Abstract
Anti-citrullinated peptides antibodies (ACPAs) have high specificity for the diagnosis of rheumatoid arthritis (RA), but their role in the pathophysiology is not fully established. The main genetic risk factor for RA, the shared epitope in major histocompatibility complex class II, is associated with ACPAs. Among certain non-human primates, 8% carry the shared epitope called H6 haplotype, and being similar to humans, are ideal candidates to study the role of ACPAs in RA. The goal of this study was to develop a macaque model of RA based on immunization against citrullinated peptides to generate an ACPA-mediated model of arthritis. Cynomolgus macaques were immunized with four citrullinated peptides from vimentin, fibrinogen, and aggrecan, known to induce T-cell response in RA patients, and received an intra-articular (IA) boost with the same four citrullinated peptides pooled. In the macaque, the T-cell response was specific to citrullinated peptides. Antibodies generated in response to immunization were cross-reactive between the citrulline and arginine peptides. The presence of the H6 haplotype did not affect the magnitude of the immune response. Since no clinical response was observed, macaques received an IA boost with the same four peptides pooled and incomplete Freund's adjuvant, which led to a prolonged neutrophil-rich mono-arthritis, preferentially in H6-positive animals. Conversely, animals boosted with incomplete Freund's adjuvant alone presented only transient mono-arthritis. This two-hit model of prolonged mono-arthritis mimics what could happen in RA. Despite the limited number of joints with disease in the macaque model, the model appears unique to study the events occurring during the preclinical phase of RA, from immunization against citrullinated peptides to the clinical appearance of disease.
Highlights
Rheumatoid arthritis (RA) is a debilitating disease that affects the joints and causes severe handicap
T-cell response to the pool of arginine peptides was greater for animals immunized with the arginine version of the peptides (2/2 animals) than the citrulline version (1/4 animals) (Figure 1A)
After intradermal immunization, the T-cell response was rather citrulline- or arginine-specific depending on the type of peptides used for immunization
Summary
Rheumatoid arthritis (RA) is a debilitating disease that affects the joints and causes severe handicap. In RA, antibodies against citrullinated peptides (ACPAs) are frequent (75% of patients) and specific to the disease (up to 98% diagnosis specificity). This very high specificity for RA has led to the inclusion of ACPAs in the latest disease diagnostic criteria from the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR 2010) [2]. In transgenic mice expressing the human major histocompatibility complex (MHC) class II shared epitope, arthritides have been induced with citrullinated peptides [3], but these results have been poorly reproduced and remain controversial [4]. The shared epitope confers increased risk of RA and was thought to increase ACPA level. The link has been suggested to rely on the increased affinity of some citrullinated peptides for the human leukocyte antigen (HLA) molecule as compared with the native unmodified peptides [5]
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