Antibodies against transglutaminases, peptidylarginine deiminase and citrulline in rheumatoid arthritis--new pathways to epitope spreading.
OBJECTIVE
The findings of the involvement of tissue transglutaminase (tTg) in the pathogenesis of coeliac disease (CD) have stimulated progress in the field of auto-immune diseases. Another calcium-dependent cysteine enzyme, peptidylarginine deiminase type 4 (PAD4), seems to be involved in the pathogenesis of rheumatoid arthritis (RA). There are obvious similarities between Tgs and PADs.


METHODS
Using enzyme-linked immuno-sorbent assays, we have measured the occurrence of antibodies against guinea pig (gp) and human recombinant (hr) tTg, PAD and citrulline in 59 controls and 184 RA-patients, of whom 71 were treated with methotrexate (mtx).


RESULTS
In addition to the expected antibodies against citrulline (62%), sera from the 113 RA-patients without mtx treatment contained significantly increased frequencies of IgG anti-PAD (35%), IgA anti-gp-tTg (34%), IgA anti-hr tTg (20%), IgG anti-gp-tTg (13%) and IgA anti-hr-FXIII (15%) compared to controls. In sera from the mtx-treated RA-patients the expression of antibodies was reduced. In patients not treated with methotrexate there was a statistically significant correlation between, on one hand, IgG anti-PAD and on the other hand, IgG anti-citrulline, IgA anti-gp-tTg, IgA anti-hr-tTg, IgG anti-gp-tTg, IgG anti-hr-tTg, or IgA anti-hr-FXIII. In the mtx-treated group these correlations were less pronounced.


CONCLUSIONS
In addition to the expected antibodies against citrulline, sera from RA-patients contained antibodies against PAD and against Tgs of at least two kinds, indicating that the specificity for anti-tTg in CD is far from complete. Most of the patients displayed more than one antibody, a possible indication of epitope spreading. MTX-treatment reduced the expression of antibodies.
Hospital Pharmacy, Malmö University Hospital, Malmö, Sweden.
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Stenberg
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D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D002956:Citrulline / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006867:Hydrolases / Q000276:immunology*; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D000076342:Protein-Arginine Deiminases; D011994:Recombinant Proteins; D011503:Transglutaminases / Q000276:immunology*
D018501:Antirheumatic Agents; D001323:Autoantibodies; D000939:Epitopes; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D002956:Citrulline; D011503:Transglutaminases; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases; D008727:Methotrexate