Antibodies Against Citrullinated Proteins and Filaggrin

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Rheumatoid arthritis is diagnosed by its clinical features, radiography, and serological tests. An important serological test is the determination of a

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Katleen F.E. Van Steendam and Dieter L. Deforce

Contents 34.1

Autoreactivity Against Filaggrin ...............

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34.2

Citrullination ...............................................

344

34.3

Citrullinated Proteins .................................

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34.4

Antibodies Against Citrullinated Proteins (ACPA) ..........................................

345

Is (Pro)Filaggrin the Trigger for ACPA Production? ................................

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34.5

References ................................................................. 346

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. In autoimmune diseases, the immune system loses the ability to distinguish between self and nonself, so self-antigens are recognized as nonself and a T- and/or B-cell immune response is initialized. The best known dysregulation of the adaptive immune response in autoimmune diseases is the production of autoantibodies. In RA, the presence of autoantibodies has already been reported: autoantibodies against fibrinogen, vimentin, filaggrin, etc. In this chapter, we will focus on the autoreactivity in RA against filaggrin and the role of these antibodies in the disease.

34.1

K.F.E. Van Steendam, PhD, PharmD D.L. Deforce, PhD, PharmD (*) Laboratory for Pharmaceutical Biotechnology, University Ghent, Harelbekestraat 72, Ghent, East-Flanders 9000, Belgium e-mail: [email protected]; [email protected]

Autoreactivity Against Filaggrin

Filaggrin, a cytokeratin filament of the epithelial cells, is involved in the organization of cytoskeletal structures in epithelial cells. Reactivity to filaggrin was first detected by Nienhuis and Mandena [1] and Young et al. [2]. They detected the antiperinuclear factor (APF) and the antikeratin antibodies (AKA), respectively. APF antibodies bind to pro-filaggrin in the perinuclear granules in epithelial cells of the human buccal mucosa [3]. The antigenic substrate of AKA, on the other hand, was rat esophagus, but AKA also recognize filaggrin in the human epidermis [4]. Interestingly, both antibodies showed a high specificity for RA (87–100 % and 73–100 %,

J.P. Thyssen, H. Maibach (eds.), Filaggrin, DOI 10.1007/978-3-642-54379-1_34, © Springer-Verlag Berlin Heidelberg 2014

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K.F.E. Van Steendam and D.L. Deforce

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respectively) [3]. The widespread use of these tests, however, was limited because of the problems in standardizing the natural substrates and since APF-positive buccal mucosa cells can only be found in approximately 5 % of the donors [5, 6]. Later on, APF and AKA antibodies were classified as anti-filaggrin antibodies (AFA) since they both recognize filaggrin [3]. More precisely, AFA are reactive with the acidic/neutral isoform of filaggrin, leading to the hypothesis that citrulline residues might be present on the epitopes [7]. Indeed, in the late 1990s, it was shown that these antibodies targeted citrullinated epitopes of (pro) filaggrin. Moreover, citrullination was essential for the autoantigenicity of filagg