title: Rheumatoid arthritis, Proteus, anti-CCP antibodies and Karl Popper.
abstract: Rheumatoid arthritis (RA) is a crippling joint disease affecting over 20 million people worldwide. The cause of RA is most probably linked to the triad of microbial trigger, genetic association and autoimmunity and can be explained using the philosophical method of Karl Popper or Popperian sequences. Ten "Popper sequences" have been identified which point to the urinary microbe Proteus mirabilis as the cause of RA: Popper sequence 1 establishes that HLA-DR4 lymphocytes injected into a rabbit evoke specific antibodies against Proteus bacteria. Popper sequence 2 establishes that antibodies to Proteus bacteria are present in RA patients from 14 different countries. Popper sequence 3 establishes that antibodies to Proteus bacteria in RA patients are disease specific since no such antibodies are found in other conditions. Popper sequence 4 establishes that when RA patients have high titres of antibodies to Proteus such bacteria are found in urinary cultures. Popper sequence 5 establishes that only Proteus bacteria and no other microbes evoke significantly elevated antibodies in RA patients. Popper sequence 6 establishes that the "shared epitope" EQR(K)RAA shows "molecular mimicry" with the sequence ESRRAL found in Proteus haemolysin. Popper sequence 7 establishes that Proteus urease contains a sequence IRRET which has "molecular mimicry" with LRREI found in collagen XI of hyaline cartilage. Popper sequence 8 establishes that sera obtained from RA patients have cytopathic properties against sheep red cells coated with the cross-reacting EQR(K)RAA and LRREI self-antigen peptides. Popper sequence 9 establishes that Proteus sequences in haemolysin and urease as well as the self antigens, HLA-DR1/4 and collagen XI, each contain an arginine doublet, thereby providing a substrate for peptidyl arginine deiminase (PAD) to give rise to citrulline, which is the main antigenic component of CCP, antibodies to which are found in early cases of RA. Popper sequence 10 establishes that antibodies to Proteus come not only from sequences crossreacting to self antigens but also from non-crossreacting sequences, thereby indicating that active RA patients have been exposed to infection by Proteus. The ten Popper sequences establish that RA is most probably caused by Proteus upper urinary tract infections, which can possibly be treated with anti-Proteus therapy.
authors.affiliation: King's College, Analytical Sciences Group, London SE1 9NN, UK. alan.ebringer@kcl.ac.uk
authors.forename: Alan
authors.initials: A
authors.lastname: Ebringer
authors.forename: Taha
authors.initials: T
authors.lastname: Rashid
authors.forename: Clyde
authors.initials: C
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D002956:Citrulline / Q000276:immunology; D003429:Cross Reactions; D000939:Epitopes / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000276:immunology; D006460:Hemolysin Proteins / Q000276:immunology; D006801:Humans; D051457:Hyaline Cartilage; D018716:Molecular Mimicry; D011512:Proteus Infections / Q000150:complications / Q000276:immunology*; D011513:Proteus mirabilis / Q000276:immunology* / Q000472:pathogenicity; D014552:Urinary Tract Infections / Q000150:complications / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D015798:HLA-DR1 Antigen; D015804:HLA-DR4 Antigen; D006460:Hemolysin Proteins; D002956:Citrulline