Li Zhanga, Yan-Jie Zhangb, Jin Chenc, Xiao-Lei Huangb, Gong-Si Fangc, Li-Juan Yangb, Yu Duanb, Jing Wangb
Medical Genetics Center, Anhui Medical College, Hefei, China
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China c Department of Clinical Laboratory Science, Anhui Medical College, Hefei, China
Published: 8th February 2018
Abstract:
“Ankylosing spondylitis (AS) is a chronic inflammatory arthritis of unknown origin. Its autoimmune origin has been suggested but never proven. Several reports have implicated K. pneumoniae as a triggering or perpetuating factor in AS; and the HLA-B27 antigen has also been found in association with AS.
But there is no satisfactory explanation of why the presence of HLA-B27 predisposes to AS and the precise role played by K. pneumoniae in the disease has not yet been clarified. However, various studies have shown that the results of molecular, immunological, and microbiological studies could establish the link between K. pneumoniae infections and HLA-B27 in the aetiopathogenesis of AS.
In this review, we have examined the evidence linking the interaction between K. pneumoniae infections and HLA-B27 in AS, and tried to exploit the possible mechanisms by which K. pneumoniae infections might induce pathologic processes to develop novel diagnostic criteria. Finally, we have also summarized some dietary regimens that could be helpful in the therapeutic management of AS patients.”
Introduction:
“Ankylosing spondylitis (AS) is a chronic inflammatory polyarthritis of spinal and large synovial joints predominantly affecting males between 20 and 30 years of age, and with a prevalence that ranges from 0.1 to 1.4% worldwide.
The characteristic clinical presentation of AS is low back pain associated with morning stiffness, characteristically eased with exercise, and a positive genetic marker but negative rheumatoid factor…
… Involvement of the gastrointestinal tract in the pathogenesis of SpA is strongly suggested because subclinical gut inflammation is present in up to 60% of patients with SpA. And SpA- associated gut inflammation has been demonstrated to be an important prognostic factor in SpA because it is associated with more extensive bone marrow edema of the sacroiliac joints and a higher risk of progression to AS…
… Moreover, T cell epitope mimicry between microbial pathogens and self-proteins has been implicated as a possible factor in the induction or exacerbation of various autoimmune diseases.
K. pneumoniae, a bacterium often present as part of the normal gut flora, but on occasions behaving as an opportunistic pathogen, which was first implicated in the etiology of the autoimmune disease AS and has been suggested to be an exacerbating agent for AS…
… It has been suggested that immune responses against the specific K. pneumoniae serotypes K26, K36, and K50 are clinically important as these serotypes evoked higher antibody levels in HLA-B27-postive AS patients, com- pared with all other K. pneumoniae serotypes.
Others have found that K2, being prevalent in the UK, may also be clinically relevant in AS patients.
The association between ankylosing spondylitis and K. pneumoniae has been intensively investigated, with conflicting results.
The initial association of K. pneumoniae to AS was that the patients were found to have an increased incidence of this organism in their stools. Ebringer et al. demonstrated increased faecal carriage of K. pneumoniae in active disease and subsequent studies of this question were supportive, and sequential studies showed that positive results for cultures for K. pneumoniae in patients with inactive disease were associated with subsequent development of the active form.
Others, however, found no correlation between the faecal carriage of K. pneumoniae and disease activity. Although these controversial epidemiological evidences exist for the relationship between microbial infections and AS, so far no other microbes apart from K. pneumoniae have been shown to have a significant etiopathogenetic role in the development of AS.
Therefore, based on numerous reports of elevated levels of antibodies against K. pneumoniae in AS patients compared to patients with other diseases or to healthy individuals, AS is thought most likely to be due to the interplay of genetic determinants and K. pneumoniae infection…
The aim of this review is two-fold: first, to critically discuss the potential inflammatory role of bacteria in AS and to stress the gaps in literature as well as the clinical and scientific perspectives in the field; second, to summarize some dietary regimens that could be helpful in the therapeutic management of AS patients.”
The link between K. pneumoniae and HLA-B27 in AS
“In 1973, a very strong association between the HLA antigen B27 (HLA-B*27) and ankylosing spondylitis was first reported in the journal Nature on March 9, 1973, by Caffrey and James and later by Schlosstein et al. [26]. This particular tissue antigen occurs in 6–8% of a normal white population, but is present in over 90% of patients with ankylosing spondylitis…
… the sites of predominant joint inflammation in AS are the sacroiliac joints and lumbar spine, and these are closely related to the lymphatic drainage of the pelvic floor and lower gastrointestinal tract.
Therefore, AS is produced by an infectious agent in the colon, carrying antigens partially cross-reacting with HLA-B27, which stimulate the formation of cross-reactive antibodies, reacting with tissue specific antigens found in the spine, sacroiliac joints and uvea.”
Gene Theory:
“There are two main gene theories have been proposed to explain this association.
The first is the one-gene theory or cross-tolerance hypothesis, which states that the B27 gene codes for an HLA molecule that stereochemically resembles antigens found in some microorganisms. Infection by such microorganisms might lead to the production of cross-reactive auto-antibodies which could be responsible for the tissue damage occurring in AS.
The another is the point is a two- gene theory or linkage disequilibrium hypothesis, which states that there is a separate susceptibility gene, closely linked with HLA- B27, whose gene product is somehow associated with the development of the AS. These disease susceptibility genes, also called “Immune Response (IR) genes” are said to code for the body’s immune reaction to specific antigens.
These IR genes are postulated to reside on the sixth chromosome and closely proximity to HLA genes. A defect in these genes results in a defect in the immune reaction to a particular antigen and, thus, a built-in susceptibility to ankylosing spondylitis.”
Receptor Theory:
“The HLA molecule is a glycoprotein and therefore it is not inconceivable that there may be structural and antigenic similarities between HLA and bacterial cell products.
These cell surface antigens can act as receptors for viruses or toxins and, thus, a patient who possesses certain antigens is susceptible to viral infections or the effects of certain bacterial toxins.
In addition, other antigens in bacterial cell wall, the membrane protein and the lipopolysaccharide (LPS), have also been studied in AS patients even though structural similarity between these components of the cell wall and HLA-B27 has not been indicated.
Cross-reactions between klebsiella and HLA-B27 antigen or ligand receptor interactions between bacterial antigens and HLA-B27 have been found by some workers.
In addition, cross reactions with bacterial antigens were also found with the monoclonal antibodies against B27 (B27M1 and B27M2). K. pneumoniae antigens may specifically modify HLA-B27 or a hypothetical B27 associated receptor, an immune response elicited by infection with such bacteria would then cross react with itself, the resulting tissue damage and clinical symptoms are caused by cytolytic attack against the infecting organism, which could then increase the susceptibility of the subject to develop the disease.
On the other hand, the receptor theory also postulates that the T-cell receptor can recognises foreign or self peptides, 8–20 amino acids in length, in association with class I or class II MHC molecules forming a trimolecular complex.
The HLA-DR1/ DR4 binding groove could present a peptide of arthritogenic origin to T cells, which may be similar to a foreign peptide bound to an HLA molecule. HLA-B27 may also have structural features that, though unique among HLA molecules, are shared with bacteria. Thus, the T-cell response is restricted by HLA molecules.”
Molecular Mimicry:
“There have been a large body of evidence based on genetic, microbiological, molecular and immunological studies suggests that K. pneumoniae is the main microbial agent implicated in the aetiopathogenesis of AS, as a triggering and/or a perpetuating factor, possibly through a mechanism of molecular mimicry with self-antigens.
Molecular mimicry, which was first proposed by Ebringer et al. group in 1976, when it was shown that several human proteins or gram- negative micro-organisms, such as K. pneumoniae, carry antigens that cross-react with HLA-B27.
K. pneumoniae microbes possess a powerful debranching enzyme, pullulanase (pulA), which is a molecular complex consisting of 17 components, some of these molecules sharing similarities with certain genetic and somatic molecules in the body and exhibiting molecular mimicry with several collagens.
pulA cross-reacts with collagens I, III and IV whereas pulD secretion protein crossreacts with HLA- B27 and myosin.
The molecular mimicry theory suggests that disease is caused by antigenic components of micro-organisms which partially resemble or cross-react with HLA molecules. This ‘molecular mimicry’ hypothesis is based on a number of homologous amino acid sequences between HLA and other molecules and on data which describe cross reactions between HLA and bacterial antigens…”
Dietary Regimens for AS patients:
“Glucocorticoids and immunosuppressive drugs are the cornerstone of the treatment for autoimmune rheumatic diseases. Yet, these medications may not be fully effective in hampering the progression of disabilities.
Moreover, the long-term use of these drugs has been associated with several deleterious effects, including bone and muscle mass wasting and cardiovascular dysfunction.
In recent years, a large amount of data have indicated that the importance of the diet in establishing the composition and metabolome of the human intestinal microbiome. On the one hand, consumption of various nutrients affects the structure of the microbial community and provides substrates for microbial metabolism.
On the other hand, the co-evolution of humans and our intestinal microbiota has led to our inter-dependent, mutualistic relationship. For example, indigestible carbohydrates in the diet are fermented by the intestinal microbiota to produce short-chain fatty acids, which regulate immune function, and intestinal hormone production.
Due to the gastrointestinal tract is both the largest endocrine and immune organ in the entire body, thus, it is tempting for scientists trying to use diet therapy against the intestinal microbiome to prevent and/or treat diseases. Further therapeutic stra- tegies could include alterations in diet and/or the composition of the intestinal microbiota to increase bacterial fermentation to resist intestinal inflammation.
A study carried out by a group from LosAngeles had shown that the mean number of faecal K. pneumoniae concentrations in individuals taking high carbohydrate/low protein diet was 40 times higher than in those having low carbohydrate/high protein diet.
It is suggested that a low-starch diet will help in decreasing the disease activity and halt the progression of the disease process in AS and possibly other disease entities of spondyloarthritides (SpAs) as the result of reduction in the bulk of microbial load in the bowel.
This interesting finding indicate that low starch diet intake might have a beneficial effect in the management of patients with AS.
In addition to the currently used anti-inflammatory and immunomodulating drugs, inclusion of low-starch diet with or without the use of antibiotics in the management of AS patients have been might be beneficial in controlling the disease progress or at least prevent the occurrence of exacerbation bouts.
Various other dietary measures have also been tried in patients with autoimmune disease, these dietary regimens involved the introduction of elemental diet and/ or the use of personal exclusion diet, especially of the sugar-containing foods and dairy products.
These forms of manipulative nutritional measures also including the use of low-starch diet are all likely to suppress the microbial load in the gut and hence reducing the anti- bacterial immune responses, alleviating the inflammatory activity status and preventing further damages at the pathological sites in the intestinal tract in patients with AS.
In conclusion, we suggest that patients with AS should be re- commended to take low-starch foods together with other currently used medical therapies as soon as the diagnosis is established and if possible stick to it throughout the disease course.”
Conclusions:
“The results of the present study suggest that in patients with ankylosing spondylitis:
(1) The development of ankylosing spondylitis appears to be related to the presence of K. pneumoniae aerogenes in the gastrointestinal tract.
(2) AS is a chronic inflammatory disease of un- known aetiology in which immunogenetic and environmental factors are involved. Immunogenetic factors are clearly represented by AS strong association to HLA-B27 and the environment by the possible role of K. pneumoniae.
(3) AS can be considered as a reactive arthritis following K. pneumoniae infection in HLA-B27 positive patients, based on consistent findings of raised anti-K. pneumoniae antibodies and the presence of molecular mimicry between the HLA-B27 molecule and bacterial antigens.
(4) Low starch diet intake might have a beneficial effect in the management of patients with AS and these patients should be recommended to take low-starch foods together with other currently used medical therapies as soon as the diagnosis is established.
However, there are many open questions still remaining on the matter, e.g. whether the increased antibody levels in AS reflect a K. pneumoniae infection, or whether they reflect some other inflammatory disorder, as antibody levels were increased also against E. coli.
The pathogenesis of AS is closely associated with HLA-B27, and the re- lationship between AS and bacterial infections has been explained by gene theory, receptor theory and molecular similarity in amino acid sequence between HLA-B27 and bacterial proteins.”
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