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Autoimmunity - an Introduction

Rheumatoid Arthritis

Citrullinated proteins seem to be involved in the pathogenesis of rheumatoid arthritis

Citrullination is a posttranslational modification of arginine by deimination, physiologically occurring during apoptosis or inflammation. The enzyme peptidylarginine deiminase (PAD) converts arginine residues to citrullin. PAD is active in inflammatory leukocytes including synovial T and B cells, macrophages, neutrophils, as well as fibroblast-like synoviocytes1).

Biochemical reaction during conversion of arginine to citrullin by PAD

Conversion of the positively charged arginine residue to neutral citrullin modifies the tertiary structure of the polypeptide chain. Cells of the immune defence are no longer able to identify the altered protein as a structure of the body itself and attack it.

Citrullinated proteins, e.g. vimentin, have been detected in the synovial membrane of patients with various forms of arthritis and in other inflamed tissues, suggesting that citrullination is associated with inflammation in general, while the development of anti-citrullinated protein-/peptide autoantibodies (ACPA) is specific to rheumatoid arthritis. In patients with rheumatoid arthritis, ACPA producing plasma cells have been identified in the synovial membrane, and higher concentrations of ACPA in the rheumatoid joint compared with the serum have been reported. This suggests that synovial citrullinated proteins are driving a local production of autoantibodies, and that the resulting immune complexes contribute to the chronic inflammation in the rheumatoid joint2).

T cell-mediated inflammation in rheumatoid arthritis
© Orgentec Diagnostika

A T cell binds to the "self"-antigen MCV (mutated citrullinated vimentin) and produces soluble factors that activate other immune cells. Macrophages attack the tissue and secrete chemical messengers which provoke uncontrolled growth of synovial cells into the joint space, where they destroy cartilage and bone. T cells and macrophages interact to promote the inflammation. Via direct cell-cell-interaction T cells stimulate B cells to produce and secrete autoantibodies.

1) Vossenaar, E. R.; Radstake, T. R. D.; van der Heijden, A.; van Mansum, M. A. M.; Dieteren, C.; de Rooij, D. J.; Barrera, P.; Zendman, A. J. W.; van Venrooij, W. J. (2004): Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. In: Ann. Rheum. Dis.. 65 , 373-381
2) Kinloch, A.; Lundberg, K.; Wait, R.; Wegner, N.; Lim, N. H.; Zendman, A. J. W.; Saxne, T.; Malmstr, V.; Venables, P. J. (2008): Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. In: Arthritis Rheum.. 58 , 2287-2295
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