Marianne van Stipdonk - Academia.edu (original) (raw)
Papers by Marianne van Stipdonk
J Neuroimmunol, 2000
The myelin-associated protein, αB-crystallin, is considered a candidate autoantigen in multiple s... more The myelin-associated protein, αB-crystallin, is considered a candidate autoantigen in multiple sclerosis (MS). In the present study, we examined the potential of αB-crystallin to induce experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Attempts to induce EAE with either bovine, rat or murine αB-crystallin or αB-crystallin peptides consistently failed. Immunization with either autologous rat or murine αB-crystallin did not trigger any antigen-specific T cell response. Immunization with bovine αB-crystallin or a synthetic peptide representing the cryptic epitope 49–64 did trigger T cell responses but these failed to crossreact with autologous rat αB-crystallin. Examination of lymphoid tissues of the Lewis rat revealed constitutive expression of αB-crystallin in thymus, spleen, and peripheral lymphocytes. Our data show that in Lewis rats, constitutive lymphoid expression of αB-crystallin is associated with a state of nonresponsiveness to autologous αB-crystallin that effectively controls the development of EAE in response to this myelin antigen.
Progress in Brain Research, 1998
Journal of immunology (Baltimore, Md. : 1950), 1999
The development of multiple sclerosis is most likely influenced by autoimmune responses to centra... more The development of multiple sclerosis is most likely influenced by autoimmune responses to central nervous system myelin proteins as well as by infections with common viruses such as EBV and human herpesvirus-6. However, much remains to be established on how these factors interact. In this study, we show that upon EBV infection, human B cells start to express alpha B-crystallin, a small stress protein that was identified previously as an immunodominant Ag of CNS myelin in multiple sclerosis patients. EBV-induced expression of alpha B-crystallin in B cells leads to HLA-DR-restricted presentation of the protein and to activation of proinflammatory alpha B-crystallin-specific Th cells. While alpha B-crystallin is present in EBV-infected human B cells, the protein is absent from human lymphoid tissues under normal conditions. This is in sharp contrast to other stress proteins such as heat-shock protein (hsp)27 and hsp60 that are ubiquitously expressed in these tissues. In addition, the ...
Journal of Neuroimmunology, 2000
Several findings indicate that infectious events play a role in the pathogenesis of multiple scle... more Several findings indicate that infectious events play a role in the pathogenesis of multiple sclerosis (MS). At the same time, T-cell autoimmunity to myelin antigens is widely believed to be crucial to the development of MS lesions. Several mechanisms have been put forward to explain the presumed link between microbial infections and myelin-directed autoimmunity. These include molecular mimicry, bystander activation including epitope spreading and superantigenic activation of T cells. Evidence that either one of these mechanisms actually occurs in MS patients, however, is still weak. Also, none of the above mechanisms explain why MS is unique to humans. We propose an alternative link between microbial infection and myelin autoimmunity, which we refer to as 'mistaken self'. In this mechanism, peripheral microbial infections of lymphoid cells prime the human T-cell repertoire not only to microbial antigens but also to the stress protein alpha B-crystallin that is expressed de novo in infected lymphoid cells. Subsequently, stress-induced accumulation of this self antigen in oligodendocytes/myelin can provoke pro-inflammatory responses as the recruited memory T-cell repertoire then mistakes the self protein for a microbial antigen. In this paper we review the currently available evidence that 'mistaken self' centering on alpha B-crystallin represents a powerful source of anti-myelin autoimmunity in a way that is unique to humans.
Journal of Neuroimmunology, 1998
The development of multiple sclerosis (MS) is most likely influenced by infectious events as well... more The development of multiple sclerosis (MS) is most likely influenced by infectious events as well as by autoinmaunity to central nervous myelin proteins. However, the way these factors interact remains to be established. Here we show that upon infection with Epstein-Barr virus human peripheral blood cells start to express etB-crystallin, a small stress protein previously described as an immunodommant myelin antigen to human T cells. EBVinduced expression of ~tB-crystallin results in HLA-DR restricted presentation and activation of otB-crystallin specific Thl T ceils. While c~B-crystallin is present in EBV-infected human B cells, the protein is not expressed in healthy human peripheral lymphoid tissues including PBMC, spleen and thymus. This is in sharp contrast to the constitutive expression of etB-crystatlin in peripheral lymphoid tissues of various other mammals and to the expression of other major stress proteins. Our data provides evidence for a novel mechanism by which common vtral infections can trigger myelin-directed autourmmnity in a way that is umque for humans.
Journal of Neuroimmunology, 2000
The myelin-associated protein, a B-crystallin, is considered a candidate autoantigen in multiple ... more The myelin-associated protein, a B-crystallin, is considered a candidate autoantigen in multiple sclerosis MS . In the present study, Ž . we examined the potential of a B-crystallin to induce experimental autoimmune encephalomyelitis EAE in Lewis rats. Attempts to induce EAE with either bovine, rat or murine a B-crystallin or a B-crystallin peptides consistently failed. Immunization with either autologous rat or murine a B-crystallin did not trigger any antigen-specific T cell response. Immunization with bovine a B-crystallin or a synthetic peptide representing the cryptic epitope 49-64 did trigger T cell responses but these failed to crossreact with autologous rat a B-crystallin. Examination of lymphoid tissues of the Lewis rat revealed constitutive expression of a B-crystallin in thymus, spleen, and peripheral lymphocytes. Our data show that in Lewis rats, constitutive lymphoid expression of a B-crystallin is associated with a state of nonresponsiveness to autologous a B-crystallin that effectively controls the development of EAE in response to this myelin antigen. q
Journal of Neuroimmunology, 2000
The stress protein aB-crystallin is an immunodominant antigen in multiple sclerosis (MS)-affected... more The stress protein aB-crystallin is an immunodominant antigen in multiple sclerosis (MS)-affected myelin for human T cells and is expressed at elevated levels in MS lesions. Using bovine aB-crystallin and synthetic peptides based on mouse aB-crystallin the ability of g7 this stress protein to induce experimental allergic encephalomyelitis (EAE) was screened in Biozzi ABH (H-2A ) mice. While whole aB-crystallin and the immunodominant T cell epitopes (49-64, 73-88, 153-168) failed to induce disease the subdominant or cryptic epitope (1-16) was weakly encephalitogenic. The lack of encephalitogenicity of whole protein and dominant epitopes may be due to the low constitutive expression of aB-crystallin in the CNS combined with a state of peripheral tolerance suggested by the constitutive expression of aB-crystallin in secondary lymphoid tissues in ABH mice. Further evidence for a role of aB-crystallin in the progression of chronic relapsing neurological disease is suggested by the development of T cell responses to aB-crystallin during MOG-induced relapsing EAE as myelin damage accumulates. Together our data indicate that normal tolerising mechanisms in ABH mice prevent the induction of EAE by aB-crystallin while the subdominant or cryptic epitope is able to circumvent these mechanisms and contribute to pathogenic myelin-directed autoimmunity following T cell activation.
Immunology Letters, 1997
Tuesday, 24 June 1997 -Oral presentations supematants from short term hsp60 T cell lines 11-4, IF... more Tuesday, 24 June 1997 -Oral presentations supematants from short term hsp60 T cell lines 11-4, IFN-y and TGF-@ were measured. In synovial fluid MNC also the expression of mRNA for IL-4, lL-6, IL-IO and TGF-fl was determined. Results: In vitro prfming with hsp60 of peripheral blood or synovial fluid MNC from patients with OA JCA led to an increased expression of CD30 on CD4+ and CD8+ T cells. Furthermore, short term hsp60 T cell lines from patients with OA JCA, but not from PA JCA patients, were capable of producing II-4 and/or TGF-fi. Finally, we found mRNA expression of II-4 in synovial fluid MNC of the vast majority of patients with OA JCA (8/g), but not in PA JCA patients. In both patient groups mRNA expression of 11-6, II-10 and TGF-/I was found. II-4 mRNA expression in synovtal fluid MNC of patients with OA JCA was associated with responsiveness to hsp60 in synovial fluid MNC.
Cellular Immunology, 2000
The myelin-associated stress protein alphaB-crystallin triggers strong proliferative responses an... more The myelin-associated stress protein alphaB-crystallin triggers strong proliferative responses and IFN-gamma production by human T cells and it is considered a candidate autoantigen in multiple sclerosis. In this study we examined the capacity of alphaB-crystallin or peptides derived thereof to induce experimental autoimmune encephalomyelitis (EAE) in SJL mice. Despite extensive efforts to induce EAE using active immunization with whole alphaB-crystallin, using adoptive transfer of lymphocytes or using peptide immunizations, no clinical or histological signs of EAE could be induced. SJL mice were unable to mount proliferative T-cell responses in vitro or delayed-type hypersensitivity responses in vivo to self-alphaB-crystallin. Also, immunization with self-alphaB-crystallin did not lead to any antibody response in SJL mice while bovine alphaB-crystallin triggered clear antibody responses within 1 week. Immunizations with alphaB-crystallin-derived peptides led to the activation of IL-4-producing Th2 cells and only a few IFN-gamma-producing Th1 cells. Peptide-specific T cells showed no cross-reactivity against whole alphaB-crystallin. The inability of SJL mice to mount proinflammatory T-cell responses against self-alphaB-crystallin readily explains the lack of EAE induction by immunization with whole protein or peptides derived from it. T- and B-cell nonresponsiveness is associated with constitutive expression of full-length alphaB-crystallin in both primary and secondary lymphoid organs in SJL mice, which is seen in other mammals as well, but not in humans.
Nature Immunology, May 1, 2001
Nat Immunol, 2001
In defense of the host, the immune system must often raise an effective cytotoxic T lymphocyte (C... more In defense of the host, the immune system must often raise an effective cytotoxic T lymphocyte (CTL) response from a small number of clonal precursors. The degree to which activation stimuli regulate the expansion and differentiation of naïve CTLs, however, remains unknown. ...
Nat Immunol, 2002
The ZAP-70 tyrosine kinase is a key component of the signaling machinery for the T cell antigen r... more The ZAP-70 tyrosine kinase is a key component of the signaling machinery for the T cell antigen receptor (TCR). Whereas recruitment and activation of ZAP-70 are relatively well understood, the proteins phosphorylated by ZAP-70 are incompletely known. We report here that VHR, a Vaccinia virus VH1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases Erk2 and Jnk, is phosphorylated at Y138 by ZAP-70.Tyr138 phosphorylation was required for VHR to inhibit the Erk2-Elk-1 pathway and, conversely, the VHR Y138F mutant augmented TCR-induced Erk2 kinase and activation of the gene encoding interleukin 2. These results suggest that VHR is a target for ZAP-70 and tempers activation of the Erk2 pathway in a ZAP-70-controlled manner.
Nat Immunol, 2001
Protein kinase C-θ (PKC-θ) is essential for mature T cell activation; however, the mechanism by w... more Protein kinase C-θ (PKC-θ) is essential for mature T cell activation; however, the mechanism by which it is recruited to the TCR signaling machinery is unknown. Here we show that T cell stimulation by antibodies or peptide–major histocompatibility complex (MHC) induces translocation of PKC-θ to membrane lipid rafts, which localize to the immunological synapse. Raft translocation was mediated by the
Proceedings of the National Academy of Sciences, 1994
T-T cell interactions have been proposed in postulated network theories of immunoregulation and a... more T-T cell interactions have been proposed in postulated network theories of immunoregulation and autoimmunity. Despite previous reports of protection induced by T-cell receptor (TcR)-derived peptides in experimental autoimmunity, no evidence for T-T cell interactions by direct recognition of processed TcRs on native T cells was obtained. Here we report that immunization of rats with overlapping sets of peptides of the TcR alpha or beta chain allowed us to detect immunogenic TcR peptides. Remarkably enough, these TcR peptides appeared to cluster within the hypervariable complementarity-determining regions of the TcR. Immunization of rats with these TcR peptides induced CD4+ TcR peptide-specific T cells, which recognized both rDNA TcR proteins and the original, arthritogenic T cell in a major histocompatibility complex class II-restricted way. These findings indicate that activated T cells can process and present their own TcR in the context of major histocompatibility complex class II molecules and, furthermore, that such peptides can be recognized by TcR variable gene-specific T cells.
J Neuroimmunol, 2000
The myelin-associated protein, αB-crystallin, is considered a candidate autoantigen in multiple s... more The myelin-associated protein, αB-crystallin, is considered a candidate autoantigen in multiple sclerosis (MS). In the present study, we examined the potential of αB-crystallin to induce experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Attempts to induce EAE with either bovine, rat or murine αB-crystallin or αB-crystallin peptides consistently failed. Immunization with either autologous rat or murine αB-crystallin did not trigger any antigen-specific T cell response. Immunization with bovine αB-crystallin or a synthetic peptide representing the cryptic epitope 49–64 did trigger T cell responses but these failed to crossreact with autologous rat αB-crystallin. Examination of lymphoid tissues of the Lewis rat revealed constitutive expression of αB-crystallin in thymus, spleen, and peripheral lymphocytes. Our data show that in Lewis rats, constitutive lymphoid expression of αB-crystallin is associated with a state of nonresponsiveness to autologous αB-crystallin that effectively controls the development of EAE in response to this myelin antigen.
Progress in Brain Research, 1998
Journal of immunology (Baltimore, Md. : 1950), 1999
The development of multiple sclerosis is most likely influenced by autoimmune responses to centra... more The development of multiple sclerosis is most likely influenced by autoimmune responses to central nervous system myelin proteins as well as by infections with common viruses such as EBV and human herpesvirus-6. However, much remains to be established on how these factors interact. In this study, we show that upon EBV infection, human B cells start to express alpha B-crystallin, a small stress protein that was identified previously as an immunodominant Ag of CNS myelin in multiple sclerosis patients. EBV-induced expression of alpha B-crystallin in B cells leads to HLA-DR-restricted presentation of the protein and to activation of proinflammatory alpha B-crystallin-specific Th cells. While alpha B-crystallin is present in EBV-infected human B cells, the protein is absent from human lymphoid tissues under normal conditions. This is in sharp contrast to other stress proteins such as heat-shock protein (hsp)27 and hsp60 that are ubiquitously expressed in these tissues. In addition, the ...
Journal of Neuroimmunology, 2000
Several findings indicate that infectious events play a role in the pathogenesis of multiple scle... more Several findings indicate that infectious events play a role in the pathogenesis of multiple sclerosis (MS). At the same time, T-cell autoimmunity to myelin antigens is widely believed to be crucial to the development of MS lesions. Several mechanisms have been put forward to explain the presumed link between microbial infections and myelin-directed autoimmunity. These include molecular mimicry, bystander activation including epitope spreading and superantigenic activation of T cells. Evidence that either one of these mechanisms actually occurs in MS patients, however, is still weak. Also, none of the above mechanisms explain why MS is unique to humans. We propose an alternative link between microbial infection and myelin autoimmunity, which we refer to as 'mistaken self'. In this mechanism, peripheral microbial infections of lymphoid cells prime the human T-cell repertoire not only to microbial antigens but also to the stress protein alpha B-crystallin that is expressed de novo in infected lymphoid cells. Subsequently, stress-induced accumulation of this self antigen in oligodendocytes/myelin can provoke pro-inflammatory responses as the recruited memory T-cell repertoire then mistakes the self protein for a microbial antigen. In this paper we review the currently available evidence that 'mistaken self' centering on alpha B-crystallin represents a powerful source of anti-myelin autoimmunity in a way that is unique to humans.
Journal of Neuroimmunology, 1998
The development of multiple sclerosis (MS) is most likely influenced by infectious events as well... more The development of multiple sclerosis (MS) is most likely influenced by infectious events as well as by autoinmaunity to central nervous myelin proteins. However, the way these factors interact remains to be established. Here we show that upon infection with Epstein-Barr virus human peripheral blood cells start to express etB-crystallin, a small stress protein previously described as an immunodommant myelin antigen to human T cells. EBVinduced expression of ~tB-crystallin results in HLA-DR restricted presentation and activation of otB-crystallin specific Thl T ceils. While c~B-crystallin is present in EBV-infected human B cells, the protein is not expressed in healthy human peripheral lymphoid tissues including PBMC, spleen and thymus. This is in sharp contrast to the constitutive expression of etB-crystatlin in peripheral lymphoid tissues of various other mammals and to the expression of other major stress proteins. Our data provides evidence for a novel mechanism by which common vtral infections can trigger myelin-directed autourmmnity in a way that is umque for humans.
Journal of Neuroimmunology, 2000
The myelin-associated protein, a B-crystallin, is considered a candidate autoantigen in multiple ... more The myelin-associated protein, a B-crystallin, is considered a candidate autoantigen in multiple sclerosis MS . In the present study, Ž . we examined the potential of a B-crystallin to induce experimental autoimmune encephalomyelitis EAE in Lewis rats. Attempts to induce EAE with either bovine, rat or murine a B-crystallin or a B-crystallin peptides consistently failed. Immunization with either autologous rat or murine a B-crystallin did not trigger any antigen-specific T cell response. Immunization with bovine a B-crystallin or a synthetic peptide representing the cryptic epitope 49-64 did trigger T cell responses but these failed to crossreact with autologous rat a B-crystallin. Examination of lymphoid tissues of the Lewis rat revealed constitutive expression of a B-crystallin in thymus, spleen, and peripheral lymphocytes. Our data show that in Lewis rats, constitutive lymphoid expression of a B-crystallin is associated with a state of nonresponsiveness to autologous a B-crystallin that effectively controls the development of EAE in response to this myelin antigen. q
Journal of Neuroimmunology, 2000
The stress protein aB-crystallin is an immunodominant antigen in multiple sclerosis (MS)-affected... more The stress protein aB-crystallin is an immunodominant antigen in multiple sclerosis (MS)-affected myelin for human T cells and is expressed at elevated levels in MS lesions. Using bovine aB-crystallin and synthetic peptides based on mouse aB-crystallin the ability of g7 this stress protein to induce experimental allergic encephalomyelitis (EAE) was screened in Biozzi ABH (H-2A ) mice. While whole aB-crystallin and the immunodominant T cell epitopes (49-64, 73-88, 153-168) failed to induce disease the subdominant or cryptic epitope (1-16) was weakly encephalitogenic. The lack of encephalitogenicity of whole protein and dominant epitopes may be due to the low constitutive expression of aB-crystallin in the CNS combined with a state of peripheral tolerance suggested by the constitutive expression of aB-crystallin in secondary lymphoid tissues in ABH mice. Further evidence for a role of aB-crystallin in the progression of chronic relapsing neurological disease is suggested by the development of T cell responses to aB-crystallin during MOG-induced relapsing EAE as myelin damage accumulates. Together our data indicate that normal tolerising mechanisms in ABH mice prevent the induction of EAE by aB-crystallin while the subdominant or cryptic epitope is able to circumvent these mechanisms and contribute to pathogenic myelin-directed autoimmunity following T cell activation.
Immunology Letters, 1997
Tuesday, 24 June 1997 -Oral presentations supematants from short term hsp60 T cell lines 11-4, IF... more Tuesday, 24 June 1997 -Oral presentations supematants from short term hsp60 T cell lines 11-4, IFN-y and TGF-@ were measured. In synovial fluid MNC also the expression of mRNA for IL-4, lL-6, IL-IO and TGF-fl was determined. Results: In vitro prfming with hsp60 of peripheral blood or synovial fluid MNC from patients with OA JCA led to an increased expression of CD30 on CD4+ and CD8+ T cells. Furthermore, short term hsp60 T cell lines from patients with OA JCA, but not from PA JCA patients, were capable of producing II-4 and/or TGF-fi. Finally, we found mRNA expression of II-4 in synovial fluid MNC of the vast majority of patients with OA JCA (8/g), but not in PA JCA patients. In both patient groups mRNA expression of 11-6, II-10 and TGF-/I was found. II-4 mRNA expression in synovtal fluid MNC of patients with OA JCA was associated with responsiveness to hsp60 in synovial fluid MNC.
Cellular Immunology, 2000
The myelin-associated stress protein alphaB-crystallin triggers strong proliferative responses an... more The myelin-associated stress protein alphaB-crystallin triggers strong proliferative responses and IFN-gamma production by human T cells and it is considered a candidate autoantigen in multiple sclerosis. In this study we examined the capacity of alphaB-crystallin or peptides derived thereof to induce experimental autoimmune encephalomyelitis (EAE) in SJL mice. Despite extensive efforts to induce EAE using active immunization with whole alphaB-crystallin, using adoptive transfer of lymphocytes or using peptide immunizations, no clinical or histological signs of EAE could be induced. SJL mice were unable to mount proliferative T-cell responses in vitro or delayed-type hypersensitivity responses in vivo to self-alphaB-crystallin. Also, immunization with self-alphaB-crystallin did not lead to any antibody response in SJL mice while bovine alphaB-crystallin triggered clear antibody responses within 1 week. Immunizations with alphaB-crystallin-derived peptides led to the activation of IL-4-producing Th2 cells and only a few IFN-gamma-producing Th1 cells. Peptide-specific T cells showed no cross-reactivity against whole alphaB-crystallin. The inability of SJL mice to mount proinflammatory T-cell responses against self-alphaB-crystallin readily explains the lack of EAE induction by immunization with whole protein or peptides derived from it. T- and B-cell nonresponsiveness is associated with constitutive expression of full-length alphaB-crystallin in both primary and secondary lymphoid organs in SJL mice, which is seen in other mammals as well, but not in humans.
Nature Immunology, May 1, 2001
Nat Immunol, 2001
In defense of the host, the immune system must often raise an effective cytotoxic T lymphocyte (C... more In defense of the host, the immune system must often raise an effective cytotoxic T lymphocyte (CTL) response from a small number of clonal precursors. The degree to which activation stimuli regulate the expansion and differentiation of naïve CTLs, however, remains unknown. ...
Nat Immunol, 2002
The ZAP-70 tyrosine kinase is a key component of the signaling machinery for the T cell antigen r... more The ZAP-70 tyrosine kinase is a key component of the signaling machinery for the T cell antigen receptor (TCR). Whereas recruitment and activation of ZAP-70 are relatively well understood, the proteins phosphorylated by ZAP-70 are incompletely known. We report here that VHR, a Vaccinia virus VH1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases Erk2 and Jnk, is phosphorylated at Y138 by ZAP-70.Tyr138 phosphorylation was required for VHR to inhibit the Erk2-Elk-1 pathway and, conversely, the VHR Y138F mutant augmented TCR-induced Erk2 kinase and activation of the gene encoding interleukin 2. These results suggest that VHR is a target for ZAP-70 and tempers activation of the Erk2 pathway in a ZAP-70-controlled manner.
Nat Immunol, 2001
Protein kinase C-θ (PKC-θ) is essential for mature T cell activation; however, the mechanism by w... more Protein kinase C-θ (PKC-θ) is essential for mature T cell activation; however, the mechanism by which it is recruited to the TCR signaling machinery is unknown. Here we show that T cell stimulation by antibodies or peptide–major histocompatibility complex (MHC) induces translocation of PKC-θ to membrane lipid rafts, which localize to the immunological synapse. Raft translocation was mediated by the
Proceedings of the National Academy of Sciences, 1994
T-T cell interactions have been proposed in postulated network theories of immunoregulation and a... more T-T cell interactions have been proposed in postulated network theories of immunoregulation and autoimmunity. Despite previous reports of protection induced by T-cell receptor (TcR)-derived peptides in experimental autoimmunity, no evidence for T-T cell interactions by direct recognition of processed TcRs on native T cells was obtained. Here we report that immunization of rats with overlapping sets of peptides of the TcR alpha or beta chain allowed us to detect immunogenic TcR peptides. Remarkably enough, these TcR peptides appeared to cluster within the hypervariable complementarity-determining regions of the TcR. Immunization of rats with these TcR peptides induced CD4+ TcR peptide-specific T cells, which recognized both rDNA TcR proteins and the original, arthritogenic T cell in a major histocompatibility complex class II-restricted way. These findings indicate that activated T cells can process and present their own TcR in the context of major histocompatibility complex class II molecules and, furthermore, that such peptides can be recognized by TcR variable gene-specific T cells.