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


CONCLUSIONS
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.
Harris
Michelle L
ML
Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Darrah
Erika
E
Lam
Gordon K
GK
Bartlett
Susan J
SJ
Giles
Jon T
JT
Grant
Audrey V
AV
Gao
Peisong
P
Scott
William W
WW
El-Gabalawy
Hani
H
Casciola-Rosen
Livia
L
Barnes
Kathleen C
KC
Bathon
Joan M
JM
Rosen
Antony
A
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D015551:Autoimmunity; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D012720:Severity of Illness Index
D001323:Autoantibodies; D015415:Biomarkers; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases