Kickas.org Forums Ankylosing Spondylitis General Discussion #1 AS Web Support Group Potential cause of arthritis found

J.- Thanks. J.



The great tragedy of science, the slaying of a beautiful theory by an ugly fact. -- Thomas Henry Huxley

Further argument that the genetics of ankylosing spondylitis is beyond HLA-B27:

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1: Arthritis Rheum 1998 Apr;41(4):588-95

A genome-wide screen for susceptibility loci in ankylosing spondylitis.

Brown MA, Pile KD, Kennedy LG, Campbell D, Andrew L, March R, Shatford JL, Weeks DE, Calin A, Wordsworth BP.

Wellcome Trust Centre for Human Genetics, Headington, UK.

OBJECTIVE: To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS).

METHODS: One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis.

RESULTS: When only the MRC set was considered, 11 markers in 7 regions achieved a P value of < or =0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10(-5)) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10(-9)). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422.

CONCLUSION: The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.

PMID: 9550467] [PubMed - indexed for MEDLINE]
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Best regards,

jcwinnie

Psoriasis Expert Named to National Academic Collaboration To Study Immune-Mediated Inflammatory Disorders

Alice Gottlieb, M.D., Ph.D., a nationally recognized expert in the development of biotechnological treatments for psoriasis at the University of Medicine and Dentistry of New Jersey (UMDNJ), has been named to a newly established prestigious academic collaboration studying a wide range of immunologic disorders.

The National Immune-Mediated Inflammatory Disorders (I.M.I.D.) Academic Platform, a collaboration of scientists and physicians from 19 leading universities and hospitals across the country, is being launched at the annual meeting of the Federation of Clinical Immunology Societies (FOCIS) in San Francisco on June 28. The Academic Platform is dedicated to the research, diagnosis, and treatment of I.M.I.D.- a group of disorders related by involvement of the immune system, including rheumatoid arthritis, Crohn's disease, multiple sclerosis, psoriasis, and asthma - that share common inflammatory pathways.

Dr. Gottlieb, a board certified specialist in internal medicine, rheumatology, and dermatology, holds the William H. Conzen Chair in Clinical Pharmacology at the University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School and is the director of its Clinical Research Center. Both a practicing dermatologist and a research scientist, she is both a professor of medicine and of molecular genetics, microbiology and immunology.

Her research over the past two decades on the pathophysiology of psoriasis has led to a new understanding of the disease. She was among the first to demonstrate that psoriasis is a T cell-mediated immune disorder and her most recent work has shown that treatment with immunobiologics targeting Tumor Necrosis Factor-alpha (Infliximab and Etanercept) clear psoriasis clinically and histologically. (my emphasis)

I.M.I.D. is characterized by immune disregulation that results in acute or chronic inflammation, causing injury to the body. Injury can include organ damage, increased morbidity, or mortality. One underlying manifestation of this immune disregulation is the inappropriate activation of inflammatory cytokines, such as IL 12, IL 6 or TNF, whose actions lead to pathological consequences.

"Launching the Academic Platform at the FOCIS meeting will allow experts from a variety of medical disciplines to share their experiences treating I.M.I.D. and will provide opportunities for meaningful research collaborations," said C. Garrison Fathman, M.D., Stanford University School of Medicine and FOCIS program co-chair of the Platform committee meeting. "The work that the Academic Platform will do to advance the study of I.M.I.D. holds enormous potential for the progression of basic science, clinical research and improved patient care that will likely impact patients' quality of life.

"While it is not often discussed, I.M.I.D. is widespread and has a significant impact on patients and the national healthcare system," Dr. Fathman said. "In fact, one in four patients admitted to hospitals across the country suffers from some form of immune-mediated inflammatory condition."

FOCIS has defined I.M.I.D. as a subspecialty, representing no single organ system or disease, but rather a pathophysiological concept that unifies the field of clinical immunology including, immunoregulation, immunodiagnosis, immunogenetics and immunotherapy.

"As we move ahead into the 21st century of medicine, the immunologist will play an increasingly important part not only in conducting I.M.I.D. research, but in diagnosing and treating patients with I.M.I.D.," said David Hafler, M.D., Harvard Medical School professor of neurology at Brigham and Women's Hospital and FOCIS co-chair. "I believe there will be a significant need for immunologists whose expertise in I.M.I.D. can potentially shape how medicine is practiced that crosses clinical specialties."

In addition to Drs. Gottlieb, Fathman and Hafler, scientists and clinicians representing 16 academic institutions have been appointed to the platform committee including Baylor College of Medicine, Cleveland Clinic Foundation, Dartmouth-Hitchcock Medical Center, David Geffen School of Medicine at UCLA, Duke University Medical Center, Feinberg School of Medicine at Northwestern University, Johns Hopkins University, Mayo Clinic, University of Alabama at Birmingham, University of Arizona College of Medicine, University of Colorado Health Sciences Center, University of Iowa College of Medicine, University of Florida College of Medicine, University of Pennsylvania School of Medicine, the University of Pittsburgh School of Medicine, and Washington University School of Medicine in St. Louis

The National Immune-Mediated Inflammatory Disorders Academic Platform is supported by an unrestricted educational grant from Centocor, Inc.
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© Copyright 2002 UMDNJ

Source:http://www.umdnj.edu/homeweb/newsroom/releases/r020703_imid.htm

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Best regards,

jcwinnie

1: Am J Pathol 2001 Mar;158(3):1101-9

Monocyte/macrophage activation by normal bacteria and bacterial products: implications for altered epithelial function in Crohn's disease.

Zareie M, Singh PK, Irvine EJ, Sherman PM, McKay DM, Perdue MH.

Intestinal Disease Research Program, McMaster University, 1200 Main St. West, Hamilton, Ontario, L8N 3Z5, Canada.

Intestinal immune cells are less reactive than those in the peripheral blood; however, such cells from patients with Crohn's disease may be more responsive to bacterial products. Our study examined if nonpathogenic bacteria or lipopolysaccharide (LPS), can affect epithelial function in the presence of monocytes/macrophages. Lamina propria mononuclear cells (LPMCs) and peripheral blood monocytes (PBMs) were obtained from patients with Crohn's disease and control patients. Filter-grown T84 epithelial monolayers were co-cultured with nonactivated or LPS-activated LPMCs or PBMs for 48 hours. Epithelial secretory [baseline short-circuit current (Isc) and DeltaIsc to forskolin] and barrier (transepithelial electrical resistance) parameters were measured in Ussing chambers. LPS-activated PBMs from both controls and patients with Crohn's disease significantly increased Isc ( approximately 300%) and reduced transepithelial electrical resistance ( approximately 40%). Epithelial function was not altered after co-culture with control LPMCs +/- LPS. However, LPMCs from patients with Crohn's disease spontaneously secreted tumor necrosis factor-alpha, and induced epithelial changes similar to those produced by LPS-activated PBMs. Co-culture with control Escherichia coli and PBMs induced comparable changes in epithelial physiology, which were abrogated by anti-tumor necrosis factor-alpha antibody. We conclude that LPMCs of patients with Crohn's disease are spontaneously activated, possibly by gram-negative luminal bacteria, and can directly cause significant alterations in epithelial ion transport and
barrier functions.

PMID: 11238058

Best regards,

jcwinnie

Very interesting,
I am currently starting a treatment developed by "Vision For Life" that addresses this very subject. It starts off with a 16 day treatment using a gental herbal body clense. Then a 16 day treatment of herbal CMO, Enzymes, and drinking eight glasses distilled water a day during this treatment. There have been some miraculous results for RA sufferers. Some have completly stopped using any meds because of it. And these are people who have had RA for many years. This treatment is supposed to cleanses the body, "joints", and blood. I'll let you know how it turns out. Keep up the good fight, Painman.

I don't understand all the techno stuff, so forgive me if this is a dumb question. But, if carbohydrates cause rheumatoid arthritis, why doesn't everybody have it?

I guess thats a fair question.. I dont believe that the article bothered to answer that question! But dont be surprised, this is a journalists writing (i think). But you can be certain that it has something to do with our genes, ie your genes make you susceptible.

Start by going to the source of the article :
http://www.arthritis.org/resources/news/carbohydrates_ra.asp
"" High levels of GAG (glycosaminoglycans), she says, could be caused by bacteria, which produce enzymes that break down connective tissue, releasing the carbohydrates. And many bacteria and other organisms produce GAG on their cell surfaces, she says, so the immune response to an invading microbe, may mistakenly discern GAG in healthy cartilage as another invader. ''That might explain why so many infections can lead to arthritis,'' she says""

I think most rheumatologists agree that there is an unknown trigger factor - otherwise why is the desease starting later in life, why not have inflammation since birth?

Anyways, dont lose sight of the infectious root of AS :-). The following journal articles talk about how rodent studies have shown that AS really is initiated by an infection. Why?, because rodents bred with HLA B27+ do not get the desease until removed from a pathogen free environment !!


Keywords used in my search queries on pubmed:
- transgenic rodent / rat spondylitis HLA B27
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Journal of Experimental Medicine, Vol 182, 1153-1158, Copyright © 1995 by Rockefeller University Press
Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies
SD Khare, HS Luthra and CS David
Department of Immunology, Mayo Clinic and Medical School, Rochester, Minnesota 55902, USA.
Human class I major histocompatibility complex allele HLA-B27 is associated with a group of human diseases called "spondyloarthropathies." Studies on transgenic rats expressing HLA-B27 and human beta 2-microglobulin have confirmed the role of HLA-B27 in disease pathogenesis. Here we report spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin (B27+ beta 2m-/- ). In the absence of beta 2-microglobulin, B27+ beta 2m-/- animals do not express the HLA-B27 transgene on the cell surface and have a very low level of CD8+ T cells. Most of the B27+ beta 2m-/- male mice showed nail changes, hair loss, and swelling in paws, which leads to ankylosis. The symptoms occur only after the B27+ beta 2m-/- mice are transferred from the specific pathogen-free mouse colony. These results suggest that aberrant assembly, transport, and expression of the HLA- B27 molecule may predispose an individual for development of the disease when exposed to an appropriate environmental trigger.
http://www.jem.org/cgi/content/abstract/182/4/1153
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Journal of Experimental Medicine, Vol 180, 2359-2364, Copyright © 1994 by Rockefeller University Press
The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats
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.
http://www.jem.org/cgi/content/abstract/180/6/2359

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http://www.mult-sclerosis.org/news/Nov2001/FullTextAnimalModelsOfAutoimmuneDiseases.html
The first spontaneous disease models that expressed a human HLA were HLA-B27–Tg rats and mice (6, 7). When animals are moved from pathogen-free environments to conventional colonies, animals from both species develop spondylitis-like features, which indicates that the onset of the disease requires an environmental trigger. The disease primarily affects male rodents, as with the human disease. These models confirmed that the gene encoding HLA-B27 itself, and not other closely linked genes, is responsible for spondylitis. But the model also generated controversies and additional questions. Why did the B27-Tg rats require more than 100 copies of the genes encoding HLA-B27 and human b2-microglobulin (b2M) for the onset of disease and why did HLA-B27 mice develop disease only in the absence of the mouse b2M? Studies in mice have suggested that the B27 molecule may reach the cell surface as an empty or free heavy chain in the absence of b2M and present an exogenous antigen to activate autoreactive T cells. Data from studies on human cells have shown that b2M-free B27 homodimers are transported to the cell surface and have the capacity to load exogenous peptides (8). These homodimers resemble a class II molecule that can present peptides in a classical class II antigen-processing pathway. Thus, the studies in rodent models and humans are converging in delineating spondylitis.

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Pronase and Papain: the following medical journal article seems to indicate that they damaged / destroyed the Klebsiella organisms "modifying factor". Which I assume would have a very very positive effect on our desease.

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."
I took this article from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3539895&dopt=Abstract

Perhaps this is a good reason to take amylase (the carbohydrate digestin enzyme) .. with food? or without food?

Me and my enzymes :-) perhaps im carried away?


*** Can Enzymes Cure?
Austrian research very positive results with trypsin rutin bromelain.
After 3 weeks enzymes were shown to be equally as effective as Voltaren
http://my.webmd.com/content/article/1668.50862
*** Efficacy and tolerance of oral hydrolytic enzymes in ankylosing spondylitis as compared with indomethacin: a controlled double-blind prospective clinical trial ***
- enzyme therapy proved to be a more successful treatment, but what enzymes were used?
http://www.mucos.cz/eng/reuma/eatoohe.htm
***** a collection of journals centred on Rheumatology and enzyme treatment. *****
http://www.mucos.cz/eng/reuma/con_reu_com.htm

Thanks, Zark. Interesting. There are quite a few mights, maybes, and coulds in that article, huh? I've run across bad information (ie nonsense) being printed a couple times before. It was only when I tried to write to one such author that I realized the "new information" that I thought might be big in my life would do more good in the cat box. So I'm ever so slightly skeptical, especially when so many of the words are "might". ;~)

The infection idea itself, however, does make sense. It'll be interesting to see whether further research reaches any more conclusions. I suspect that my own AS could have been triggered by a bout with a mono-like illness in my early 20's. I'll bet there are quite a few people on this forum who can look back and remember an infection that happened around the same time their bones started hurting.