The link between Proteus mirabilis, environmental factors and autoantibodies in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a relatively common and potentially disabling immune-mediated inflammatory systemic disease, predominantly affecting women and characterised by multiple small joint arthritis. Extensive data supports the roles of genetic, environmental and microbial factors in the triggering and development of this disease. Proteus mirabilis is considered as the main microbial culprit in the causation of RA. The evidence for the role of these microbes in RA and their links with commonly associated autoantibodies such as rheumatoid factors and anti-citrullinated peptide antibodies have been elucidated together with their relations with some of the non-microbial environmental factors which have been implicated in the aetiopathogenesis of RA. The most likely mechanism in the development of RA is "molecular mimicry" where Proteus antigens were found to share homologous sequences, which cross-react with certain self-antigens present in synovial tissues. This could raise possibilities for implementing a new therapeutic strategy in the treatment of RA.

The Link Between Klebsiella and Ankylosing Spondylitis in Worldwide Geographical Locations.

Ankylosing spondylitis (AS) is a world-wide chronic inflammatory disease of the axial skeleton most likely caused by a microbial factor in genetically susceptible individuals. Over the last 40 years extensive data has been produced which shows that the majority of patients with AS possess the HLA-B27 genetic marker. Significantly elevated levels of Klebsiella antibodies have been demonstrated in 1556 AS patients in 16 different countries with various geographical locations. Other evidence for the link between Klebsiella and AS include increased fecal isolation rates of Klebsiella microbes in AS patients together with shared molecular and immunological cross-reactivity features existing between Klebsiella antigens and HLA-B27 and collagens I, III and IV. Anti-Klebsiella measures could possibly be included with the currently used medical treatment in the management of patients with AS.

Fundamental immunological problems associated with "transmissible spongiform encephalopathies".

"Bovine spongiform encephalopathy", "scrapie", as well as Creutzfeldt-Jakob disease and kuru belong to a group of related neurological conditions termed "transmissible spongiform encephalopathies". These diseases are based on the LD50 measurement whereby saline brain homogenates are injected into experimental animals and when 50% of them develop symptoms, this is considered as transmission of the disease, but the gold standard for diagnosis is autopsy examination. However, an untenable assumption is being made in that saline brain homogenates do not cause tissue damage but it is known since the time of Pasteur, that they give rise to "post-rabies vaccination allergic encephalomyelitis". This is the fundamental flaw in the diagnosis of these diseases. A way forward, however, is to examine infectious agents, such as Acinetobacter which show molecular mimicry with myelin and elevated levels of antibodies to this microbe are found in multiple sclerosis patients and animals affected by "bovine spongiform encephalopathy".

Raised incidence of ankylosing spondylitis among Inuit populations could be due to high HLA-B27 association and starch consumption.

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis mainly affecting the spinal joints. It would appear that the most likely causative agent in the development of AS is an environmental factor in the genetically susceptible, HLA-B27 positive, individuals. Extensive data from several countries support the notion that Klebsiella pneumonia bacteria are the most likely culprit in the causation of AS. These microbes possess antigens which resemble HLA-B27 and spinal collagens. Increased intake of high-starch diet is directly proportional to the gut-associated bacterial load, especially in the large intestine, and among these microbial agents, Klebsiella is considered as one of the main constituting components. Therefore, a low-starch diet intake alongside the currently used medical therapeutic modalities could be beneficial in the management of patients with early AS. It is suggested that a change in the dietary habits from high protein, low-starch marine components to the Westernized high-starch diet among the Inuit peoples of Alaska and Canada could be considered as one of the main contributing factors in the increased prevalence of AS during the last few decades within this genetically unmixed native population.

Rheumatoid arthritis is caused by a Proteus urinary tract infection.

Genetic, molecular and biological studies indicate that rheumatoid arthritis (RA), a severe arthritic disorder affecting approximately 1% of the population in developed countries, is caused by an upper urinary tract infection by the microbe, Proteus mirabilis. Elevated levels of specific antibodies against Proteus bacteria have been reported from 16 different countries. The pathogenetic mechanism involves six stages triggered by cross-reactive autoantibodies evoked by Proteus infection. The causative amino acid sequences of Proteus namely, ESRRAL and IRRET, contain arginine doublets which can be acted upon by peptidyl arginine deiminase thereby explaining the early appearance of anti-citrullinated protein antibodies in patients with RA. Consequently, RA patients should be treated early with anti-Proteus antibiotics as well as biological agents to avoid irreversible joint damages.

The role of Klebsiella in Crohn's disease with a potential for the use of antimicrobial measures.

There is a general consensus that Crohn's disease (CD) develops as the result of immune-mediated tissue damage triggered by infections with intestinal microbial agents. Based on the results of existing microbiological, molecular, and immunological studies, Klebsiella microbe seems to have a key role in the initiation and perpetuation of the pathological damage involving the gut and joint tissues in patients with CD. Six different gastroenterology centres in the UK have reported elevated levels of antibodies to Klebsiella in CD patients. There is a relationship between high intake of starch-containing diet, enhanced growth of gut microbes, and the production of pullulanases by Klebsiella. It is proposed that eradication of these microbes by the use of antibiotics and low starch diet, in addition to the currently used treatment, could help in alleviating or halting the disease process in CD.

The link between ankylosing spondylitis, Crohn's disease, Klebsiella, and starch consumption.

Both ankylosing spondylitis (AS) and Crohn's disease (CD) are chronic and potentially disabling interrelated conditions, which have been included under the group of spondyloarthropathies. The results of a large number of studies support the idea that an enteropathic pathogen, Klebsiella pneumoniae, is the most likely triggering factor involved in the initiation and development of these diseases. Increased starch consumptions by genetically susceptible individuals such as those possessing HLA-B27 allelotypes could trigger the disease in both AS and CD by enhancing the growth and perpetuation of the Klebsiella microbes in the bowel. Exposure to increased levels of these microbes will lead to the production of elevated levels of anti-Klebsiella antibodies as well as autoantibodies against cross-reactive self-antigens with resultant pathological lesions in the bowel and joints. Hence, a decrease of starch-containing products in the daily dietary intake could have a beneficial therapeutic effect on the disease especially when used in conjunction with the currently available medical therapies in the treatment of patients with AS and CD.

The role of Acinetobacter in the pathogenesis of multiple sclerosis examined by using Popper sequences.

Multiple sclerosis (MS) is an autoimmune neurological disorder. The role of 'Acinetobacter' has been examined using the method of Karl Popper and involves nine "Popper sequences". (1) The frequency of MS increases with latitudes in the Northern Hemisphere, and the reverse is found in the Southern Hemisphere. (2) Sinusitis is found frequently at colder latitudes. (3) Sinusitis occurs frequently in patients with MS. (4) Specific sequences of bovine myelin when injected into experimental animals will produce a neurological disorder resembling MS which is called "experimental allergic encephalomyelitis". (5) Computer analysis of myelin shows molecular mimicry with sequences found in Acinetobacter. (6) Antibodies to Acinetobacter bacteria are found in MS patients. (7) Acinetobacter bacteria are located on human skin and in the nasal sinuses. (8) IgA antibodies are preferentially elevated in the sera of MS patients, thereby suggesting the trigger microbe is acting across a mucosal surface probably located in the nasal sinuses. (9) Only Acinetobacter bacteria and no other microbes evoke statistically significant titres of antibodies in MS patients. These nine Popper sequences suggest that MS is most probably caused by infections with Acinetobacter bacteria in the nasal sinuses, and this could have therapeutic implications.

Autoimmunity in Rheumatic Diseases Is Induced by Microbial Infections via Crossreactivity or Molecular Mimicry.

A general consensus supports fundamental roles for both genetic and environmental, mainly microbial, factors in the development of autoimmune diseases. One form of autoimmune rheumatic diseases is confined to a group of nonpyogenic conditions which are usually preceded by or associated with either explicit or occult infections. A previous history of clinical pharyngitis, gastroenteritis/urethritis, or tick-borne skin manifestation can be obtained from patients with rheumatic fever, reactive arthritis, or Lyme disease, respectively, whilst, other rheumatic diseases like rheumatoid arthritis (RA), ankylosing spondylitis (AS), and Crohn's disease (CD) are usually lacking such an association with a noticeable microbial infection. A great amount of data supports the notion that RA is most likely caused by Proteus asymptomatic urinary tract infections, whilst AS and CD are caused by subclinical bowel infections with Klebsiella microbes. Molecular mimicry is the main pathogenetic mechanism that can explain these forms of microbe-disease associations, where the causative microbes can initiate the disease with consequent productions of antibacterial and crossreactive autoantibodies which have a great impact in the propagation and the development of these diseases.

Gut-mediated and HLA-B27-associated arthritis: an emphasis on ankylosing spondylitis and Crohn's disease with a proposal for the use of new treatment.

Ankylosing spondylitis (AS) and Crohn's disease (CD), especially when associated with spondylitis are interrelated conditions included within the categories of spondyloarthropathic disease entities. They share some common clinical, genetic, and microbiological findings. An extensive amount of studies which have been carried out by various independent groups throughout the world have shown that Klebsiella pneumoniae microorganisms could be suggested as the most likely etiopathogenetic triggers for AS and CD based on the molecular mimicry mechanism and the existence of the evidence for immunological, microbiological, and molecular link between Klebsiella and self antigens. It is proposed that the use of low starch diet in conjunction with the currently used treatment might help in the eradication of Klebsiella microbes from the bowel and could result in the stoppage and alleviation of the disease process in patients with AS and/or CD.

Therapy: Gut-mediated autoimmune arthritis treated with antibiotics.

Bacterial infection is known to trigger a number of autoimmune disorders, an observation that indicates a potentially important role for antibiotics in treating these diseases. Indeed, results from an experimental model of autoimmune arthritis in mice suggest that antibiotics can prevent the onset of disease.

Autoimmune diseases: Solution of the environmental, immunological and genetic components with principles for immunotherapy and transplantation.

Autoimmune diseases have environmental and genetic components. These are the microbial trigger, the immunity system component and the genetic component. Here we describe these components and how they interact. Known microbial triggers are Streptococcus pyogenes for rheumatic carditis, Proteus mirabilis for rheumatoid arthritis and Klebsiella pneumoniae for ankylosing spondylitis. The immunity system component has been clarified by realisation that no autoimmune disease is caused by loss of suppressor T cells. This leaves Burnet's forbidden clones, clearly seen in Graves' disease, as the immunological defect. With wide scope for clonal diversification by somatic gene mutations, to prevent frequent autoimmunity the immunity system is policed by the histocompatibility system. This dictates the immune response repertoire by deleting complementary clones (H Gene Theory). We show molecular evidence of how specific histocompatibility antigens can predispose to an autoimmune disease by influencing choice of the microbial antigen to which the immunity system reacts. Because of the unlucky random element in the somatic mutations involved in their development, forbidden clones are unlikely to reappear in new immune repertoires developing after immune ablation and autologous bone marrow cell reconstitution, as observed clinically. Isolation of autoantigens and their attachment to cytotoxic moieties could provide specific immunotherapy for autoimmune diseases. Kaplans's discovery that xenografts can be accepted without rejection after immune ablation followed by autologous and xenogeneic bone marrow inoculation, could enable widespread use of pig grafts for humans.

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

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.

Rheumatoid arthritis is caused by Proteus: the molecular mimicry theory and Karl Popper.

Rheumatoid arthritis is a crippling and disabling joint disease affecting over 20 million people. It occurs predominantly in women and smokers, and affects the HLA-DR1/4 individuals who carry the "shared epitope" of amino acids EQRRAA. The cause of this disease was investigated by the methods of the philosopher of science Karl Popper who suggested that scientific research should be based on bold conjectures and critical refutations. The "Popper sequences" generate new facts which then change or alter the original problem. The new facts must then be explained by any new theory. Using the "molecular mimicry" model, it was found that Proteus bacteria possess an amino acid sequence ESRRAL in haemolysin which resembles the, shared epitope, and another sequence in urease which resembles type XI collagen. Antibodies to Proteus bacteria have been found in 14 different countries. It would appear that rheumatoid arthritis is caused by an upper urinary tract infection by Proteus bacteria. Anti-Proteus therapy should be assessed in the management of this disease separately or in conjunction with existing modalities of therapy.

Role of Klebsiella and collagens in Crohn's disease: a new prospect in the use of low-starch diet.

Crohn's disease is suggested to result from a microbially triggered immune-mediated autoimmune process, involving mainly the terminal ileum and ileo-caecal junction. Klebsiella pneumoniae shares certain molecular structures present in pullulanase pulA and pulD secretion enzymes with various self-antigens present in collagens and HLA-B27 molecules, respectively. A link exists between high dietary starch intake and the growth of intestinal microflora, involving especially Klebsiella microbes. Increased exposure to Klebsiella in the gut as the result of high starch intake would lead to high production of antiKlebsiella antibodies as well as autoantibodies to the cross-reactive self-antigens with the resultant inflammation at the pathological sites. Eradication of these microbes from the gut in patients with Crohn's disease with the use of low-starch diet and antibacterial agents as well as immunomodulatory measures could be beneficial in the management of this disease.

Rheumatoid arthritis in smokers could be linked to Proteus urinary tract infections.

There is an interplay between genetic and environmental factors in the induction and development of rheumatoid arthritis (RA). The RA-associated HLA-DRB1 alleles which contain the shared epitope moiety as well as microbial triggers such as Proteus are involved in the aetiopathogenesis of this disease. Increased association between Proteus urinary tract infections (UTIs) and RA on one hand and the link between smoking and UTIs on the other hand could explain the increased frequency of RA among smokers. Novel therapeutic and prophylactic measures are proposed, which might help to treat and/or prevent the disease process in individuals who are susceptible to develop RA.

B27 disease is a new autoimmune disease that affects millions of people.

"B27 disease" is a new autoimmune disease that afflicts millions of people throughout the world. "B27 disease" occurs in individuals who have ankylosing spondylitis (AS) or preankylosing spondylitis and/or uveitis and are also positive for HLA-B27. Molecular mimicry between the bowel microbe Klebsiella and the HLA-B27 molecule, as well as the spinal collagens types I, III, and IV, indicates a pathological mechanism involving autoimmunity. Antibodies to Klebsiella microbes have been reported in AS patients from 18 different countries. Sera from patients with AS show complement-dependent cytopathic activity against sheep red cells coated with HLA-B27 peptide antigens. Diagnosis of B27 disease can lead to early treatment, involving low-starch diet, sulfasalazine, and immunosuppressive and biological agents so as to prevent the irreversible bony changes of established classical AS. The concept of B27 disease provides a new approach to the study and treatment of these disorders and needs to be evaluated in prospective studies by the world rheumatological community.

Rheumatoid arthritis is linked to Proteus--the evidence.

Rheumatoid arthritis (RA) is a chronic inflammatory arthritic and potentially disabling condition, mainly affecting women of middle age and having characteristic clinical features. Various microbial agents were implicated in the causation of RA. Extensive literature based on the results of various genetic, microbiological, molecular, and immunological studies carried out by independent research groups supports the role of Proteus mirabilis bacteria in the etiopathogenesis of RA. New diagnostic markers and criteria and the use of a novel therapeutic protocol in the form of antibiotic and dietary measures are suggested to be used together with current treatments in the management of RA. Prospective longitudinal studies with the use of antimicrobial measures in patients with RA are required to establish the therapeutic benefit of this microbe-disease association.

Ankylosing spondylitis is linked to Klebsiella--the evidence.

Ankylosing spondylitis (AS) is a chronic inflammatory spinal and large-joint arthritic and potentially disabling condition, mainly affecting males of young age groups. Extensive literature based on the results of various genetic, microbiological, molecular and immunological studies carried out by independent research groups suggests that Klebsiella pneumoniae is the main microbial agent being implicated as a triggering and/or perpetuating factor in the etiopathogenesis of AS. Novel diagnostic markers and criteria based on the association with high anti-Klebsiella antibodies could be used in the detection of AS patients during early stages of the disease, and together with the current treatments might help in implementing the use of new therapeutic anti-microbial measures in the management of AS. Prospective longitudinal studies with the use of anti-microbial measures in patients with AS are required to establish the therapeutic benefit of this microbe-disease association.