Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis

Abstract

Objective Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)–specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD‐4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti–PAD‐4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti–PAD‐4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD‐4 polymorphisms influence the anti–PAD‐4 autoantibody response. Methods Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti–PAD‐4 autoantibodies by immunoprecipitation of in vitro–translated PAD‐4. The epitope(s) recognized by PAD‐4 autoantibodies were mapped using various PAD‐4 truncations. PAD‐4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method. Results PAD‐4 autoantibodies were found in 36–42% of RA patients, and were very infrequent in controls. Recognition by anti–PAD‐4 autoantibodies required the 119 N‐terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti–PAD‐4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti–PAD‐4 antibodies were associated with more severe joint destruction in RA. Conclusion Our findings indicate that anti–PAD‐4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti–PAD‐4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD‐4 protein, potentially contributing to disease propagation.

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…CD-PTPN22 (D195A/C227S) was generated through site-specific mutagenesis. The expression vectors for PAD2 and PAD4 were provided by Hyejeong Lee at Vanderbilt University (Nashville, Tennessee, USA) and Anthony Rosen at The Johns Hopkins School of Medicine (Baltimore, Maryland, USA) (64,65), respectively.…”

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

“…The physiological conditions and the specific arginine residues targeted for deimination by PPAD and/or host PADs remain differential. For example, PPAD requires a higher pH for its activity and preferentially targets carboxy-terminal and free arginine residues [20] cleaved by arginine-gingipains (Rgps). The human PADs, on the other hand, exclusively citrullinate internal peptidyl arginine residues [11,21], which are activated following an influx of calcium ions from the extracellular environment or from the cytosol [22].…”

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

“…Полагают, что синтез этих ан-тител может определять связь между кишечным дисбио-зом и развитием аутоиммунного процесса при РА. Нако-нец, в сыворотках пациентов с РА обнаруживаются ауто-антитела, распознающие ПАД-4 [95], которая, как уже от-мечалось, играет ключевую роль в цитруллинировании белков. Имеются данные об обнаружении анти-ПАД ан-тител в преклиническую фазу РА, обычно в сочетании с АЦЦП [96].…”