Elsevier

Autoimmunity Reviews

Volume 9, Issue 4, February 2010, Pages 216-223
Autoimmunity Reviews

Rheumatoid arthritis, Proteus, anti-CCP antibodies and Karl Popper

https://doi.org/10.1016/j.autrev.2009.10.006Get rights and content

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.

Introduction

One of the greatest problems in modern medicine is the origin and treatment of the disabling, arthritic condition “rheumatoid arthritis” (RA) which is known to affect approximately 1% of the U.K. population and over 20 to 30 million people throughout the world.

Although it has been suggested that RA is an “autoimmune disease” the origin of the condition is to some extent unknown except that it affects women three to four times more frequently than men. The disease seems to start predominantly in the 40s to 60s age group and with a rising demographic survival it is likely that there will be more patients diagnosed with RA in the future. The prospect that there will be an increasing number of RA patients in the coming decades may produce an increasing social and financial burden to society. It is thus imperative to find the cause of this disease so that medical steps can be undertaken to control this problem.

It is proposed in this critical analysis to use the methods advocated by the great philosopher of science Sir Karl Popper to see if some light can be thrown on the origin of this disease. Preliminary studies have shown that the “Popper sequences” provide a powerful method of studying scientific problems such as RA [1]. If the cause of RA can be found, then appropriate steps can be taken in the early stages of the condition so that both medical problems of the patients and financial costs to society can be minimised to the mutual benefits of both groups.

Section snippets

Karl Popper and science

Popper was a great critic of the Baconian myth that all science starts with observations and then slowly and cautiously proceeds to theories. It was the great merit of Popper to point out that “science” starts with “problems”. It is the identification of the “problem” that starts a research worker speculating as to how to arrive at a solution which will throw some light on the puzzle or question he is trying to answer. Without “problems to resolve”, without “puzzles to elucidate” there is no

Popper's scientific method

The Austrian–British philosopher of science, Sir Karl Popper (1902–1994) was born in Vienna, lectured in New Zealand and became Professor at the London School of Economics. He wrote many books including his classical “Logik der Forschung” (1934).

Popper proposed that a scientific theory could not be proved but could be disproved or falsified. The theory that “All tigers are carnivorous” is disproved by the observation of a single vegetarian tiger. Popper proposed a powerful analytical method to

The properties of the problem of RA

To investigate a “scientific problem” it is relevant to note the properties of the problem which define the puzzle or enquiry.

The properties of the RA problem would appear to be the following:

  • (1)

    Sex ratio: RA is found 3–4 times more frequently in women than men.

  • (2)

    Smokers: RA is found more frequently in smokers than non-smokers [5]. However smokers suffer more from urinary tract infections than non-smokers.

  • (3)

    Post-puerperal onset: RA often starts 3–6 weeks after the end of a pregnancy. However urinary

First Popper sequence

The link between RA and human histocompatibility antigens, particularly HLA-DW4 was discovered by Stastny in 1976, using leucocyte cultures obtained from American RA patients [9]. Later this link between class-II HLA antigens was confirmed when HLA-DR4 was demonstrated in English RA patients to be present more frequently than in the general population [10]. It has been described that a majority of RA patients belong either to the HLA-DR4 group in England and the USA or HLA-DR1 in Israel [11].

Therapeutic implications

The probable cause of the onset of RA has been identified through the demonstration of ten “Popper sequences”, each of which provided a new fact about the disease. If any other theory were to be suggested, it would have to account for the “new facts” uncovered by this Popperian analysis.

The accessory properties of the RA problem, such as the link to smokers or onset in the post-puerperal period can be accounted for by the published evidence that smokers have a greater frequency of urinary tract

Conclusions

The aetiopathogenetic mechanism of RA could be explained on the basis of environmental (microbial) triggering, molecular mimicry or cross-reactivity between bacterial and self antigens and the maintenance of the pathological process via autoimmunity. The most likely bacterial candidate is P. mirabilis. These bacteria cause recurrent upper urinary tract infections with the production of considerably sufficient amount of cross-reactive antibodies which could bind and attack the targeted antigens

Take-home messages

  • RA is a common disabling arthritic condition which is most likely caused by upper urinary tract infections with Proteus mirabilis.

  • Scientific data support the linkage between RA, smoking, urinary tract infections, shared epitope HLA haplotype susceptibility, as well as elevated levels of anti-Proteus and anti-CCP antibodies.

  • The aetiopathogenetic mechanism of RA can be explained on the basis of immune-mediated microbial trigger and molecular mimicry using the philosophical method of Karl Popper.

Acknowledgements

This study was supported by the Trustees of the Middlesex Hospital, the Arthritis Research Campaign (EO514) and the “American Friends of King's College London”.

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