Neutrophils and their contribution to autoimmunity in rheumatoid arthritis

Abstract

In recent years, one of the most exciting findings by researchers investigating the pathogenesis of rheumatoid arthritis (RA) has been the identification of citrullinated (deiminated) proteins as autoantigens (Klareskog et al. 2008; Schellekens et al. 1998; Sebbag et al. 1995). Anti-citrullinated protein antibodies (ACPA) can be found several years before the onset of arthritis (Rantapää-Dahlqvist et al. 2003). In patients with undifferentiated arthritis, the presence of ACPA is highly associated with progression towards RA. In fact, ACPA-positive RA patients generally develop a more severe disease, and the gene environmental interactions identified for RA such as smoking, HLA genotype and single-nucleotide polymorphism in the gene PTPN22 are all associated with autoimmunity to deiminated proteins (Kallberg et al. 2007). Taken together, these observations suggest that ACPA are likely to be involved in the pathogenesis of RA. However, since in many patients these auto-antibodies can be detected years before the onset of disease, it appears that ACPA alone are not sufficient to cause disease. We now have detailed information about many features of ACPA, including their affinity maturation, immunoglobulin isotypes, the citrullinated antigens they are specific for and the time course of their appearance (Amara et al. 2013; Lundberg et al. 2012; Rantapää-Dahlqvist et al. 2003; Suwannalai et al. 2012). Currently, there is also great interest in the triggers that lead to the transition from asymptomatic ACPA-positive individuals to the activation of disease symptoms and onset of RA. Changes observed at the onset of joint inflammation include an increase in the epitope spreading of ACPA and an increase in the range of isotypes (Ioan-Facsinay et al. 2008; van de Stadt et al. 2011; van der Woude et al. 2010).