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alphaB-Crystallin In Multiple Sclerosis

  1. Mistaken self, a novel model that links Microbial infections with Myelin-directed AutoImmunity in Multiple Sclerosis
    J NeuroImmunol 2000 Jun 1;105(1):46-57

  2. Tolerance controls EncephalitoGenicity of alphaB-crystallin in the Lewis rat
    J NeuroImmunol 2000 Mar 1;103(2):103-11

  3. High prevalence of anti-alpha-Crystallin AntiBodies in Multiple Sclerosis: correlation with severity and activity of disease
    Acta Neurol Scand 1999 Sep;100(3):139-47

  4. HLA-DR-restricted presentation by human B-Cells of alphaB-Crystallin, a candidate autoantigen in Multiple Sclerosis
    J Immunol 1999 Jan 1;162(1):129-35

  1. Presentation of alphaB-Crystallin to T-Cells in active Multiple Sclerosis lesions: An early event following Inflammatory DeMyelination
    J Immunol 2000 Apr 15;164(8):4359-66

  2. EncephalitoGenic and Immunogenic potential of the stress protein alphaB-Crystallin in Biozzi ABH (H-2A(g7)) mice
    J NeuroImmunol 2000 Apr 3;104(1):47-57

  3. EBV-induced expression and HLA-DR-restricted presentation by human B-Cells of alphaB-Crystallin - Candidate AutoAntigen In Multiple Sclerosis
    J Immunol 162: 129-35 (1999)

  4. The Small Heat-Shock Protein alphaB-Crystallin as Candidate AutoAntigen in Multiple Sclerosis
    Nature 1995 Jun 29;375(6534):798-801

  5. CD4 T-Cell epitopes of human alphaB-Crystallin
    J NeuroSci Res 2004 Feb 15;75(4):516-23

  6. Antibodies to Myelin Basic Protein, Myelin Oligodendrocytes Peptides, alphaB-Crystallin, Lymphocyte activation and Cytokine production in patients with Multiple Sclerosis
    J Intern Med 2003 Oct;254(4):363-74

  7. AutoAntibodies against alpha B-Crystallin, a candidate AutoAntigen in Multiple Sclerosis, are part of a normal human Immune repertoire
    Mult Scler 2006 Jun;12(3):287-93




#1

Presentation Of alphaB-Crystallin To T-Cells In Active Multiple Sclerosis Lesions: An Early Event Following Inflammatory DeMyelination

Bajramovic JJ, Plomp AC, Goes Av, Koevoets C, Newcombe J, Cuzner ML, van Noort JM
J Immunol 2000 Apr 15;164(8):4359-66
TNO Prevention and Health, Division of Immunological and Infectious Diseases, Leiden, The Netherlands; and Free University, Faculty of Medicine, Dept of Cell Biology and Immunology, Dept of NeuroChemistry, Amsterdam, The Netherlands
PMID#10754336; UI# 20219278
Abstract

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, alphaB-Crystallin has been shown to be an important Myelin Ag to human T-Cells.

Since alphaB-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, alphaB-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 alphaB-Crystallin.

The disappearance of alphaB-Crystallin from Macrophages even before MOG was confirmed by in vitro studies; within 6 h after Myelin-uptake, alphaB-Crystallin disappears from the Phagosomes.

alphaB-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 alphaB-Crystallin-primed T-Cells in terms of proliferation and IFN-gamma secretion.

In addition, alphaB-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, alphaB-Crystallin is available for functional presentation to T-Cells early during Inflammatory DeMyelination.



#2

EncephalitoGenic And Immunogenic Potential Of The Stress Protein alphaB-Crystallin In Biozzi ABH (H-2A(g7)) Mice

Thoua NM, van Noort JM, Baker D, Bose A, van Sechel AC, van Stipdonk MJ, Travers PJ, Amor S
J NeuroImmunol 2000 Apr 3;104(1):47-57
Rayne Institute, United Medical and Dental Schools of Guy's and St Thomas', Dept of Immunology, London, UK
PMID# 10683514; UI# 20184260
Abstract

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 Tolerizing 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.



#3

EBV-Induced Expression And HLA-DR-Restricted Presentation By Human B-Cells of alphaB-Crystallin - Candidate AutoAntigen In Multiple Sclerosis

Van Sechel AC; Bajramovic JJ; Van Stipdonk MJ; Persoon-Deen C; Geutskens SB; Van Noort JM
J Immunol 162: 129-35 (1999)
TNO Prevention and Health, Division of Immunological and Infectious Diseases, Leiden, The Netherlands
UI# 99101469
Abstract

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 alphaB-Crystallin, a small Stress Protein that was identified previously as an ImmunoDominant Ag of CNS Myelin in Multiple Sclerosis patients.

EBV-induced expression of alphaB-Crystallin in B-Cells leads to HLA-DR-restricted presentation of the protein and to activation of proinflammatory alphaB-Crystallin specific T-Helper Cells.

While alphaB-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) HSP27 and HSP60 that are ubiquitously expressed in these tissues.

In addition, the absence of alphaB-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 alphaB-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 alphaB-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.



#4

The Small Heat-Shock Protein alphaB-Crystallin As Candidate AutoAntigen In Multiple Sclerosis

van Noort JM, van Sechel AC, Bajramovic JJ, el Ouagmiri M, Polman CH, Lassmann H, Ravid R
Nature 1995 Jun 29;375(6534):798-801
TNO Prevention and Health, Division of Immunological and Infectious Diseases, Leiden, The Netherlands
PMID# 7596414
Abstract

The identification of key Antigens in human Autoimmune Diseases is a crucial step towards the development of specific intervention.

The AutoAntigen(s) relevant to Multiple Sclerosis (MS) probably reside in Myelin of the Central Nervous System, the target of the disease.

Here we examine proliferative responses of human peripheral blood T-Cells to the complete collection of Myelin proteins fractionated by reversed-phase high-performance liquid chromatography.

Myelin isolated from MS-affected Brain contained a single protein fraction to which T-Cells from MS patients and from healthy controls showed dominant responses.

This highly ImmunoGenic protein was identified as alphaB-Crystallin, a small Heat Shock Protein.

ImmunoHistoChemical examination of MS lesions revealed the presence of Oligodendrocytes and Astrocytes with raised alphaB-Crystallin expression, which were not found in unaffected Myelin.

Our findings indicate that alphaB-Crystallin serves as Immunodominant Myelin Antigen to human T-Cells when expressed at the elevated levels found in active MS lesions.



#5

CD4 T-Cell Epitopes Of Human alphaB-Crystallin

Chou YK, Burrows GG, LaTocha D, Wang C, Subramanian S, Bourdette DN, Vandenbark AA
J Neurosci Res 2004 Feb 15;75(4):516-23
Oregon Health and Science University, Department of Neurology, Portland, Oregon 97201, USA
PMID# 14743435
Abstract

Of potential importance to Multiple Sclerosis (MS), Oligodendroglial alphaB-Crystallin is expressed and associated with the Myelin sheath at the earliest stage of MS lesion development.

We selected T-Cell lines specific for human alphaB-Crystallin from Peripheral Blood Mononuclear Cells (PBMC) of HLA-DR2 homozygous MS patients and found that the alphaB-Crystallin-specific T-Cells were CD4+ and restricted by DRB1*1501, and expressed Th1 Cytokines.

The CD4 T-Cell Epitopes of human alphaB-Crystallin were determined by proliferation of alphaB-Crystallin-specific T-Cell lines to 17 20-mer synthetic overlapping Peptides spanning the entire molecule of human alphaB-Crystallin.

It was found that the HLA-DR2 donor-derived alphaB-Crystallin,-specific T-Cell lines proliferated to alphaB-Crystallin Peptides 21-40, 41-60, and to a lesser extent, 131-150.

These T-Cell proliferation responses were associated with IntraCellular expression of InterLeukin-2 (IL-2) and secretion of Interferon-gamma (IFN-γ), and Tumor Necrosis Factor-alpha (TNF-alpha).

The Amino Acid sequences of these Peptides were compatible with predicted HLA-DR2-restricted binding motifs.

PBMC of an early active MS patient proliferated to the Epitope-containing Peptides significantly better than did those of later stage MS patients or healthy controls.

Taken together, these findings suggest that AutoReactive alphaB-Crystallin,-specific Th1 Cells may have the potential to contribute to MS pathogenesis.

Copyright 2004 Wiley-Liss, Inc.



#6

Antibodies To Myelin Basic Protein, Myelin Oligodendrocytes Peptides, alphaB-Crystallin, Lymphocyte Activation And Cytokine Production In Patients With Multiple Sclerosis

Vojdani A, Vojdani E, Cooper E
J Intern Med 2003 Oct;254(4):363-74
ImmunoSciences Lab., Inc., Beverly Hills Facility, USA
PMID# 12974875
Abstract

Objective
To measure Neuron-specific Humoral and Cellular Immune parameters in MRI-positive patients with Multiple Sclerosis (MS).

Background
It has been postulated from animal models for MS and in situ evidence in MS patients that AntiBodies, activated T-Cells and Proinflammatory Cytokines are involved in the destruction of Myelin Sheaths and loss of Oligodendrocytes in active areas.

Subjects And Methods
Blood samples were obtained from 20 healthy control subjects and 20 patients with abnormal MRI and clinical diagnosis of MS.

Sera were tested for levels of IgG, IgM and IgA against Myelin Basic Protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG) peptides, and a small Heat-Shock Protein, alphaB-Crystallin.

Lymphocytes were isolated and cultured in the presence or absence of MBP, MOG Peptides and alpha-ß-Crystallin, measured for stimulated T-Cells, Cytokine production and compared with controls.

Results
Patients with MS showed the highest levels of IgG, IgM or IgA AntiBodies against one or all three tested Antigens.

Moreover, in the presence of MBP, MOG Peptides or alphaB-Crystallin, a significant percent- age of Lymphocytes from MS patients underwent blast transformation.

Which resulted in high levels of Interferon-gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF-alpha) and Tumor Necrosis Factor-beta (TNF-ß) production. Sensitivity of these assays was 60-80% and specificity, 65-70%.

Conclusions
Detection of AntiBodies against MBP, MOG Peptides, alphaB-Crystallin, Lymphocyte stimulation and production of Proinflammatory Cytokines in response to these Antigens could be used as surrogate markers for the confirmation of MS diagnosis.

A combination of AntiBodies, Lymphocyte activation or Cytokine production with abnormal MRI may significantly increase the sensitivity and specificity of MS diagnosis.



#7

AutoAntibodies Against alpha B-Crystallin, A Candidate AutoAntigen In Multiple Sclerosis, Are Part Of A Normal Human Immune Repertoire

van Noort JM, Verbeek R, Meilof JF, Polman CH, Amor S
Mult Scler 2006 Jun;12(3):287-93
TNO Quality of Life, Division of Biomedical Research, Leiden, The Netherlands
PMID# 16764341
Abstract

Human T-Cell responses to the Stress Protein alpha B-Crystallin in Multiple Sclerosis (MS)-affected Brain samples are dominant when compared to other Myelin Antigens.

The establishment of the apparent Autoimmune repertoire against this Antigen has been suggested to involve cross-priming during Viral infection.

Yet, another possibility would be that determinant spreading during Ocular inflammation could generate a response to alpha B-Crystallin, since it is also a major component of the eye.

In this study, we compared Serum IgG, IgA and IgM repertoires against a range of eye lens-derived Ocular Antigens using Sera from healthy control subjects and MS patients with or without Uveitis.

This comparison revealed that among Ocular Antigens, alpha B-Crystallin is the dominant target Antigen for serum AutoAntibodies in both MS patients and healthy controls. Uveitis generally did not affect the AntiBody reactivity profile.

These data provide further support for the notion that a normal adult human Immune System is selectively reactive to alpha B-Crystallin and they indicate that this responsiveness is unlikely to result from determinant spreading following Ocular inflammation.



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