Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian α‐enolase and arthritis in DR4‐IE–transgenic mice

AJ Kinloch, S Alzabin, W Brintnell… - Arthritis & …, 2011 - Wiley Online Library
AJ Kinloch, S Alzabin, W Brintnell, E Wilson, L Barra, N Wegner, DA Bell, E Cairns…
Arthritis & Rheumatism, 2011Wiley Online Library
Objective To examine the hypothesis that the subset of rheumatoid arthritis (RA)
characterized by antibodies to citrullinated α‐enolase is mediated by Porphyromonas
gingivalis enolase in the context of DR4 alleles. Methods Recombinant human α‐enolase
and P gingivalis enolase, either citrullinated or uncitrullinated, were used to immunize DR4‐
IE–transgenic mice and control mice (class II major histocompatibility complex–deficient
[class II MHC−/−] and C57BL/6 wild‐type mice). Arthritis was quantified by measurement of …
Objective
To examine the hypothesis that the subset of rheumatoid arthritis (RA) characterized by antibodies to citrullinated α‐enolase is mediated by Porphyromonas gingivalis enolase in the context of DR4 alleles.
Methods
Recombinant human α‐enolase and P gingivalis enolase, either citrullinated or uncitrullinated, were used to immunize DR4‐IE–transgenic mice and control mice (class II major histocompatibility complex–deficient [class II MHC−/−] and C57BL/6 wild‐type mice). Arthritis was quantified by measurement of ankle swelling in the hind paws and histologic examination. Serum IgG reactivity with α‐enolase and citrullinated α‐enolase was assayed by Western blotting and enzyme‐linked immunosorbent assay (ELISA). Antibodies to peptide 1 of citrullinated α‐enolase (CEP‐1) and its arginine‐bearing control peptide, REP‐1, were also assessed by ELISA.
Results
Significant hind‐ankle swelling (≥0.3 mm) occurred in DR4‐IE–transgenic mice immunized with citrullinated human α‐enolase (9 of 12 mice), uncitrullinated human α‐enolase (9 of 12 mice), citrullinated P gingivalis enolase (6 of 6 mice), and uncitrullinated P gingivalis enolase (6 of 6 mice). Swelling peaked on day 24. None of the control groups developed arthritis. The arthritic joints showed synovial hyperplasia and erosions, but there was a paucity of leukocyte infiltration. Antibodies to human α‐enolase, both citrullinated and unmodified, and to CEP‐1 and REP‐1 were detectable in all immunized mice except the class II MHC−/− control mice.
Conclusion
This is the first animal model that links an immune response to P gingivalis enolase to an important subset of RA, defined by antibodies to citrullinated α‐enolase in the context of DR4. The fact that arthritis and anti–CEP‐1 antibodies were induced independent of citrullination of the immunizing antigen suggests that the unmodified form of α‐enolase may be important in initiating the corresponding subset of human RA.
Wiley Online Library