T cell recognition of a highly conserved epitope in heat shock protein 60: self-tolerance maintained by TCR distinguishing between asparagine and aspartic acid.

Cross-reactive T cell recognition of self-heat shock proteins (hsp) has been ascribed a regulatory role in inflammatory arthritis in both animal models and human disease. The previous work implies that a repertoire for epitopes in self-hsp60 should exist in normal subjects. Accordingly, we sought to generate self-hsp60-reactive T cell clones from a healthy individual using a highly purified preparation of recombinant human (Hu) hsp60. Epitope mapping using synthetic peptides and truncated constructs indicated that the T cell clones obtained actually recognized hsp60 derived from Escherichia coli. Using a series of alanine-substituted peptides and additional appropriate synthetic peptides, it was demonstrated that the clones maintain self-tolerance because of their sensitivity to an asparagine to aspartic acid sequence difference between E. coli and HuHsp60 in the epitope-containing peptide. In addition, despite substantial conservation of sequence, the homologous peptide from HuHsp60 did not compete with the E. coli-derived peptide for recognition or antagonize responses by acting as an altered peptide ligand. The results suggest that, even when the immune system targets a highly conserved epitope in bacterial hsp60, self-tolerance is maintained. Furthermore, the finding that T cell clones specific for minor contaminant proteins in HuHsp60 preparations can readily be isolated raises the possibility that the HuHsp60 facilitates presentation of antigenic proteins to the immune system.

Arthritis associated with enteric infection.

Reactive arthritis is classically seen following infection with enteric pathogens such as Yersinia, Salmonella, Campylobacter and Shigella. Inflammatory arthritis has also been described following other enteric infection with organisms such as Clostridium difficile, Brucella and Giardia. Furthermore, arthritis is seen in Whipple's disease, caused by the actinomycete Tropheryma whippelii. This chapter reviews the current understanding of these conditions (with the exception of Brucella, which is discussed in a subsequent chapter). The epidemiology is reviewed, and the contribution of both host and organism to the aetiology and pathogenesis is discussed with particular discussion of the role of HLA-B27 in host susceptibility. Recent work exploring evidence for traffic of pathogenic organisms to the joint is highlighted. A practical approach to the diagnosis and management of the condition is then formulated based, where possible, on clinical trial evidence.