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.

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.

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.

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.

A possible link between Crohn's disease and ankylosing spondylitis via Klebsiella infections.

Crohn's disease (CD) is an immune-mediated gastrointestinal inflammatory disease, which could arise from an interplay between genetic and environmental factors. Klebsiella microbes were suggested to have a vital role in the initiation and perpetuation of the disease through the mechanism of molecular mimicry. This proposition is based on the results of various studies where significantly elevated levels of antibodies against the whole bacteria or preparations from Klebsiella microbes and antibodies to collagen types I, III, IV, and V were detected in patients with CD and patients with ankylosing spondylitis (AS). Molecular similarities were found between Klebsiella nitrogenase and HLA-B27 genetic markers and between Klebsiella pullulanase and collagen fibers types I, III, and IV. Furthermore, significantly positive correlations and cross-reactivity binding activities were observed between anti-Klebsiella and anticollagen antibodies among patients with CD and AS. Early treatment of CD patients with anti-Klebsiella measures is proposed, which may involve the use of antibiotics and low starch diet together with other traditionally used immunomodulatory, immunosuppressive, or biologic agents.

From rabies to transmissible spongiform encephalopathies: an immune-mediated microbial trigger involving molecular mimicry could be the answer.

The concept of experimental allergic encephalomyelitis (EAE) being linked to both rabies post-vaccination encephalomyelitis and multiple sclerosis (MS) has raised the intriguing question whether animal studies carried out for the induction and transmission of transmissible spongiform encephalopathies (TSEs) using brain antigens including prions do have a similar immunopathogenetic mechanism. Although an essential link between autoimmunity and MS has been well established, its role in the pathogenesis of TSEs is generally lacking. However, auto-antibodies to myelin proteins and/or other neuronal antigens such as neurofilaments and prion proteins have been reported in animals with bovine spongiform encephalopathy (BSE) and scrapie as well as in patients with Creutzfeld-Jakob disease (CJD) and kuru. Acinetobacter has been suggested as a possible triggering microbial factor in the initiation of the autoimmune responses in these diseases because bacterial molecular sequences resemble brain antigens, especially in animals affected with BSE and patients with MS and CJD. These possibilities need to be evaluated further with longitudinal prospective studies carried out on larger numbers of animals or humans with such diseases. The transplantation of saline suspensions of brain homogenates will evoke immunological responses and therefore, the results in the study of MS and other neurological diseases have to be interpreted with caution.

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.

Acinetobacter immune responses in multiple sclerosis: etiopathogenetic role and its possible use as a diagnostic marker.

Multiple sclerosis (MS) is the most common cause of neurologic disability among young people. The etiology of MS is controversial, but immune responses are considered to somehow be involved. The diagnosis of MS depends on a combination of various clinical and laboratory features, but apart from some myelin-neuronal autoantibody profiles or oligoclonal bands in the cerebrospinal fluid no other serologic diagnostic test or marker has yet been discovered. However, the presence of antibodies to Acinetobacter species in MS patients opens the possibility of developing a composite laboratory diagnostic marker, the myelin-Acinetobacter-neurofilament index. Whether Acinetobacter is the triggering agent of MS remains to be determined, but the measurement of anti-Acinetobacter antibodies could be used as a marker of disease activity. To evaluate this, prospective randomized controlled studies should be performed with MS patients, especially in the early stages of the disease.

Bovine spongiform encephalopathy, multiple sclerosis, and creutzfeldt-jakob disease are probably autoimmune diseases evoked by Acinetobacter bacteria.

Bovine spongiform encephalopathy (BSE) belongs to a group of conditions named together as transmissible spongiform encephalopathies (TSE). They are fatal neurodegenerative diseases that include "scrapie" in sheep, Creutzfeldt-Jakob disease (CJD) and kuru in humans, and chronic wasting disease in deers. BSE-affected animals suffer from "hindquarters" paralysis, which is also one of the main features of "experimental allergic encephalomyelitis" (EAE). EAE is considered an animal model of multiple sclerosis (MS) and lower limb ataxia is often observed in MS patients. The presence of clinical and histopathological similarities in these diseases suggests a common pathology. Specific brain peptides, which produce EAE, were shown to have "molecular mimicry" with the soil and skin saprophytic microbe, Acinetobacter. BSE-affected animals and patients suffering from MS have been found to have elevated levels of antibodies to both Acinetobacter and Pseudomonas bacteria, as well as autoantibodies to both white and gray matter brain components. The hypothesis is proposed that Acinetobacter/Pseudomonas bacteria may have evoked both BSE and MS through the mechanism of "molecular mimicry" and autoimmunity in a similar way to Streptococcus microbes producing rheumatic fever and Sydenham's chorea. The possibility that CJD patients may show similar features remains to be determined.

A possible link between multiple sclerosis and Creutzfeldt-Jakob disease based on clinical, genetic, pathological and immunological evidence involving Acinetobacter bacteria.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the nervous system. There is an increasingly likelihood that MS could be triggered/perpetuated by environmental (microbial) agents. Sporadic Creutzfeldt-Jakob disease (sCJD) is a relatively rare but fatal disease, which shows various clinical, genetic, pathological and immunological features through which it resembles a severe form of MS. The disease in some patients with MS may show a rapidly downhill course with death occurring within one to two years and a similar situation occurs in sCJD. The occurrence of these comparative similarities between MS and sCJD could be explained on the basis that both of these conditions might be sharing a common aetiopathogenic factor such as infection by Acinetobacter microbes and this possibility could be investigated further by carrying out immunological studies on a relatively large numbers of patients with MS and CJD.

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".

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.

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.

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.

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.