Immune recognition of citrullinated epitopes

Abstract

SummaryConversion 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 posttranslational 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.

Autoreactive T cells in type 1 diabetes

“…A PTM epitope exists in the insulin A chain (A1-A13): T cell recognition requires oxidized cysteine residues at A6 and A7, with the formation of a vicinal disulfide bond between them (60). Other forms of PTM include citrullination (163) and transglutamination, which enhance GAD65 peptide binding to HLA-DRB1*04:01 and modulate recognition by modifying amino acids at TCR contact positions (164). Memory T cells reacting with these PTM epitopes were detected in blood at a higher frequency in T1D patients than controls.…”

HIPs and HIP-reactive T cells

“…Post‐translational protein modifications alter the chemical makeup of proteins and have been implicated in the loss of self‐tolerance in various autoimmune diseases . In this context, the recent discovery of hybrid insulin peptides (HIPs) as post‐translationally modified CD4 T cell epitopes in type 1 diabetes (T1D) has gained significant interest.…”

Peptidylarginine deiminase 4 concentration, but not PADI4 polymorphisms, is associated with ICU mortality in septic shock patients

“…Thus, the study of pathways that modulate the inflammatory process could improve the current knowledge in sepsis physiopathology and identify potential therapeutic targets. In this scenario, the citrullination process has become a hot topic, and has been identified in several inflammatory diseases 2, 3…”

“…This enzymatic conversion has an important role in immune system function and in gene regulation 2, 3. In humans, there are five highly related calcium‐dependent PADs, which have been designated as PADs 1‐4 and PAD6.…”

“…PAD4 participates in post‐translational modifications of histones, one of the major focus areas of epigenetic research 2, 4. Citrullination of histones, in particular histone H3, is one of the major points for inflammatory signals that trigger the neutrophil response to infections 2, 3, 4, 5. Nevertheless, citrullinated histone H3 is also important in the development of neutrophils extracellular traps (NETs) 5, 6.…”