Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis?

Abstract

Peptidylarginine deiminases (PADs) convert arginine within a peptide (peptidylarginine) into peptidylcitrulline. Citrullination by human PADs is important in normal physiology and inflammation. Porphyromonas gingivalis, a major pathogen in periodontitis, is the only prokaryote described to possess PAD. P. gingivalis infection may generate citrullinated peptides, which trigger anti-citrullinated peptide antibodies. In susceptible individuals, host protein citrullination by human PADs in the joint probably perpetuates antibody formation, paving the way for the development of chronic arthritis. Blockades of bacterial and human PADs may act as powerful novel therapies by inhibiting the generation of the antigens that trigger and sustain autoimmunity in rheumatoid arthritis.

Figure 1

Simplified model illustrating the hypothesis that Porphyromonas gingivalis-mediated citrullination triggers anti-citrulline autoimmunity in rheumatoid arthritis. Citrullination by P. gingivalis peptidylarginine deiminase (PAD) in the inflammatory context of periodontitis produces bacterial and host-derived citrullinated peptides to which the immune system mounts a humoral immune response with the production of peptidylcitrulline antibodies. Inflammation-induced citrullination by human PAD enzymes in the gingiva is also possible (dashed arrow). Tissue injury and inflammation in the joint lead to activation of human PAD enzymes and citrullination of host proteins, such as a-enolase, vimentin, fibrin(ogen), and collagen type II. Peptidylcitrulline antibodies bind citrullinated host and bacterial peptides, which may show molecular mimicry, and in genetically susceptible individuals (presence of the certain HLA alleles), intra- and intermolecular epitope spreading leads to a sustained immune response with the formation of high-affinity antibodies to host citrullinated proteins.

Figure 2

Alignment of amino acid sequence of catalytic domains of Porphyromonas gingivalis PAD (PPAD) (residues 86 to 363), AIH from Dyadobacter fermentans DSM 18053 (locus Dfer_2630, residues 60 to 352), and human PAD4 (residues 306 to 556). Residues identical in PPAD and AIH and/or PAD4 are highlighted. Guanidino-binding (#) and catalytic residues (*) that are conserved in all families of guanidino-group modifying enzyme superfamily are indicated. The amino-terminal sequence of each enzyme is unique. In PAD4, the amino-terminal portion is folded into two consecutive immunoglobulin-like β-sandwich domains preceding the catalytic domain harboring the α/β-propeller fold [51]. A long 200-residue carboxy-terminal extension of PPAD is predicted to adopt an immunoglobulin-like β-sandwich structure [50]. AIH, agmatine iminohydrolase; PAD, peptidylarginine deiminase.