Studies That Show the Link Between Ankylosing Spondylitis and Klebsiella p.

In addition to genetic factors, environmental factors (such as infection by bacteria, viruses or parasites) are thought to play a major role in the development of autoimmune diseases.  Autoimmunity occurs when the immune system attacks its own host tissue.  There is much evidence linking many different infectious agents to various autoimmune diseases.  As the body develops antibodies against the pathogen, those same antibodies also mistakenly attack tissue in the body that resembles the pathogen.  In what way does the tissue resemble the pathogen?  The pathogen may carry elements that are similar in amino acid sequence or in structure.   
Some examples of autoimmune diseases linked to infectious agents include, but are not limited to:
Myocarditis- This is a condition that causes inflammation of the heart.  The most common cause is infection by Coxsackievirus B (CVB), a virus.  
Sydenham Chorea and Tourette's Syndrome- Infection with Streptococcus pyogenes, a bacteria, can also lead to inflammation of the heart, as immunity against the bacteria leads to damage to the organ.  Infection with this bacteria has also been linked to Sydenham chorea and Tourette's syndrome. Patients with these disorders often have autoantibodies that damage the basal ganglia in the brain.
Chagas disease- This condition is caused by infection with the protozoan parasite T. cruzi. 10–30% of infected individuals develop the disease.  Although the chronic phase usually affects the heart, a subset of patients develop motor dysfunction of the gastrointestinal tract, essentially through the immune system's destruction of neurons of the enteric nervous system (the nervous system that governs the function of the G.I. tract).
Lyme disease- This disease is caused by the tick-borne spirochete Borrelia burgdorfeii (Bb). Sixty percent of untreated patients develop arthritis that can last for several years, mainly in large joints.  A subset of patients will progress from acute to chronic arthritis despite treatment with antibiotics.  There are several rodent models in which arthritis is induced upon infection with Bb.
 
Herpetic stromal keratitis (HSK)- It is caused by corneal infection by herpes simplex virus (HSV) and can lead to blindness.  The symptoms of HSK can be alleviated with immunosuppressive drugs,  confirming that HSK is an autoimmune disease.
 
Guillain–Barré syndrome (GBS)- This disease is a paralytic illness shown to be caused by autoantibodies to pathogens. Although several microorganisms have been associated with GBS development, Campylobacter jejuni is the most extensively studied pathogen.
Multiple sclerosis (MS)- This condition also has autoimmune implications. In total, more than 24 viral agents have been linked to MS.
(The role of Infections in Autoimmune Disease.  A M Ercolini, S D Miller. Clin Exp Immunol. 2009 Jan; 155(1): 1–15.  doi: 10.1111/j.1365-2249.2008.03834.x)
Reactive Arthritis- This type of painful arthritis is another autoimmune condition that follows an infection in the urinary tract, genitals, or intestinal tract The offending bacteria are: Campylobacter, Salmonella, Shigella and Yersinia, Chlamydia and Clostridium Difficile.

 

Ankylosing Spondylits-  Infection has also long been suspected, since the 1950's, in the development of Ankylosing Spondylitis, although the specific bacteria was unknown at that time. It was in the 1970's when the gram negative pathogen Klebsiella p. was implicated in the disease process, and since that time a large body of evidence has linked this microbe to Ankylosing Spondylitis, as well as to Crohn's Disease.  

In one particular study published in "Current Rheumatology Reviews" in 2006 called "Ankylosing Spondylitis, HLA-B27 and Klebsiella – An Overview: Proposal For Early Diagnosis and Treatment", it mentions that a total of 24 studies carried out on 1330 AS patients and 1191 healthy controls involving 15 different countries showed significantly elevated Klebsiella antibodies in AS patients when compared to controls. These antibody observations were demonstrated by independent groups, using a number of different immunological methods and coming from many countries throughout the world.
 
Rats with the HLA-B27 gene that were raised in germ-free environments do not develop AS.  When transferred to a environment that is not germ-free, they developed the condition.  This is strong evidence that a pathogen plays an important role in the development of the disease, thus requiring an environmental "trigger" in addition to being genetically susceptible.    Also supporting this fact is that studies have shown when one identical human twin has Ankylosing Spondylitis, the other twin also has the disease in only 35%-75% of the time, thus proving that there is more than just a genetic factor at play.
It is important to note that the elevated antibodies against Klebsiella were only found in AS patients who were experiencing active flare ups of disease activity, as defined by using the “Bath AS Disease Activity Index” (BASDAI), especially when used in conjunction with increased levels of Erythrocyte Sedimentation Rates (ESR’s or Sed rates) and C-reactive protein (CRP) measurements. The elevated antibodies were not found in AS patients who were not actively inflamed.  Therefore, it was not surprising when another study conducted in Canada failed to find a correlation between AS patients and elevated Klebsiella antibody levels, as the disease activity status was not even taken into consideration or documented.
The study goes on to explain that there are also similarities between Klebsiella and the collagen tissues of the human body.  Thus, when the immune system forms antibodies against Klebsiella, it also mistakenly attacks the collagen through a process called "moleculary mimicry", specifically type I, type III, IV and type V collagens.  It just so happens that these types of collagens are found in the tendons, spine, large joints and uvea, the very sights of inflammation involved in AS.  In fact, both patients with AS as well as patients with Crohn's disease were found to have these elevated levels of Klebsiella antibodies to type I, III, IV and V collagens. 
This suggests a possible therapeutic intervention.  If the Klebsiella microbe could be somehow reduced in quantity or even eliminated, it might be of benefit to AS patients. Since Klebsiella requires dietary starch as a nutrient to grow, the study concludes that eliminating starch from one's diet could reduce the activity of the disease.
What about patients who are HLA-B27 negative?  While definitely the minority of Ankylosing Spondylitis patients are HLA-B27 negative, this is still a valid question.  Perhaps, however, the question should be re-worded as "what about patients who tested AT ONE TIME to be HLA-B27 negative?"  The reason for this clarification is because some doctors, including Doctor Alan Ebringer of London England, found that a large percentage of the patients who came to him stating that they previously tested as HLA-B27 negative were actually found to be HLA-B27 positive upon re-testing.  So, the test is obviously not 100% accurate. 
 
For those who are, indeed, genuinely HLA-B27 negative, whether Klebsiella is involved in this group is at this time unclear.   Still, since the vast majority of AS patients are indeed HLA-B27 positive, the Klebsiella connection and the subsequent therapeutic intervention by diet modification and elimination of starch in the diet, is an exciting and relevant discovery.
You Can Download This Study on Ankylosing Spondylitis, HLA-B27 and Klebsiella HERE.
In addition, another study published in 2017 called "Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are Present in Ankylosing Spondylitis" confirmed that the presence of antibodies against Klebsiella were detected in 88 out of 100 patients with AS, but not in healthy control donors.  This is a marker that is present, then, in a large percentage of patients with AS and could be a useful biomarker that could help in the diagnosis and monitoring of disease activity in patients. 
 
In addition to antibodies against Klebsiella, autoantibodies were also discovered in AS patients.  Autoantibodies are antibodies that the body creates against itself.  These types of antibodies are present in autoimmune diseases. 
 
So far, up until now the specific identification of particular autoantibodies in the AS patient have not been accepted  among some in the medical field, leading to the theory that AS might be an auto-inflammatory disease, rather than an autoimmune disease.  However, this study proves and confirms the previously identified antibody reaction detected in the vast majority of patients with Ankylosing Spondylitis, supporting the conclusion that Ankylosing Spondylitis fits the criteria for an autoimmune disease.  
REFERENCES:
The Link between Ankylosing Spondylitis, Crohn’s Disease, Klebsiella, and Starch Consumption.  Taha Rashid, Clyde Wilson, Alan Ebringer. Clin Dev Immunol. 2013; 2013: 872632. Published online 2013 May 27. doi: 10.1155/2013/872632
Bacterial antibodies in ankylosing spondylitis.  Mäki-Ikola O1, Lehtinen K, Granfors K, Vainionpää R, Toivanen P.  Clin Exp Immunol. 1991 Jun;84(3):472-5.
Molecular mimicry and ankylosing spondylitis: possible role of a novel sequence in pullulanase of Klebsiella pneumoniae.
M Fielder, SJ Pirt, I Tarpey, C Wilson, P Cunningham, C Ettelaie, A Binder, S Bansal and A Ebringer. FEBS Letters 1995, 369: 243-248.
Crossreactivity between Klebsiella aerogenes species and B27 lymphocyte antigens as an aetiological factor in ankylosing spondylitis. A Ebringer, P Cowling, N Ngwa Suh, DCO James and RW Ebringer In “HLA and Disease”, Ed. Dausset and Svejgaard. Editions INSERM (Paris), 1976, 58: 27. (June 1976)
Ankylosing spondylitis: Klebsiella and HLA-B27.  RW Ebringer, D Cooke, DR Cawdell, P Cowling and A Ebringer Rheumatology & Rehabilitation 1977, 16: 190-196.
Ankylosing spondylitis, HLA-B27 and Klebsiella. II. Crossreactivity studies with human tissue typing sera.  H Avakian, J Welsh,A Ebringer and C Entwistle.  British Journal of Experimental Pathology 1980, 61: 92-96.
IgA antibodies in ankylosing spondylitis. AK Trull,R Ebringer,GS Panayi,D Colthorpe,A Ebringer and DCO James. Scandinavian Journal of Rheumatology 1983, 12: 249-253.
Etiopathogenesis of ankylosing spondylitis and the crosstolerance hypothesis.  A Ebringer, M Baines, M Childerstone, M Ghuloom and T taszynska.  In: “Spondyloarthropathies.” Edited by M Ziff and SB Cohen. Raven Press.  New York. Advances in Inflammation Research 1985, 9: 101-128.
Klebsiella antibodies in ankylosing spondylitis and Proteus antibodies in rheumatoid arthritis.  A Ebringer, NL Cox, I Abuljadayel, M Ghuloom, S Khalafpour, T Ptaszynska,  F Shodjai-Moradi and C Wilson.  British Journal of Rheumatology 1988, 27: (Suppl.2) 72-85.
Ankylosing spondylitis and Klebsiella-reactive arthritis.  A Ebringer.  Journal of Orthopaedic Rheumatology 1988, 1: 243-250.
Crohn’s disease may be linked to Klebsiella.  A.Ebringer and T.Rashid Clinical Rheumatology 2007; 26: 289-297.

Other Studies: