Tolerogenic citrullinated peptide for arthritis

Disease-specific autoantibodies directed against post-translation citrullinated proteins/peptides (ACPAs) are specific serological markers for rheumatoid arthritis (RA) and have been accepted as one of the classification criteria for the disease. Beyond diagnosis these autoantibodies have also been shown also to predict disease severity. These autoantibodies can be detected several years prior to the clinical onset of RA, with increasing titers overtime, as disease onset is established. Citrullination is a post-translational modification of proteins in which arginine is converted into citrulline, an unnatural amino acid which is not encoded by DNA. The reaction is catalyzed by calcium-dependent peptidyl arginine deiminase (PAD). Citrullinated proteins have been detected in the synovial membranes and synovial fluid of patients with various forms of arthritis. Protein citrullination has been shown to be involved in immune tolerance breakdown in experimental autoimmune arthritis. Only small amounts of citrullinated proteins is found in the normal synovial tissue, whereas active citrullination has been clearly associated with RA. In addition, ACPAs are strongly associated with increased risk of developing RA in healthy individuals. Their presence in RA patients is associated with a more erosive arthritis and poorer response to therapy [1]. It is reasonable to assume that citrullinated peptides are among the earliest arthritic autoantigens that may be suitable as potential candidates for specific immune tolerance induction. The finding of an immunodominant citrullinated peptide as antigen-specific immunomodulatory agents capable for restoration of the altered autoimmune response in RA seems to be an interesting target for intercepting the disease. The possible mechanisms by which autoantigens or their derivatives induce specific tolerance are based on frequent administrations of low dose soluble antigens. By these means administration of a synthetic peptide could manipulate the interaction of antigen presenting cells (APCs) with lymphocytes. This tolerogenic presentation displayed on MHC class II-expressing T cells (T-APC) induces partial signals in Ag-specific T cell clones including deletion, anergy and suppression of the autoreactive cells. Administration of a citrullinated filaggrin peptide as a prophylactic measure to prevent collagen induced arthritis prior to induction in DBA mice has been shown to be successful and to protect mice from developing arthritis [2]. This study reasoned this finding by the ability of the citrullinated peptide to bind ACPA and to induce tolerance of citrullinated-peptide specific T cells. However, one of the difficulties in developing effective tolerogenic peptides for immune tolerance strategies in RA is the selection of a specific antigen since the autoimmune response is against multiple targets; diverse citrullinated proteins in different synovial structures. The question is, therefore, which specific citrullinated autoantigens drives the immune response in RA and whether those antigens are the best to be employed for immune tolerance restoration. It was shown that the most prevalent citrullinated autoantigens, in arthritic joints are: citrullinated fibrinogen, vimentin, collagen type II and α-enolase [3]. Therefore we constructed a multi-antigenic peptide for immune tolerance specific for RA. The peptide is composed of sequence of known citrullinated autoantigens (filaggrin, β-fibrinogen, collagen type II and vimentin) in analogy to the mix of citrullinated peptides that are used currently in diagnostic sera tests. One of our peptide Editorial