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Shared amino acid sequences between major histocompatibility complex class II glycoproteins, type XI collagen and
C Wilson1, A Ebringer, K Ahmadi
1Division of Biomolecular Sciences, King's College, London, United Kingdom.
Objectives:
To show molecular similarity between two sequences of Proteus mirabilis (haemolysin--ESRRAL; urease--IRRET) with HLA-DR antigens (EQRRAA) which are associated with rheumatoid arthritis (RA) and type XI collagen (LRREI), respectively; and, in patients with RA, to measure levels of antibody against a 16-mer synthetic peptide containing the ESRRAL sequence, and the haemolysin and urease proteins of Proteus mirabilis.
Methods:
The homologous sequences EQRRAA and ESRRAL were modelled with Alchemy III, using the crystalline structure of DRB1*0101 (HLA-DR1). Sera from 40 patients with RA, 30 with ankylosing spondylitis (AS), and 30 controls were tested against synthetic ESRRAL peptide and the haemolysin of Proteus mirabilis by enzyme linked immunosorbent assay. Similar tests were also carried out on sera from 20 patients with RA, 40 with AS, and 15 controls, against Proteus mirabilis urease.
Results:
Molecular modelling of the homologous sequences ESRRAL/EQRRAA and IRRET/LRREI showed stereochemical similarities. Antibodies to the 16-mer synthetic peptide containing the ESRRAL sequence, the haemolysin, and urease proteins were significantly increased in RA patients compared with AS patients (p < 0.001) and healthy controls (p < 0.001). No such increases were observed with three control peptides including the EDERAA sequence of DRB1*0402 (HLA-DR4/Dw10), the haemolysin proteins of Streptococcus pyogenes and Vibrio parahaemolyticus, and the urease of Bacillus pasteurii.
Conclusion:
The additive effect of the immune responses to the two Proteus mirabilis antigens, haemolysin (ESRRAL) and urease (IRRET), could be relevant in the aetiopathogenesis of RA.
Insights
Molecular similarities between Proteus mirabilis proteins and human antigens suggest a link to rheumatoid arthritis (RA). Increased antibodies to these bacterial proteins in RA patients indicate a potential role in disease development.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) pathogenesis is complex, with potential links to microbial triggers.
- Molecular mimicry between microbial antigens and self-antigens is a proposed mechanism in autoimmune diseases.
Purpose of the Study:
- To investigate molecular similarities between Proteus mirabilis antigens (haemolysin, urease) and human leukocyte antigen (HLA)-DR molecules associated with RA.
- To quantify antibody levels against these bacterial antigens in patients with RA.
Main Methods:
- Molecular modeling was used to compare homologous sequences of bacterial proteins and HLA-DR antigens.
- Enzyme-linked immunosorbent assays (ELISAs) were performed to measure antibody levels against synthetic peptides and bacterial proteins in patient sera.
Main Results:
- Stereochemical similarities were observed between Proteus mirabilis haemolysin (ESRRAL) and HLA-DR (EQRRAA), and between urease (IRRET) and type XI collagen (LRREI).
- Significantly elevated antibodies to the ESRRAL peptide, haemolysin, and urease were found in RA patients compared to ankylosing spondylitis patients and healthy controls.
- Control peptides and proteins did not elicit similar immune responses in RA patients.
Conclusions:
- The findings suggest a potential role for immune responses to Proteus mirabilis haemolysin and urease in the aetiopathogenesis of rheumatoid arthritis.
- Molecular mimicry may contribute to the autoimmune response in RA.