Antibodies to citrullinated proteins: molecular interactions and arthritogenicity

Abstract

The discovery of antibodies specific for citrullinated protein epitopes [anti-citrullinated protein antibodies (ACPAs)] is a hallmark for the diagnosis and prognosis of rheumatoid arthritis (RA) and will also be a useful tool for understanding the fundamental pathologic processes. There are several essential questions pertaining to ACPA that remain to be explored, such as understanding the early specificity of the underlying T-cell recognition, whether the production of ACPA is a primary or secondary process, and in the event of such antibodies being arthritogenic, whether they could possibly regulate the disease development. To answer these questions, animal models are needed, but unfortunately ACPA is not a prominent feature of any of the classical animal models of RA. However, we showed recently that ACPA can be isolated from animals susceptible to collagen-induced arthritis that are specific for citrullinated type II collagen (CII). The citrulline specificity could be visualized, and the specificity is determined primarily by a direct interaction with citrulline. We also demonstrated that these antibodies are specific for the citrullinated epitopes and are pathogenic in vivo. A new hypothesis to explain how inflammation in RA can be directed to cartilaginous joints and be self-perpetuating is suggested, which involves recognition of post-translational modifications (glycosylation and citrullination) on CII by T and B cells that can have both arthritogenic and regulatory consequences.

Celastrus-derived Celastrol Suppresses Autoimmune Arthritis by Modulating Antigen-induced Cellular and Humoral Effector Responses

“…Studies in RA patients (1,10,11) and animal models of arthritis (43) have revealed the pathogenic effects of antibodies. Antibodies against type II collagen (43, 44) and glucose-6-phosphate isomerase (45) are examples of pathogenic antibodies as revealed in mice with collagen-induced arthritis and K/BXN mice, respectively.…”

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…The presence of anti-citrullinated protein antibodies (ACPA) is a unique feature of rheumatoid arthritis (RA) (1,2). Citrullinated proteins are generated by deimination catalyzed by peptidyl arginine deiminases (PADs), including PAD1-4 and PAD6 (3).…”

Cross‐reactivity of a human IgG1 anticitrullinated fibrinogen monoclonal antibody to a citrullinated profilaggrin peptide

“…3 Antibodies to citrullinated proteins are among the most specific described in RA and are believed to play a role in the pathogenesis of the disease. [4][5][6][7][8] These antibodies were originally identified by Schellekens et al, 9 who described specific antibody reactivity to a profilaggrin peptide containing the modified amino acid citrulline. The post-translational generation of citrulline, referred to as citrullination or deimination, is a modification of the side chain of arginine, where the guanidino group is replaced by an ureido group.…”

“…4,10 Antibodies specific for citrullinated proteins recognize a variety of citrullinated autoantigens, including a-enolase, fibrinogen, type II collagen, and vimentin, and are collectively identified as anticitrullinated peptide/protein antibodies (ACPA). [11][12][13][14][15] These ACPA responses, primarily characterized by IgG 1 and IgG 4 subtypes (99 and 98% of ACPA-positive RA patient sera, respectively), have been found to be present up to years before disease onset and to be highly specific (98%) and sensitive (up to 80%) for RA. [16][17][18][19][20][21] Thus, APCA are used as a supplement to clinical diagnosis of RA.…”