Autoantibodies in rheumatoid arthritis - rheumatoid factor, anticitrullinated protein antibodies and beyond

Abstract

Purpose of review: RA is characterized by the presence of autoantibodies among which rheumatoid factors (RFs) and antimodified protein antibodies (AMPA) are serological hallmarks of the disease. In recent years, several novel insights into the biology, immunogenetics and clinical relevance of these autoantibodies have been obtained, which deserve to be discussed in more detail.

Recent findings: RFs from RA patients seem to target distinct epitopes which appear to be quite specific for RA. Determination of immunoglobulin A (IgA) isotypes of RF and anticitrullinated protein antibodies (ACPA) may provide prognostic information because their presence is associated with reduced therapeutic responses to TNF inhibitors. Furthermore, IgA levels are increased in RA patients and IgA immune complexes are more potent than immunoglobulin G (IgG) complexes in inducing NET formation. Concerning AMPAs, investigations on variable domain glycosylation (VDG) revealed effects on antigen binding and activation of autoreactive B cells. Studies on pathogenetic involvement of ACPA suggest Janus-faced roles: on the one hand, ACPA may be involved in joint destruction and pain perception while on the other hand protective anti-inflammatory effects may be attributed to a subset of ACPAs.

Summary: The autoimmune response in RA is extremely complex and still far from being fully understood. Antibodies are not only valuable diagnostic biomarkers but also seem to play pivotal roles in the pathophysiology of RA.

Box 1

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FIGURE 1

Proteins are synthesized in the cytosol by translating the genomic information carried messenger RNA in a polypeptide or protein. After translation proteins can be modified enzymatically or chemically. Three posttranslational modifications (PTMs) are intimately connected to RA as 50–70% of RA patients harbor (auto)antibodies (antimodified protein antibodies) to proteins carrying citrulline, homocitrulline and/or acetyllysine.

FIGURE 2

All IgG1 antibodies contain N-linked glycans in the Fc region of the molecule because of the presence of an N-linked glycosylation in the Fc-tail (red antibody). ACPA contain, next to this typical Fc-glycan, also N-linked glycans in the variable domain through the introduction of N-linked glycosylation-sites by somatic hypermutation, a T-cell dependent process. ACAP, anticitrullinated protein antibodies; IgG, immunoglobulin G.