Breakdown of CTL tolerance to self HLA-B*2705 induced by exposure to Chlamydia trachomatis.
There is a strong association between seronegative arthritis and HLA B27, but it is still unresolved whether the contribution of B27 to disease pathogenesis is solely as a restriction element for an arthritogenic peptide, or whether B27 itself serves as an autoantigen. This study uses transgenic rats to address the question as to whether exposure to an arthritogenic pathogen can alter tolerance to B27. Unlike their nontransgenic counterparts, B27-transgenic rats are tolerant of B27 immunization using either B27(+) splenocytes or plasmid DNA and do not develop anti-B27 CTL. However, if splenocytes from such immunized animals are exposed to Chlamydia in vitro, CTL are generated that lyse B27(+) targets. No killing was seen with targets transfected with control B7, B14, B40, or B44. This phenomenon was not observed with immunization by nontransgenic splenocytes, or HLA-A2 DNA alone. Using targets expressing mutated B27, we show that the epitope for autoreactive CTL recognition of B27 involves the Lys(70) amino acid residue in the alpha(1) domain of the MHC class I molecule. The generation of CTL with specificity for B27 under these conditions demonstrates that tolerance to B27 can be subverted by CHLAMYDIA: This indicates a dynamic interrelationship between the pathogen and B27, which may have important implications for B27-related spondyloarthropathies triggered by intracellular bacteria.
Popov
Igor
I
Division of Rheumatology, Toronto Western Hospital, University Health Network, and Toronto Western Research Institute, Toronto, Ontario, Canada.
Dela Cruz
Charles S
CS
Barber
Brian H
BH
Chiu
Basil
B
Inman
Robert D
RD
D000818:Animals; D030801:Animals, Genetically Modified; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D002692:Chlamydia trachomatis / Q000276:immunology*; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007739:L Cells; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew / Q000235:genetics; D017634:Self Tolerance / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000382:microbiology; D014162:Transfection
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen