Subsequently, an anti-C5a preventive vaccine with an unnatural amino acid p-nitrophenylalanine (4NPA) replacing a tyrosine residue, especially at position 35, in the murine C5a molecule, was found to induce loss of tolerance towards the endogenous protein, which partly protected mice against arthritis development while strongly reducing the disease severity [54]. This evidence concerns the gene C5AR1 and arthritic joint disease.