A pH-induced modification of CII increases its arthritogenic properties.
Immunoreactivity to collagen type II (CII) has been implicated in the pathogenesis of rheumatoid arthritis. Patients have been described to have an acidic pH in their inflamed synovial tissue. It is known that protein structures are modified by environmental pH, thus it is plausible that changes in synovial pH could affect the conformation of proteins like CII. Posttranslational modifications could alter the biophysical properties of cartilage proteins leading to autoimmunity. In this study we investigated if arthritogenicity of CII was affected by changes in pH, and if so, this could be correlated to altered protein conformation. Immunisation with CII at neutral pH induced a milder disease than did CII at acidic pH. All animals elicited a humoral response to CII, although with a significantly higher IgG1/IgG2b-ratio in the pH 7.4 group. Analysis by circular dichroism and electron microscopy indicated less fibrillation of CII at low pH as compared to neutral pH. Our results suggest that CII is more immunogenic and arthritogenic in an acidic environment than in a neutral environment. We can correlate these findings to pH-induced conformational changes of CII. Hence, self-tolerance to CII might be affected by changes in pH leading to altered and increased arthritogenicity.
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska Hospital, CMM L8:04, 171 76 Stockholm, Sweden. karin.lundberg@cmm.ki.se
Karin
K
Lundberg
Lars
L
Ottosson
Ewa
E
Westman
Maria
M
Sunnerhagen
Kjell
K
Hultenby
Helena Erlandsson
HE
Harris
D000136:Acid-Base Equilibrium / Q000276:immunology / Q000502:physiology*; D000818:Animals; D000917:Antibody Formation; D001172:Arthritis, Rheumatoid / Q000209:etiology*; D024043:Collagen Type II / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D011487:Protein Conformation; D051381:Rats; D011917:Rats, Inbred Lew; D017634:Self Tolerance; D013582:Synovial Fluid
D024043:Collagen Type II