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A chronic model of arthritis supported by a strain-specific periarticular lymph node in BALB/c mice.

Baddack U, Hartmann S, Bang H, Grobe J, Loddenkemper C, Lipp M, Müller G - Nat Commun (2013)

Bottom Line: However, BALB/c mice generate significantly higher titres of anticollagen and anticitrullinated peptide antibodies, show a stronger progressive joint destruction, and in the chronic phase the disease spreads between joints.Concomitant to the observation of a more severe pathology, we discovered a previously undescribed small periarticular lymph node in close proximity to the knee joint of BALB/c mice, which acts as the primary draining lymph node for the synovial cavity.Our model more closely reflects the pathology of rheumatoid arthritis than classical models of arthritis and is hence particularly suitable for further studies of disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück-Center of Molecular Medicine, Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.

ABSTRACT
Current animal models of arthritis only partially reflect the complexity of rheumatoid arthritis and typically lack either chronicity or autoantibody formation. Here we describe a model that combines features of antigen-induced arthritis and collagen-induced arthritis, which can be efficiently induced in BALB/c and C57BL/6 mice. However, BALB/c mice generate significantly higher titres of anticollagen and anticitrullinated peptide antibodies, show a stronger progressive joint destruction, and in the chronic phase the disease spreads between joints. Concomitant to the observation of a more severe pathology, we discovered a previously undescribed small periarticular lymph node in close proximity to the knee joint of BALB/c mice, which acts as the primary draining lymph node for the synovial cavity. Our model more closely reflects the pathology of rheumatoid arthritis than classical models of arthritis and is hence particularly suitable for further studies of disease pathogenesis.

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BALB/c mice develop high titres of ACPA after arthritis induction.Serum of untreated, immunized or arthritic BALB/C and C57BL/6 mice was tested with ELISA for antibodies against ACPA: CCP (a) and MCV (b). Time points: healthy untreated, 4 days after first immunization (−17 days), 4 days after second immunization (−10 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction), and late chronic phase (8–9 weeks after induction). White bars indicate mean values for BALB/c, grey bars for C57BL/6 samples. Data is representative of two independent experiments with 8–15 animals per time point and group. (c) The presence of pertussis toxin during immunization influences ACPA levels. BALB/c mice were immunized according to the ACIA scheme with or without PTx and levels of anti-CCP antibodies compared at different disease stages. Time points: 4 days after second immunization (−9 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction). Mice were immunized according to the ACIA scheme with either PTx (circles) or PBS instead of PTx (triangles). Statistics: Mann–Whitney-U-test (n.s.: not significant, *P<0.05, **P<0.01, ***P<0.001).
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f5: BALB/c mice develop high titres of ACPA after arthritis induction.Serum of untreated, immunized or arthritic BALB/C and C57BL/6 mice was tested with ELISA for antibodies against ACPA: CCP (a) and MCV (b). Time points: healthy untreated, 4 days after first immunization (−17 days), 4 days after second immunization (−10 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction), and late chronic phase (8–9 weeks after induction). White bars indicate mean values for BALB/c, grey bars for C57BL/6 samples. Data is representative of two independent experiments with 8–15 animals per time point and group. (c) The presence of pertussis toxin during immunization influences ACPA levels. BALB/c mice were immunized according to the ACIA scheme with or without PTx and levels of anti-CCP antibodies compared at different disease stages. Time points: 4 days after second immunization (−9 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction). Mice were immunized according to the ACIA scheme with either PTx (circles) or PBS instead of PTx (triangles). Statistics: Mann–Whitney-U-test (n.s.: not significant, *P<0.05, **P<0.01, ***P<0.001).

Mentions: Current models of arthritis usually fail to recapitulate the formation of ACPA. These autoantibodies, however, are the most important biomarker for RA development in clinical practise. The best-known triggers for antibodies to citrullinated peptides are filaggrin, CII, α-enolase, fibrin(ogen) and vimentin. Antibodies directed against a mutated citrullinated isoform of vimentin (MCV) can also be detected in the synovial fluid of RA patients. These anti-MCV antibodies seem to have a higher sensitivity for RA compared with antibodies against artificial CCPs12. We were able to detect both, anti-CCP and anti-MCV antibodies in the serum of BALB/c and C57BL/6 mice in the ACIA model (Fig. 5). Antibodies to CCP were already detectable at day −10 before arthritis induction. Serum titres of anti-CCP antibodies that are significantly higher in BALB/c than in C57BL/6 mice increased until day 10 after immunization, then they reached a plateau (Fig. 5a). In contrast, elevated titres of anti-MCV autoantibodies become apparent shortly after arthritis induction (day 4). Similar to anti-CCP, antibody titres reach a maximum at day 10 after arthritis induction. Compared with BALB/c mice C57BL/6 animals are inefficient in the induction of anti-MCV antibodies (Fig. 5b). The high titres of ACPA in ACIA led us to investigate whether PTx, which is included in the classical immunization scheme of AIA but not CIA91314, has an impact on ACPA formation. Similar to the observation that PTx boosts the antibody-response to mBSA in AIA, we observed significantly higher levels of ACPA in BALB/c mice receiving PTx compared with BALB/c mice receiving PBS (Fig. 5c). Still, the generation of ACPA does not depend on PTx as ACPA formation is delayed but robust also in the absence of PTx as adjuvant.


A chronic model of arthritis supported by a strain-specific periarticular lymph node in BALB/c mice.

Baddack U, Hartmann S, Bang H, Grobe J, Loddenkemper C, Lipp M, Müller G - Nat Commun (2013)

BALB/c mice develop high titres of ACPA after arthritis induction.Serum of untreated, immunized or arthritic BALB/C and C57BL/6 mice was tested with ELISA for antibodies against ACPA: CCP (a) and MCV (b). Time points: healthy untreated, 4 days after first immunization (−17 days), 4 days after second immunization (−10 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction), and late chronic phase (8–9 weeks after induction). White bars indicate mean values for BALB/c, grey bars for C57BL/6 samples. Data is representative of two independent experiments with 8–15 animals per time point and group. (c) The presence of pertussis toxin during immunization influences ACPA levels. BALB/c mice were immunized according to the ACIA scheme with or without PTx and levels of anti-CCP antibodies compared at different disease stages. Time points: 4 days after second immunization (−9 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction). Mice were immunized according to the ACIA scheme with either PTx (circles) or PBS instead of PTx (triangles). Statistics: Mann–Whitney-U-test (n.s.: not significant, *P<0.05, **P<0.01, ***P<0.001).
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f5: BALB/c mice develop high titres of ACPA after arthritis induction.Serum of untreated, immunized or arthritic BALB/C and C57BL/6 mice was tested with ELISA for antibodies against ACPA: CCP (a) and MCV (b). Time points: healthy untreated, 4 days after first immunization (−17 days), 4 days after second immunization (−10 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction), and late chronic phase (8–9 weeks after induction). White bars indicate mean values for BALB/c, grey bars for C57BL/6 samples. Data is representative of two independent experiments with 8–15 animals per time point and group. (c) The presence of pertussis toxin during immunization influences ACPA levels. BALB/c mice were immunized according to the ACIA scheme with or without PTx and levels of anti-CCP antibodies compared at different disease stages. Time points: 4 days after second immunization (−9 days), acute phase (4 days after induction), transition phase (10 days after induction), early chronic phase (3 weeks after induction). Mice were immunized according to the ACIA scheme with either PTx (circles) or PBS instead of PTx (triangles). Statistics: Mann–Whitney-U-test (n.s.: not significant, *P<0.05, **P<0.01, ***P<0.001).
Mentions: Current models of arthritis usually fail to recapitulate the formation of ACPA. These autoantibodies, however, are the most important biomarker for RA development in clinical practise. The best-known triggers for antibodies to citrullinated peptides are filaggrin, CII, α-enolase, fibrin(ogen) and vimentin. Antibodies directed against a mutated citrullinated isoform of vimentin (MCV) can also be detected in the synovial fluid of RA patients. These anti-MCV antibodies seem to have a higher sensitivity for RA compared with antibodies against artificial CCPs12. We were able to detect both, anti-CCP and anti-MCV antibodies in the serum of BALB/c and C57BL/6 mice in the ACIA model (Fig. 5). Antibodies to CCP were already detectable at day −10 before arthritis induction. Serum titres of anti-CCP antibodies that are significantly higher in BALB/c than in C57BL/6 mice increased until day 10 after immunization, then they reached a plateau (Fig. 5a). In contrast, elevated titres of anti-MCV autoantibodies become apparent shortly after arthritis induction (day 4). Similar to anti-CCP, antibody titres reach a maximum at day 10 after arthritis induction. Compared with BALB/c mice C57BL/6 animals are inefficient in the induction of anti-MCV antibodies (Fig. 5b). The high titres of ACPA in ACIA led us to investigate whether PTx, which is included in the classical immunization scheme of AIA but not CIA91314, has an impact on ACPA formation. Similar to the observation that PTx boosts the antibody-response to mBSA in AIA, we observed significantly higher levels of ACPA in BALB/c mice receiving PTx compared with BALB/c mice receiving PBS (Fig. 5c). Still, the generation of ACPA does not depend on PTx as ACPA formation is delayed but robust also in the absence of PTx as adjuvant.

Bottom Line: However, BALB/c mice generate significantly higher titres of anticollagen and anticitrullinated peptide antibodies, show a stronger progressive joint destruction, and in the chronic phase the disease spreads between joints.Concomitant to the observation of a more severe pathology, we discovered a previously undescribed small periarticular lymph node in close proximity to the knee joint of BALB/c mice, which acts as the primary draining lymph node for the synovial cavity.Our model more closely reflects the pathology of rheumatoid arthritis than classical models of arthritis and is hence particularly suitable for further studies of disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück-Center of Molecular Medicine, Department of Tumor Genetics and Immunogenetics, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.

ABSTRACT
Current animal models of arthritis only partially reflect the complexity of rheumatoid arthritis and typically lack either chronicity or autoantibody formation. Here we describe a model that combines features of antigen-induced arthritis and collagen-induced arthritis, which can be efficiently induced in BALB/c and C57BL/6 mice. However, BALB/c mice generate significantly higher titres of anticollagen and anticitrullinated peptide antibodies, show a stronger progressive joint destruction, and in the chronic phase the disease spreads between joints. Concomitant to the observation of a more severe pathology, we discovered a previously undescribed small periarticular lymph node in close proximity to the knee joint of BALB/c mice, which acts as the primary draining lymph node for the synovial cavity. Our model more closely reflects the pathology of rheumatoid arthritis than classical models of arthritis and is hence particularly suitable for further studies of disease pathogenesis.

Show MeSH
Related in: MedlinePlus