Proteoglycan‐induced arthritis and recombinant human proteoglycan aggrecan G1 domain–induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis

Abstract

Objective. To develop a simplified and relatively inexpensive version of cartilage proteoglycan-induced arthritis (PGIA), an autoimmunity model of rheumatoid arthritis (RA), and to evaluate the extent to which this new model replicates the disease parameters of PGIA and RA.Methods. Recombinant human G1 domain of human cartilage PG containing "arthritogenic" T cell epitopes was generated in a mammalian expression system and used for immunization of BALB/c mice. The development and progression of arthritis in recombinant human PG G1-immunized mice (designated recombinant human PG G1-induced arthritis [GIA]) was monitored, and disease parameters were compared with those in the parent PGIA model.Results. GIA strongly resembled PGIA, although the clinical symptoms and immune responses in mice with GIA were more uniform than in those with PGIA. Mice with GIA showed evidence of stronger Th1 and Th17 polarization than those with PGIA, and antimouse PG autoantibodies were produced in different isotype ratios in the 2 models. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies were detected in both models; however, serum levels of IgG-RF and anti-CCP antibodies were different in GIA and PGIA, and both parameters correlated better with disease severity in GIA than in PGIA.Conclusion. GIA is a novel model of seropositive RA that exhibits all of the characteristics of PGIA. Although the clinical phenotypes are similar, GIA and PGIA are characterized by different autoantibody profiles, and the 2 models may represent 2 subtypes of seropositive RA, in which more than 1 type of autoantibody can be used to monitor disease severity and response to treatment.

Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis

“…For the CIA model, some disease markers, such as ACPA, are detected at low levels, but ACPA levels may increase with more aggressive immunization resulting in more severe disease [32,33,55]. Arthritis induced with cartilage PG [56,57] or with the recombinant N-terminal G1 domain of PG (GIA) [58] in aging BALB/c females more closely resembles human RA than the arthritis induced in other animal models. Similarities with RA include high susceptibility of older female mice to PGIA or GIA, the recessive mode of disease inheritance and the presence of genetic susceptibility loci that are also found in RA patients [58,59].…”

“…Arthritis induced with cartilage PG [56,57] or with the recombinant N-terminal G1 domain of PG (GIA) [58] in aging BALB/c females more closely resembles human RA than the arthritis induced in other animal models. Similarities with RA include high susceptibility of older female mice to PGIA or GIA, the recessive mode of disease inheritance and the presence of genetic susceptibility loci that are also found in RA patients [58,59]. As in humans, mice with PGIA or GIA also produce both RF and ACPA, and exhibit spondylitis not usually seen in most other rodent models (Table 1) [58].…”

“…Similarities with RA include high susceptibility of older female mice to PGIA or GIA, the recessive mode of disease inheritance and the presence of genetic susceptibility loci that are also found in RA patients [58,59]. As in humans, mice with PGIA or GIA also produce both RF and ACPA, and exhibit spondylitis not usually seen in most other rodent models (Table 1) [58]. …”

Interleukin-9 and T helper type 9 cells in rheumatic diseases

“…Citrullinated arthritogenic aggrecan peptide has been considered to be a biomarker of RA, having been identified in the peripheral blood of RA patients, and has shown to stimulate a specific CD4 response [38][39][40]. It is considered a candidate autoantigen for RA, being one of the principle proteoglycans for cartilage extracellular matrix functioning in cushioning synovial joints, self-antigens that share a common sequence at position 70-74 of the human leucocyte antigen Drelated (HLA-DR) b-chain in 90% of RA patients [38,41].…”

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

“…domain-specific autoimmune responses lead to peripheral and axial arthritis in the arthritissusceptible BALB/c mice [172][173][174][175][176][177], and full disease development requires multiple epitopes on G1 [171]. Since these mouse models develop similar symptoms, these models will be discussed together in below section.…”