Research & Abstracts

Dr Brady discusses the epidemic of autoimmune disorders

Alan Ebringer - a trail blazer who researched the relationship between 
diet, Klebsiella, and Ankylosing Spondylitis

H. pylori and Klebsiella are currently the most likely pathogenic causes for AS based on research to date.

"90% AS patients suffer from Hp infection"

Arthritis Res Ther. 2012; 14(Suppl 1): P74.
Published online Feb 9, 2012. doi:  10.1186/ar3675
Helicobacter pylori infection in rheumatic diseases

Hongyan Wen,1 Jing Luo,1 Junxia Li,1 and Xiaofeng Li1
Author information ? Article notes ? Copyright and License information ?

Due to a number of factors, Helicobacter pylori (Hp) infection is increasingly recognized as highly prevalent in many populations and of increasing health concern. Hp infection has been associated with digestive diseases and rheumatic diseases[1]. It remains unclear whether all or part patients of rheumatic diseases should be routinely screened for Hp infection. We have examined predictors of Hp infection in rheumatic diseases so as to define who might benefit most from screening.

292 patients with rheumatic diseases were recruited through outpatient rheumatology clinics between 2005-2008. The study was approved by the Second Hospital of Shanxi Medical University Ethics Committees, and all participating patients signed an informed consent form. The description of this study is 3-fold: to evaluate the relationship between Hp and rheumatic diseases, to assess the relationship between Hp and rheumatoid arthritis (RA), to explore the relationship between Hp and ankylosing spondylitis (AS).

Patients of rheumatic diseases were significantly more likely to be Hp infection than health control (89 vs 42%, P < 0.01). The study revealed that 88% of RA patients and 90% AS patients suffer from Hp infection. RA patients carried a diagnosis of Hp, a higher prevalence of the value of CRP was associated with the DAS28(Disease Activity Scor-28) (r = 0.287,P = 0.034). AS patients carried a diagnosis of Hp, a higher prevalence of the value of MMP-3(matrix metalloproteinase-3, MMP-3) was associated with the BASDI(Bath AS Disease Activity Index) (r = 0.435,P = 0.009).

Patients of RA and AS are associated with a high prevalence of Hp infection rate. Hp infection may be play an important role in RA and AS.

Next steps
Further investigation with other rheumatic diseases are planned.

PMCID: PMC3332420


"H. pylori showed the highest percentage of positivity in all 3 patient groups (66.7% in the AAU, 73.3% in the SpA and 80% in the AAU+SpA group)" 

"H. pylori affected GI permeability in both SpA and EndG patients...SpA patients taking chronic NSAID had increased gastroduodenal permeability only when H. pylori-positive ...Eradication therapy may help to maintain epithelial barrier function and possibly influence clinical improvement in patients with SpA." 


This study showed Klebsiella having a "modifying factor" reacting with HLA-B27 lymphocytes and other cells. "Pronase and papain destroyed the modifying factor activity whereas trypsin and alpha-chymotrypsin degraded the factor into smaller fragments without destroying its ability to modify B27 AS- lymphocytes."
Hum Immunol 1986 Nov;17(3):224-38
Upfold LI, Sullivan JS, Geczy AF.
Biochemical studies on a factor isolated from Klebsiella K43-BTS1 that cross-reacts with cells from HLA-B27 positive patients with ankylosing spondylitis.

A component of the cell walls of certain enteric bacteria has been identified that cross-reacts with an HLA-B27-associated cell-surface structure on lymphocytes and other cell types from patients with ankylosing spondylitis. This component, or "modifying factor," from one particular organism, Klebsiella K43-BTS1, has been studied in detail. A purification scheme has been developed using preparative electrofocusing and gel-permeation high performance liquid chromatography techniques and the purified material used in various characterization studies. A previous study demonstrated that the modifying factor has an approximate molecular weight of 30,000 and an isoelectric point of 5.4-5.5. In this study two-dimensional gel electrophoresis experiments demonstrated that the modifying factor is associated with a single protein component of the cell wall of this organism. Pronase and papain destroyed the modifying factor activity whereas trypsin and alpha-chymotrypsin degraded the factor into smaller fragments without destroying its ability to modify B27 AS- lymphocytes. Neuraminidase did not affect the modifying factor itself but did affect B27 AS- lymphocytes such that they became unresponsive to modification. Sugar inhibition studies suggested that sugar groups are probably not involved in the function of the modifying factor. The availability of purified modifying factor should permit more detailed chemical analyses as well as functional studies to determine the significance of this molecule to the pathogenesis of ankylosing spondylitis.
PMID: 3539895 [PubMed - indexed for MEDLINE]

Autoantibodies to HLA B27 in the sera of HLA B27 patients with ankylosing spondylitis and Reiter's syndrome. Molecular mimicry with Klebsiella pneumoniae as potential mechanism of autoimmune disease.

Schwimmbeck et al. 166 (1): 173
Published July 1, 1987 // JEM vol. 166 no. 1 173-181
The Rockefeller University Press, doi: 10.1084/jem.166.1.173

P L Schwimmbeck, D T Yu, and M B Oldstone

Ankylosing spondylitis (AS) and Reiter's syndrome (RS) both show a strong correlation with the HLA B27 haplotype. We studied whether sharing of homologous amino acid sequences in the HLA B27 antigen with an invading microbe might occur, and if so, what is the biological significance of such homology. In a computer search of the Dayhoff data bank, we found a homology of six consecutive amino acids between HLA B27.1 antigen residues 72-77 and Klebsiella pneumoniae nitrogenase residues 188-193. These shared sequences are hydrophilic, suggesting locations on molecules exposed to the cell surface. Immunochemical analysis showed that 18 of 34 sera from patients with RS (53%) and 7 of 24 sera from patients with AS (29%) contained antibodies that bound to a synthesized peptide sequence representing residues 69-84 of HLA B27.1. In contrast, only 1 of 22 sera from healthy, B27+ controls (5%) contained antibodies to this peptide (p less than 0.01). Sera from three HLA B27- patients with RS did not possess antibodies to the HLA B27 peptide. Additionally, greater than 40% of HLA B27 patients with AS or RS had antibodies to Klebsiella residues 184-193, while none of the normal nonarthritic HLA B27 haplotype subjects did. Our results suggest that an autoimmune response(s) directed against HLA B27.1 may be a pathogenic mechanism in a subset of patients with AS and RS. Further, this response may initially be induced against Klebsiella pneumoniae, a microorganism that shares sequence homology with HLA B27.


Mouse studies show evidence that AS is initiated by a common pathogen :
"The disease occurs primarily in males, and requires the presence of gut enterobacteria or other exogenous factor(s) because mice born in a pathogen-free environment stay healthy and only develop the disorder after they are removed from the pathogen-free environment to a conventional facility. Inflammation of the joints in these animals requires the CD4( ) T-cells, whereas development of nail changes is independent of such cells. The disease can be prevented by injection of an antibody specific against the free heavy chain of B27 prior to their leaving the germ-free environment. "

The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats

Journal of Experimental Medicine, Vol 180, 2359-2364
JD Taurog, JA Richardson, JT Croft, WA Simmons, M Zhou, JL Fernandez-Sueiro, E Balish and RE Hammer
Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235.

A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.


Cross-reacting bacterial determinants in ankylosing spondylitis

Am J Med. 1988 Dec 23;85(6A):54-5.

Sullivan JS, Prendergast JK, Geczy AF, Edmonds JP, McGuigan LE, Edwards CM.
New South Wales Red Cross Blood Transfusion Service, Sydney, Australia.

The importance of the association between the human histocompatibility antigen human leukocyte antigen-B27 and ankylosing spondylitis is undisputed, but its biologic significance remains unresolved. We have demonstrated specific cross reactivity between a range of enteric bacteria and a specific determinant found only on the surfaces of cells from human leukocyte antigen-B27-positive persons with ankylosing spondylitis. We have proposed that the genetic element coding for this cross-reactive determinant is mobile and that its acquisition by B27-positive cells in vivo represents an important step in the eventual development of ankylosing spondylitis.

Publication Types:
* Review
* Review, Tutorial

PMID: 2462351 [PubMed - indexed for MEDLINE]

Full Text available here:
Grouped caging predisposes male mice to ankylosing enthesopathy


Annals of the Rheumatic Diseases, 1996, Vol 55, 645-647
S Weinreich, J Capkova, B Hoebe-Hewryk, C Boog and P Ivanyi
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam.

OBJECTIVE: To evaluate the number of males per cage as a possible risk factor for murine ankylosing enthesopathy (ANKENT)--a spontaneous joint disease with parallels to human seronegative spondylarthropathies-- since ANKENT shows incomplete penetrance of genetic susceptibility factors among individuals living in a stable environment. METHODS: Frequency of ANKENT was compared among males housed with females, with other males, or alone. RESULTS: In three independent cohorts, a trend was observed that males housed with females rarely develop the disease, in contrast to males housed with other males (P < 0.25, P < 0.05, and P < 0.01). Furthermore, no males caged alone developed ANKENT, whereas disease did occur in males grouped together (P < 0.01). When healthy males (retired breeders) were recaged either alone or with other males, ANKENT developed among the grouped males only (P < 0.005). CONCLUSIONS: Caging males together is a relative risk factor for ANKENT. Grouped caging may perturb the immune system through endocrine pathways or modify microbiological load through behaviour (for example, infection due to biting).
Ankylosing spondylitis and infections of the female urogenital tract.
Rheumatol Int. 1998;17(5):181-4.

Lange U, Berliner M, Ludwig M, Schiefer HG, Teichmann J, Weidner W, Schmidt KL.
Department of Rheumatology/University Giessen, Bad Nauheim, Germany.

Thirty-two female patients with confirmed ankylosing spondylitis (AS) and 33 women of similar age with pure ileitis terminalis Crohn were examined for genitourinary infection. Urethral syndrome was found in 15 out of 32 patients with AS: 11 of them had urethritis and 4 urethritis associated with vaginitis. Five women of the control group suffered from urethritis. In all cases with genitourinary infection, Chlamydia trachomatis was isolated. By comparing the AS-patients (urogenital infection group and the non-infected group) with regard to other present clinical parameters, it was found, as expected, that the erythrocyte sedimentation rate in the 1st hour was significantly higher in the infected group. In addition, the infected patients had a significantly higher incidence of enthesopathy, involvement of the spinal column, and higher C-reactive protein values (CRP > or = 5 mg/l). A family history of AS was equally present. Other clinical parameters, such as inflammatory involvement of the joints and HLA-B27 correlation, did not differ significantly between infected and non-infected patients.

PMID: 9542778 [PubMed - indexed for MEDLINE]

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