Immunopathogenesis and prevention of uveitis with the Behçet's disease-specific peptide linked to cholera toxin B.

Abstract

Behcet’s disease (BD) is a multisystemic disease affecting mucocutaneous, ocular, central nervous system, joint and vascular tissues. The aetiology of BD has been associated with a variety of microorganisms, especially Herpes simplex virus and some strains of Streptococcus sanguis. A common microbial agent may be involved, such as heat shock protein (HSP) which has significant homology with human cellular HSP. The evidence in favour of HSP as an aetiological factor in BD is based on T cell proliferative responses and B cell antibodies to the defined HSP60 epitope p336-351 in patients with BD in Britain, Japan and Turkey. The proportion of γδ T cells is significantly increased in BD and HSP65 or HSP70 upregulates γδ T cells. The peptide determinant defined in patients with BD elicits uveitis in Lewis rats when administered by the oral mucosal or systemic route. It is noteworthy that the MICA gene is a cell stress response gene and shares nucleotide sequences with the human HSP70 promoter. The cytokine and chemokine networks stimulated by HSP induce polarisation towards the TH1 cytokines during active disease. The evidence from these studies has converged towards the concept that the multi-system immunopathology of BD is generated by an over-reaction to microbial stress proteins. We now demonstrate that p336-351 induced uveitis in rats can be prevented by oral tolerization with the peptide linked to recombinant cholera toxin B subunit. Preliminary evidence in an open clinical trial suggests that this novel tolerizing strategy may be effective in preventing relapse of uveitis in BD.