tested individually in three separate
experiments. B, The same number of cells were cultured
as described above in the presence of rGAD65 (50 µg/ml), rHSP60 (20
µg/ml), PPD (10 µg/ml), or Con A (2.5 µg/ml). The proliferative
responses from the splenocytes of female wt (
) or B cell-deficient
(
) NOD mice that had been tested individually in triplicate cultures
were measured as described above, and cumulative data from three
separate experiments (2–3 mice/group in each experiment) were
expressed as mean stimulation indexes. *p <
0.0001; **p = 0.003.
) and congenitally B cell-deficient
(
). Data are from one of two
representative experiments and represent the geometric mean of
triplicate determinations.