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The role of cross-reactivity between mycobacteria and joint tissues in the aetiology of rheumatoid arthritis with particular reference to terminal N-acetylglucosamine and 65 kilodalton heat shock protein

Sharif, Mohammed; (1991) The role of cross-reactivity between mycobacteria and joint tissues in the aetiology of rheumatoid arthritis with particular reference to terminal N-acetylglucosamine and 65 kilodalton heat shock protein. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Several historical and recent reports have implicated mycobacteria or autoantigens cross-reactive with mycobacteria in the aetiology of rheumatoid arthritis (RA). Thus adjuvant arthritis can be transferred to naive rats with a T cell clone responsive to the mycobacterial 65 kDa heat shock protein (hsp65). Moreover agalactosyl IgG [Gal(O)], of which the oligosaccharides lack terminal galactose and terminate in N-acetylglucosamine (GlcNAc), occurs with increased frequency in RA and some mycobacterial infections. The cell walls of bacteria including mycobacteria are rich in terminal GlcNAc and the hsp65 is one of the immunodominant antigens of mycobacteria. The present study was undertaken to establish whether GlcNAc and/or hsp65-directed autoimmunity could occur in RA. Using a monoclonal antibody (mAb) which binds to terminal GlcNAc of Gal(O) the presence of large quantities of immunoreactive GlcNAc has been demonstrated in the joints of RA patients. It was also discovered that a subset of monocytes from both RA and normal donors transiently expresses membrane GlcNAc in culture. Affinity-purified anti-GlcNAc from both pooled normal and RA sera binds to IgG heavy chains on western blots. A murine mAb raised against mycobacterial antigen and a rabbit polyclonal antibody to hamster hsp65 were used to document the presence of a major band of around 65 kDa in synovial fluid (SF) from inflamed joints and immune complexes from RA patients. This protein was thought to be the human homologue of the mycobacterial hsp65. However, this molecule is about 7 kDa larger than the affinity-purified hsp65 from human placenta and it appeared unlikely that this molecule is of bacterial origin. This observation therefore casts doubt on several earlier reports where anti-mycobacterial antibodies were used to show increased expression of hsp65 in rheumatoid joints. The latter antibodies bind to several different components of human tissue and were not selected for specificity to human tissue. Therefore, mAbs were made to the human hsp and it has been shown that the major band at 65 kDa in SF is not the human homologue of the bacterial hsp65. Human hsp is present in the joint but at very low concentration and in SDS PAGE runs at about 58 kDa. Moreover, the previous reports showing increased expression of the hsp in joint tissues are inaccurate. First, it is clear that the presence of the hsp in rheumatoid tissues is not RA specific and secondly the distribution is also rather different from that described using the anti-mycobacterial antibodies. The levels of IgA and IgG antibodies to mycobacterial hsp65 are raised in RA sera and at least some of these IgG antibodies appeared to be autoantibodies. Moreover in RA SF a significant rise in the levels of IgA and IgG antibodies to the human hsp58 was found. There appears to be a correlation between raised levels of Gal(O) and antibody to hsp65 in mice, however no such correlation was found in RA sera or synovial fluid. Moreover, anti-GlcNAc antibody was not associated with raised Gal(O), and neither anti-GlcNAc nor antibody to hsp65 appear to lack galactose.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of cross-reactivity between mycobacteria and joint tissues in the aetiology of rheumatoid arthritis with particular reference to terminal N-acetylglucosamine and 65 kilodalton heat shock protein
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Rheumatoid arthritis
URI: https://discovery.ucl.ac.uk/id/eprint/10114193
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