Citrullinated host protein

Citrullinated host proteins are the products of a post-translational modification known as deimination, where Peptidylarginine Deiminase (PAD) enzymes convert positively charged arginine residues into neutrally charged citrulline (Vossenaar et al., 2003, BioEssays). This modification significantly alters the protein's electronic charge and folding, often leading to the creation of neoepitopes that the immune system may recognize as foreign (Alghamdi et al., 2019, Journal of Inflammation Research). In autoimmune conditions like Rheumatoid Arthritis (RA), these proteins—including citrullinated vimentin, fibrinogen, and alpha-enolase—serve as the primary targets for anti-citrullinated protein antibodies (ACPAs), which are hallmark diagnostic biomarkers and drivers of joint inflammation (Schellekens et al., 1998, JCI). Beyond autoimmunity, citrullination is frequently upregulated in the tumor microenvironment due to cellular stress and inflammation, resulting in the presentation of citrullinated peptides as neoantigens on MHC class II molecules. This has enabled the development of novel immunotherapies, such as the Modi-1 vaccine, which primes T-cells to target and destroy cancer cells presenting these modified proteins (Scancell Holdings plc, 2024). Current therapeutic research focuses on both the inhibition of PAD enzymes to prevent the formation of these proteins and the exploitation of these neoantigens for targeted cancer immunotherapy (BMS, ClinicalTrials.gov).

Other names

Deiminated proteinCitrullinated neoantigenCit-proteinCitrullinated autoantigen

Therapeutic strategies involve the induction of Th1 cytotoxic T-cell responses against citrullinated neoantigens presented on MHC class II molecules or the reduction of citrullinated protein levels through the small-molecule inhibition of Peptidylarginine Deiminase (PAD) enzymes.