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Biomedical subjects

J M van Noort

Publications and source records attributed to J M van Noort.

At least 19 recordsLinked to original sources
PubMed2000

T- and B-cell nonresponsiveness to self-alphaB-crystallin in SJL mice prevents the induction of experimental allergic encephalomyelitis.

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.

Adoptive Transfer↗
PubMed2000

Differential expression of stress proteins in human adult astrocytes in response to cytokines.

Various lines of evidence suggest a close relationship between heat shock proteins (hsp) and several autoimmune diseases such as arthritis, diabetes and multiple sclerosis. While enhanced expression of hsp in autoimmune diseases is often regarded as a non-specific bystander effect of the inflammatory process, surprisingly little is known on hsp regulation by inflammatory mediators such as cytokines. In this study cytokine-induced expression of hsp60, hsp27 and alphaB-crystallin was studied in cultures of primary human adult astrocytes at the mRNA as well as at the protein level. We show differential hsp expression patterns in response to pro-inflammatory and immunoregulatory cytokines. Hsp60 expression was found to be enhanced in response to cytokines as diverse as IL-1beta, TNF-alpha, IL-4, IL-6 and IL-10. Upregulation of hsp27, however, was primarily induced by immunoregulatory cytokines like IL-4, IL-6 and TGF-beta whereas alphaB-crystallin expression was found to be enhanced by the pro-inflammatory cytokine TNF-alpha only. None of the cytokines studied was able to enhance expression of all three hsp simultaneously. These results show that in human astrocytes induced expression of hsp27 and alphaB-crystallin is dependent on the presence of a defined set of stimuli, while induced expression of hsp60 is a much less selective event. This highly differential pattern of hsp expression in response to inflammatory mediators known to play an important role in the pathogenesis of autoimmune diseases indicates that hsp responses are specific rather than non-specific bystander responses.

Adjuvants, Immunologic↗
PubMed2000

Mistaken self, a novel model that links microbial infections with myelin-directed autoimmunity in multiple sclerosis.

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.

Autoimmunity↗
PubMed2000

Presentation of alpha B-crystallin to T cells in active multiple sclerosis lesions: an early event following inflammatory demyelination.

In the development of multiple sclerosis (MS), (re)activation of infiltrating T cells by myelin-derived Ags is considered to be a crucial step. Previously, alpha B-crystallin has been shown to be an important myelin Ag to human T cells. Since alpha B-crystallin is an intracellular heat shock protein, the question arises at what stage, if any, during lesional development in MS this Ag becomes available for CD4+ T cells. In 3 of 10 active MS lesions, alpha B-crystallin could be detected inside phagocytic vesicles of perivascular macrophages, colocalizing with myelin basic protein and myelin oligodendrocyte glycoprotein (MOG). Although the detectability of MOG in phagosomes is considered as a marker for very recent demyelination, MOG was detected in more macrophages and in more lesions than alpha B-crystallin. The disappearance of alpha B-crystallin from macrophages even before MOG was confirmed by in vitro studies; within 6 h after myelin-uptake alpha B-crystallin disappears from the phagosomes. Alpha B-crystallin-containing macrophages colocalized with infiltrating T cells and they were characterized by expression of MHC class II, CD40, and CD80. To examine functional presentation of myelin Ags to T cells, purified macrophages were pulsed in vitro with whole myelin membranes. These macrophages activated both myelin-primed and alpha B-crystallin-primed T cells in terms of proliferation and IFN-gamma secretion. In addition, alpha B-crystallin-pulsed macrophages activated myelin-primed T cells to the same extent as myelin-pulsed macrophages, whereas myelin basic protein-pulsed macrophages triggered no response at all. These data indicate that, in active MS lesions, alpha B-crystallin is available for functional presentation to T cells early during inflammatory demyelination.

Antigen Presentation↗
PubMed2000

Encephalitogenic and immunogenic potential of the stress protein alphaB-crystallin in Biozzi ABH (H-2A(g7)) mice.

The stress protein alphaB-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 alphaB-crystallin and synthetic peptides based on mouse alphaB-crystallin the ability of this stress protein to induce experimental allergic encephalomyelitis (EAE) was screened in Biozzi ABH (H-2A(g7)) mice. While whole alphaB-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 alphaB-crystallin in the CNS combined with a state of peripheral tolerance suggested by the constitutive expression of alphaB-crystallin in secondary lymphoid tissues in ABH mice. Further evidence for a role of alphaB-crystallin in the progression of chronic relapsing neurological disease is suggested by the development of T cell responses to alphaB-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 alphaB-crystallin while the subdominant or cryptic epitope is able to circumvent these mechanisms and contribute to pathogenic myelin-directed autoimmunity following T cell activation.

Animals↗
PubMed2000

Tolerance controls encephalitogenicity of alphaB-crystallin in the Lewis rat.

The myelin-associated protein, alphaB-crystallin, is considered a candidate autoantigen in multiple sclerosis (MS). In the present study, we examined the potential of alphaB-crystallin to induce experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Attempts to induce EAE with either bovine, rat or murine alphaB-crystallin or alphaB-crystallin peptides consistently failed. Immunization with either autologous rat or murine alphaB-crystallin did not trigger any antigen-specific T cell response. Immunization with bovine alphaB-crystallin or a synthetic peptide representing the cryptic epitope 49-64 did trigger T cell responses but these failed to crossreact with autologous rat alphaB-crystallin. Examination of lymphoid tissues of the Lewis rat revealed constitutive expression of alphaB-crystallin in thymus, spleen, and peripheral lymphocytes. Our data show that in Lewis rats, constitutive lymphoid expression of alphaB-crystallin is associated with a state of nonresponsiveness to autologous alphaB-crystallin that effectively controls the development of EAE in response to this myelin antigen.

Animals↗
PubMed2000

Anti-alpha B-crystallin immunoreactivity in inflammatory nervous system diseases.

alpha B-Crystallin, a small heat shock protein, is an immunodominant antigen with increased tissue expression in demyelination. To investigate the humoral response against alpha B-crystallin, the sera and CSF samples of patients with multiple sclerosis (MS), Guillain-Barré syndrome (GBS), neuro-Behçet's disease (NBD) and other non-inflammatory neurological diseases (NIND) were screened by enzyme-linked immunosorbent assay for anti-alpha B-crystallin IgG and IgM antibodies. Serum and CSF IgG antibody responses to alpha B-crystallin were significantly elevated only in NBD patients (serum IgG, NBD 1.29 +/- 0.49 vs. NIND 0.95 +/- 0.39, P = 0.01; CSF IgG, NBD 1.22 +/- 0.64 vs. NIND 0.81 +/- 0.35, P = 0.01). Similarly, high serum IgM antibody titres were also detected in NBD (1.83 +/- 0.72 vs. 1.16 +/- 0.49, P = 0.0005) and in MS (1.57 +/- 1.07, P = 0.046), whereas elevated CSF IgM responses were observed only in GBS (2.09 +/- 1.09 vs. 1.41 +/- 0.7, P = 0.007). Humoral responses against alpha B-crystallin are increased in NBD and GBS, which may implicate this central nervous system antigen in the causation and pathogenesis of these inflammatory nervous system disorders.

Adult↗
PubMed2000

The stress kit: a new method based on competitive reverse transcriptase-polymerase chain reaction to quantify the expression of human alphaB-crystallin, Hsp27, and Hsp60.

We describe a reverse transcriptase-polymerase chain reaction method for the semiquantitative detection of mRNAs encoding the human heat shock proteins alphaB-crystallin, Hsp27, and Hsp60. The method involves the coamplification of cellular mRNA-derived cDNA with a dilution series of a competitor fragment (internal standard), using 1 primer pair common to both templates. Internal standards were based on cellular-derived cDNA engineered to be slightly smaller to differentiate between the target and the standard on electrophoretic separation. Initial cDNA quantitations can be corrected for possible variations during cDNA synthesis by standardizing to the levels of beta-actin-encoding cDNA. We show that the coamplified templates accumulate in a parallel manner with the cellular-derived cDNA throughout both the exponential and the nonexponential phase of amplification. Furthermore, we illustrate the utility of this technique by quantifying increased expression of alphaB-crystallin, Hsp27, and Hsp60 mRNA in astroglioma cells on heat shock.

Astrocytoma↗
PubMed1999

EBV-induced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis.

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 absence of alpha B-crystallin from lymphoid tissues in humans is unique as compared with other mammals. All other species examined, including rodents, sheep, and primates, showed constitutive expression of alpha B-crystallin in secondary lymphoid tissues and sometimes even in the thymus. Since constitutive lymphoid expression most likely results in immunologic tolerance, such a state of tolerance to alpha B-crystallin can be expected for all of these species, but not for humans. When taken together, our data provide evidence for a novel mechanism by which common viral infections can trigger myelin-directed autoimmunity in a way that is unique for humans.

Animals↗
PubMed1998

Purification of the stress protein alpha B-crystallin and its differentially phosphorylated forms.

The stress protein alpha B-crystallin was recently identified as a component of central nervous system myelin that is strongly immunogenic to human T cells. Stress-induced alpha B-crystallin that accumulates in the central nervous system is phosphorylated and recent evidence indicates that both rodent and human T cells can discriminate between differentially phosphorylated forms of alpha B-crystallin. For immunological studies, therefore, the availability of purified preparations of alpha B-crystallin and its various differentially phosphorylated forms would be especially useful. Here we describe a rapid and simple method for the purification of alpha B-crystallin from adult bovine eye lenses by a combination of size-exclusion chromatography and reversed-phase high-performance liquid chromatography. This yields a preparation of purified alpha B-crystallin that contains all the various differentially phosphorylated forms of the protein. Subsequent anion-exchange chromatography under denaturing conditions permits the separation of these phosphorylated forms of alpha B-crystallin into purified fractions with a defined number of phosphorylated serines.

Animals↗
PubMed1998

Antigen-specific therapies in multiple sclerosis.

Multiple sclerosis is the major neurological disease of young adults in the western world, affecting about 1 per 1,000. It is characterised by chronic or recurrent lesions of inflammatory damage in the white matter of the central nervous system. Within such lesions, the protective myelin sheath is stripped off axons by infiltrated macrophages which leads to impaired conductivity. The inflammatory process most likely starts by activation of helper T cells directed against local myelin antigens. Currently, efforts are directed at specifically blocking such myelin-reactive helper T cells in order to control the disease. In this chapter, immunological features of multiple sclerosis and the experimental animal model for the disease, experimental allergic encephalomyelitis, are discussed. Next, an overview is presented on myelin antigens that have been suggested to play a role as target antigens in MS. Finally, strategies are discussed that are currently employed to selectively block the activation of T-cells reactive against myelin antigens.

Adult↗
PubMed1998

T cells discriminate between differentially phosphorylated forms of alphaB-crystallin, a major central nervous system myelin antigen.

Factors such as developmental stage or physiological and infectious stress may change patterns of post-translational protein modification. In order to determine whether such regulated types of modification may influence T cell responsiveness to self proteins we examined the T cell response of SJL (H-2s) mice to alphaB-crystallin, a small heat shock protein that can exist in differentially phosphorylated forms. Epitope mapping revealed the presence of two T cell epitopes that are presented by I-As. One major epitope including residues 41-56 contains an amino acid residue (Ser45) that can be phosphorylated as the result of aging or stress. Accordingly, T cells from SJL mice discriminate between preparations of alphaB-crystallin that differ in their extent of phosphorylation at the level of whole protein as well as at the level of determinant-specific responses. Phosphorylation at Ser45 does not prevent binding of the peptide 41-56 to I-As and computer-assisted modelling of the peptide-MHC complex suggests that the phosphate group of the bound peptide extends outwards from the peptide-binding cleft and may thus be available for direct contact with TCR. Together, our data provide evidence that stress-inducible phosphorylation of alphaB-crystallin creates neo-determinants for T cells and, therefore, may contribute to the breakdown of peripheral tolerance to this self protein.

Amino Acid Sequence↗
PubMed1998

Space-time clustering of multiple sclerosis cases around birth.

OBJECTIVES: To investigate whether infectious events around birth and during early infancy are likely to be of relevance in MS pathogenesis. SUBJECTS AND METHODS: Data are available from two regions in The Netherlands: Groningen (n=320) and Rotterdam (n=226). Simultaneous clustering in birth date and birth location of MS cases is tested by the methods of Mantel, Knox and Jacquez. RESULTS: No evidence was found for a space-time interaction between place and time of birth. CONCLUSION: Perinatal infectious events are unlikely to be a major factor in determining MS susceptibility.

Age Distribution↗
PubMed1997

Expression of alphaB-crystallin in glia cells during lesional development in multiple sclerosis.

The small heat shock protein alphaB-crystallin was recently identified as a dominant human T-cell antigen in myelin derived from multiple sclerosis (MS) patients. Using immunohistochemical techniques, oligodendrocytes as well as astrocytes in MS lesions were shown to express alphaB-crystallin. In the present study we examined the expression of alphaB-crystallin, human natural killer cell marker (HNK-1; as a marker for immature oligodendrocytes) and heat shock protein 60 (hsp60) in glia cells at different stages of MS lesion development i.e. in early active lesions, late active lesions and inactive lesions. The results demonstrate that already at the earliest stages of lesional development a subpopulation of oligodendrocytes express detectable levels of alphaB-crystallin. In active lesions about 5-10% of all oligodendrocytes were found to express alphaB-crystallin, whereas in inactive lesions the relative number of alphaB-crystallin-expressing oligodendrocytes was approximately tenfold less. For astrocytes the relative number of alphaB-crystallin-expressing cells was 40-50% for all three types of lesions. Also, alphaB-crystallin-expressing oligodendrocytes and astrocytes displayed different patterns of distribution in lesional areas. These data suggest different regulatory pathways for alphaB-crystallin expression in either type of glia cell. No correlation was found between expression patterns of HNK-1 and alphaB-crystallin indicating that the subpopulation of alphaB-crystallin-expressing oligodendrocytes consisted of both mature and immature oligodendrocytes. In addition, no correlation was found between expression of hsp60 and alphaB-crystallin in MS lesions suggesting different regulatory pathways for either hsp.

Astrocytes↗
PubMed1996

A novel population of CD4+CD56+ myelin-reactive T cells lyses target cells expressing CD56/neural cell adhesion molecule.

CD56 is a member of the neural cell adhesion molecule family expressed on cells of the central nervous system and also on NK cells. Previous studies suggest the involvement of CD56 in effector-to-target cell conjugation mediated by NK cells. It was shown recently that CD56 is also expressed by subpopulations of CD8+ and CD4+ T cells. The present study describes the functional characteristics of CD4+CD56+ T cell lines established from blood of multiple sclerosis patients by stimulation with myelin basic protein (MBP). CD4+CD56+, MBP-specific T cell lines were able to lyse MBP-pulsed target cells in an HLA class II-restricted fashion. At the same time, they mediated MHC-unrestricted lysis of CD56+ target cells such as CD56+ lymphoid or glial tumor cells, but not of the typical NK target, K562. A number of experimental results including separation of CD4+CD56+ T cells into CD56 high and low expressing populations, cold target inhibition, as well as killing of CD56-transfected cells indicate that homotypic CD56 interactions are involved in the MHC-unrestricted lysis. CD56 interactions are not sufficient but are required for effector/target interaction. Our findings raise the possibility that CD4+CD56+ T cells sharing properties of both typical Ag-specific Th0-like T cells and NK cells might be involved in damage of tissues expressing CD56/neural cell adhesion molecule, such as the central nervous system. Thus, we provide evidence for a novel mechanism that could lead to organ-specific autoreactivity.

Biomarkers↗
PubMed1996

Multiple sclerosis: an altered immune response or an altered stress response?

The pathogenesis of multiple sclerosis (MS), the major neurological disease of young adults in the Western world, is still poorly understood, and no effective therapy to block MS is available as yet. The clinical symptoms of MS result from inflammatory damage to the insulating myelin sheath of axons in the CNS and-at later stages-to axons themselves. A local autoimmune process involving activation of helper T cells against CNS protein components is likely to be crucial in this development. Especially at the first stages of MS, therapies aimed at the selective downregulation of MS-specific autoimmune responses may contribute to controlling the disease. Key to the success of such approaches is the identification of CNS proteins that are the target of local T cell responses. We recently identified the small heat-shock protein alpha B-crystallin as the single immunodominant myelin antigen in MS-affected myelin. This review discusses the functional and therapeutic implications of this finding along with other data on MS, and hypothesizes that an inappropriate stress response within the CNS itself is crucial as an initiating event in disease development.

Adult↗