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Molecular mimicry: any role in the pathogenesis of spondyloarthropathies?
R Lahesmaa1, M Skurnik, P Toivanen
1Department of Medical Microbiology, Turku University, Finland.
Abstract:
Ankylosing spondylitis and reactive arthritis are seronegative spondyloarthropathies, which are strongly associated with HLA-B27. Despite intensive investigation, the basis for this association is not clear. However, in recent years one favored hypothesis to explain this linkage has been that of molecular mimicry, i.e., sharing of linear or conformational epitopes common to microbial antigens and host structures. During the past few years several examples of molecular mimicry between HLA-B27 and microbial antigens have been described. Heat shock proteins, among others, have been considered as target candidates for autoimmune phenomena, because of the high degree of homology between bacterial and mammalian species. Reactive arthritis triggered by Yersinia or Salmonella provides a unique model for studying the pathogenetic mechanisms underlying human inflammatory joint diseases in general, because the arthritogenic microbes are known and well-characterized. We have described two bacterial proteins that share amino acid homology with HLA-B27, namely YadA (Yersinia adhesin) and OmpH, outer surface proteins of Yersinia and Salmonella, respectively. Notably, the area of identity of these amino acid sequences is located in the same place on the HLA-B27 molecule as a hexapeptide identical between Klebsiella nitrogenase and HLA-B27, and a pentapeptide shared by a Shigella flexneri protein and HLA-B27. We have investigated immune responses to a panel of synthetic peptides based on the HLA-B27-homologous portions of pathogen-specific antigens in patients with reactive arthritis and ankylosing spondylitis. One third of the patients have antibodies to the synthetic peptides. However, instead of recognizing the HLA-B27-homologous portion, the antibodies are directed against the flanking sequences of the synthetic peptides. The concept of the role of molecular mimicry between HLA-B27 and microbial antigens in the pathogenesis of spondyloarthropathies is discussed, with a conclusion that no convincing evidence for its significance exists at the present.
Insights
Molecular mimicry between HLA-B27 and microbial antigens is hypothesized to cause spondyloarthropathies like ankylosing spondylitis. However, studies show antibodies target flanking sequences, not HLA-B27 mimicry, questioning this theory's significance.
Area of Science:
- Immunology
- Rheumatology
- Microbiology
Background:
- Ankylosing spondylitis and reactive arthritis are linked to HLA-B27.
- Molecular mimicry, where microbial antigens resemble host structures, is a leading hypothesis for this association.
- Bacterial proteins like YadA and OmpH show homology with HLA-B27.
Purpose of the Study:
- To investigate the role of molecular mimicry between HLA-B27 and microbial antigens in spondyloarthropathies.
- To examine immune responses to HLA-B27-homologous sequences in patients with reactive arthritis and ankylosing spondylitis.
Main Methods:
- Synthesized peptides based on HLA-B27-homologous portions of bacterial antigens.
- Tested for antibodies against these peptides in patients with reactive arthritis and ankylosing spondylitis.
- Analyzed antibody targets within the synthetic peptides.
Main Results:
- One-third of patients had antibodies to the synthetic peptides.
- Antibodies primarily recognized flanking sequences, not the HLA-B27-homologous regions.
- No convincing evidence for molecular mimicry's role in spondyloarthropathy pathogenesis was found.
Conclusions:
- The study challenges the molecular mimicry hypothesis in HLA-B27-associated spondyloarthropathies.
- Antibody responses in patients target non-homologous regions of microbial antigens.
- Further research is needed to elucidate the pathogenesis of these inflammatory joint diseases.