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Cross-reactivity between the rheumatoid arthritis-associated motif EQKRAA and structurally related sequences found in
H Tiwana1, C Wilson, A Alvarez
1Infection and Immunity Group, King's College, London, United Kingdom.
Abstract:
Cross-reactivity or molecular mimicry may be one of the underlying mechanisms involved in the etiopathogenesis of rheumatoid arthritis (RA). Antiserum against the RA susceptibility sequence EQKRAA was shown to bind to a similar peptide ESRRAL present in the hemolysin of the gram-negative bacterium Proteus mirabilis, and an anti-ESRRAL serum reacted with EQKRAA. There was no reactivity with either anti-EQKRAA or anti-ESRRAL to a peptide containing the EDERAA sequence which is present in HLA-DRB1*0402, an allele not associated with RA. Furthermore, the EQKRAA and ESRRAL antisera bound to a mouse fibroblast transfectant cell line (Dap.3) expressing HLA-DRB1*0401 but not to DRB1*0402. However, peptide sequences structurally related to the RA susceptibility motif LEIEKDFTTYGEE (P. mirabilis urease), VEIRAEGNRFTY (collagen type II) and DELSPETSPYVKE (collagen type XI) did not bind significantly to cell lines expressing HLA-DRB1*0401 or HLA-DRB1*0402 compared to the control peptide YASGASGASGAS. It is suggested here that molecular mimicry between HLA alleles associated with RA and P. mirabilis may be relevant in the etiopathogenesis of the disease.
Insights
Molecular mimicry between the bacterium Proteus mirabilis and rheumatoid arthritis (RA) susceptibility sequences may contribute to RA development. This study found specific bacterial peptides mimic sequences found in RA-associated HLA alleles.
Area of Science:
- Immunology
- Microbiology
- Genetics
Background:
- Rheumatoid arthritis (RA) pathogenesis may involve molecular mimicry.
- Certain HLA-DRB1 alleles are associated with RA susceptibility.
Purpose of the Study:
- To investigate potential molecular mimicry between RA susceptibility sequences and bacterial peptides.
- To explore the role of Proteus mirabilis in RA etiopathogenesis.
Main Methods:
- Antiserum-based binding assays were used to test cross-reactivity between peptides.
- Peptide binding to cell lines expressing specific HLA-DRB1 alleles was assessed.
Main Results:
- Antiserum against RA susceptibility sequence EQKRAA bound to bacterial peptide ESRRAL, and vice versa.
- These specific peptides bound to HLA-DRB1*0401 (RA-associated) but not HLA-DRB1*0402 (not associated with RA).
- Other related bacterial and self-peptide sequences showed no significant binding to the tested HLA alleles.
Conclusions:
- Molecular mimicry between Proteus mirabilis and RA-associated HLA alleles is suggested as a potential mechanism in RA development.
- This mimicry may involve specific bacterial peptides and RA-associated HLA variants.
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