Immune recognition of citrullinated epitopes

Abstract

Conversion of arginine into citrulline is a post-translational modification that is observed in normal physiological processes. However, abnormal citrullination can provoke autoimmunity by generating altered self-epitopes that are specifically targeted by autoantibodies and T cells. In this review we discuss the recognition of citrullinated antigens in human autoimmune diseases and the role that this modification plays in increasing antigenic diversity and circumventing tolerance mechanisms. Early published work demonstrated that citrullinated proteins are specifically targeted by autoantibodies in rheumatoid arthritis and that citrullinated peptides are more readily presented to T cells by arthritis-susceptible HLA class II 'shared epitope' proteins. Emerging data support the relevance of citrullinated epitopes in other autoimmune diseases, including type 1 diabetes and multiple sclerosis, whose susceptible HLA haplotypes also preferentially present citrullinated peptides. In these settings, autoimmune patients have been shown to have elevated responses to citrullinated epitopes derived from tissue-specific antigens. Contrasting evidence implicates autophagy or perforin and complement-mediated membrane attack as inducers of ectopic citrullination. In either case, the peptidyl deiminases responsible for citrullination are activated in response to inflammation or insult, providing a mechanistic link between this post-translational modification and interactions with the environment and infection. As such, it is likely that immune recognition of citrullinated epitopes also plays a role in pathogen clearance. Indeed, our recent data suggest that responses to citrullinated peptides facilitate recognition of novel influenza strains. Therefore, increased understanding of responses to citrullinated epitopes may provide important insights about the initiation of autoimmunity and recognition of heterologous viruses.

Keywords: T cells; antigens/peptides/epitopes; arthritis (including rheumatoid arthritis); autoimmunity; diabetes.

Figure 1

Conversion of arginine to citrulline by peptidyl arginine deiminase. The conventional amino acid arginine is enzymatically converted into its polar analogue citrulline in a calcium‐dependent manner. This reaction consumes one water molecule and yields one ammonia, converting the positively charged ketamine group into a neutral ketone group.

Figure 2

Selective T‐cell responses to citrullinated influenza peptides. (a) Representative T‐cell responses to citrullinated (upper panels) or unmodified (lower panels) influenza peptides, visualized using HLA class II tetramers loaded with the corresponding peptides using T‐cell lines that were expanded in vitro from the peripheral blood of immunized patients with DRB1*04:01 haplotypes. For analysis, cells were co‐stained using anti‐CD4 allophycocyanin. (b) Representative T‐cell responses to citrullinated influenza peptides for an influenza virus‐infected patient (upper panels) or immunized patient (lower panels).