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Rheumatology Advance Access originally published online on October 5, 2004
Rheumatology 2005 44(1):40-50; doi:10.1093/rheumatology/keh414
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Rheumatology Vol. 44 No. 1 © British Society for Rheumatology 2004; all rights reserved

PAPER

Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis

X. Chang1, R. Yamada1, A. Suzuki1, T. Sawada2, S. Yoshino3, S. Tokuhiro1 and K. Yamamoto1,2

1 Laboratory for Rheumatic Diseases, SNP Research Center, Institute of Physical and Chemical Research (RIKEN), Kanagawa, 2 Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo and 3 Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan.

Correspondence to: R. Yamada, Laboratory for Rheumatic Diseases, SNP Research Center, Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: ryamada{at}src.riken.go.jp

Objectives. Peptidylarginine deiminases (PADIs) convert peptidylarginine into citrulline via post-translational modification. Anti-citrullinated peptide antibodies are highly specific for rheumatoid arthritis (RA). Our genome-wide case–control study of single-nucleotide polymorphisms found that the PADI4 gene polymorphism is closely associated with RA. Here, we localized the expression of PADI4 and the citrullinated protein product in synovial RA tissue.

Methods. We used immunohistochemistry, double immunofluorescent labelling and western blotting.

Results. We found that PADI4 is extensively expressed in T cells, B cells, macrophages, neutrophils, fibroblast-like cells and endothelial cells in the lining and sublining areas of the RA synovium. We also found extracellular and intracellular expression of PADI4 in fibrin deposits with loose tissue structures where apoptosis was widespread. Unlike PADI4, citrullinated protein generally appeared in fibrin deposits that were abundant in the RA synovium. The citrullinated fibrin aggregate was immunoreactive against immunoglobulin (Ig) A and IgM, but not IgG and IgE. Although a little PADI4 was expressed in osteoarthritic and normal synovial tissues, significant citrullination was undetectable.

Conclusions. The results showed that PADI4 is mainly distributed in cells of various haematopoietic lineages and expressed at high levels in the inflamed RA synovium. The co-localization of PADI4, citrullinated protein and apoptotic cells in fibrin deposits suggests that PADI4 is responsible for fibrin citrullination and is involved in apoptosis. The immunoreactivity of citrullinated fibrin with IgA and IgM in the RA synovium supports the notion that citrullinated fibrin is a potential antigen of RA autoimmunity.

KEY WORDS: Rheumatoid arthritis, Peptidylarginine deiminase 4 (PADI4), Citrullination, Fibrin, Synovial tissue


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