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Thanks, Gerard. You are correct in your interpretation. I was pointing out that specific Ebringer article reported elevated IgM, IgG, IgA.

However, no need to defend me and, besides, I don't think you can dissuade Bilko from his attacks. The best defense and all that... This thread needs to deteriorate rapidly to each shouting, "Liar, Liar, Pants on Fire!"

And, you bring up an important part. It would seem that the Klebsiella Konspiracy is greatly founded on the presence of IgA. Yet, you say it is an indication of gram negative bacteria.

How about a microbiology lesson? What does the presence of immunoglobulin A indicate?

Best regards,

jcwinnie

Gerard,

it has obviously not missed your attention that after nearly three days he has not responded to my calling him dishonest. People who lie easily, when caught out, just move on as though nothing happened. You must also appreciate that his reference to E. coli and P. mirabilis was significant. If antibody levels to these were raised in AS then suspicion moves away from K. pneumoniae and sustains his allegation of a 'klebsiella konspiracy'.

There was a thread a few weeks ago when he misquoted something Jan (twisks) posted. She got very upset and asked for an apology. All she got was more nonsense.

jc is exploiting our presumption to assume integrity in others. But clearly he himself has little.

'Pain is a state of conciousness. Understanding is not'

Edited by bilko on 07/29/02 09:11 AM (server time).

Postscript to Microbiology Lesson Request

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"The increase in the titres of anti-klebsiella IgA may be due to increased permeability of the gut to bacterial antigens, leading to an increased IgA response in the gut mucosa and permitting the release of IgA into the circulation. As the increased antibody titres were seen in Crohn's disease and rheumatoid arthritis as well as in ankylosing spondylitis the response may be nonspecific, occurring because of possible underlying inflammatory bowel disease in these conditions."

Cooper R, Fraser SM, Sturrock RD, Gemmell CG. Raised titres of anti-klebsiella IgA in ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease. Br Med J (Clin Res Ed) 1988 May 21;296(6634):1432-4.

And while the IgA response is not specific for the different diseases the reactions of AS patients probably will be due to molecular mimicry between anti KLebsiella IgA (or one of the other antibodies) and a AS patient specific factor like HLAB27.
Gerard

" Support bacteria - they're the only culture some people have."
-Stephen Wright-

Gerard,

This seems like "deja vu all over again," to quote Yogi Berra.

I know that you are giving me the word brought down from the mount. There certainly are those who put forth the "molecular mimicry" hypothesis, as there are those who say, "Maybe," and those that dispute it.

Pro

Molecular mimicry has been demonstrated between Klebsiella pneumoniae pulD secretion protein (DRDE) and HLA-B27 (DRED). A second molecular mimicry crossreactivity has been demonstrated between Klebsiella pulA (pullulanase) enzyme (Gly-X-Pro) and types I, III and IV collagens.

Source: Ebringer web site http://www.kcl.ac.uk/kis/schools/life_sciences/life_sci/Ebringer.html

Maksymowych suspects that a process of molecular mimicry occurs in people who have AS, with the result that some of the bacterial proteins start to look identical to those that arise from the breakdown of the body's proteins.

Source: Prof punctures inflammatory joint disease

In AS genotypes, connective tissues are mistaken by the IgA antibodies for K. pneumoniae, and destruction of local structures will occur. This reaction has been termed “molecular mimicry,” and the mechanism has been supported by strong evidence, to the extent that the exact sequence in the identifying surface structure has been identified.

Merchant, J. AS Dietary Primer. https://www.kickas.org/as_dietary_primer.shtml

"The mechanism for the disease process is described in the Medical Center section "Molecular Mimicry" article, but essentially we produce an immunoglobulin (an IgA) in response to the presence of a bacterium (called Klebsiella pneumoniae; Kp). While this Kp-specific IgA consumes the bacterium, it happens to mistake certain outer surface protein for Kp, also, and begins destroying it, too. It is an 'anti-self,' or autoimmune reaction."

Merchant, J. Post on Klebisella Reactive Arthritis.

Maybe

Autoreactive T cells may contribute to this process by recognition of cross-reactive self-epitopes (ie, molecular mimicry between bacterial and self-antigens). Autoreactive T cells may as well be inappropriately upregulated by bacterial superantigens, or by local inflammatory reactions leading to the uncovering of former cryptic self-epitopes.

Marker-Hermann E, Schwab P. T-cell studies in the spondyloarthropathies. Curr Rheumatol Rep 2000 Aug;2(4):297-305.

There is some degree of mimicry between some enteric bacterial antigens and B27 molecules, the extent of causation of AS by which is not yet clearly understood.

Inflammatory spinal disorders, Reiters and Bodan, Spine, 23(24), 1998, 2763-2764.

Molecular mimicry between Klebsiella or other bacterial antigens and HLA-B27 has been suggested in the pathogenesis of AS. The specificity of increased immunoreactivity against Klebsiella remains to be assessed against the abundant anaerobic bacterial flora.

Tiwana H, Wilson C, Walmsley RS, Wakefield AJ, Smith MS, Cox NL, Hudson MJ, Ebringer A. Antibody responses to gut bacteria in ankylosing spondylitis, rheumatoid arthritis, Crohn's disease and ulcerative colitis. Rheumatol Int 1997;17(1):11-6.

Con

Instead of recognizing the HLA-B27 homologous portion, the antibodies are directed against the left flanking sequence of the synthetic peptide. Similar results were obtained regarding antibody response to Klebsiella nitrogenase derived synthetic peptide included in the panel of controls; the response was not restricted to patients with reactive arthritis nor was it specifically directed against the sequence shared by HLA-B27 and Klebsiella pneumoniae nitrogenase. The present results do not support the role of molecular mimicry or cross-reactive antibodies in the pathogenesis of spondyloarthropathies.

Lahesmaa R, Skurnik M, Granfors K, Mottonen T, Saario R, Toivanen A, Toivanen P. Molecular mimicry in the pathogenesis of spondyloarthropathies. A critical appraisal of cross-reactivity between microbial antigens and HLA-B27. Br J Rheumatol 1992 Apr;31(4):221-9.

As crossreactive antibodies against bacteria and HLA-B27 were equally present in sera from patients and controls, the pathogenetic significance of molecular mimicry between various bacteria and HLA-B27 is questionable. Furthermore, the regions of the B27 molecule that are supposed to be crossreactive with bacteria, differ in one or more amino acids among the distinct B27 subtypes.

Ringrose JH. HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27. Ann Rheum Dis 1999 Oct;58(10):598-610.

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P.S. You are correct about my dirty little secret. I read the abstracts I can get from PubMed; I am unable to afford purchasing all the full research articles. Although, I think I would shell out the coin for a copy of the full spread regarding the claim of Ebringer's success that John keeps making, but not substantiating.

Best regards,

jcwinnie


Now give me a good murder mystery on the other hand...

Jonathan,
The sun comes up every day, and I don't mind...
I like your list of pro, maybe and con articles. May I add however some critical remarks to the Ringrose (con) article. Mister Ringrose did no research on AS patients he only searched Pubmed for articles to criticise them. Personally I think your own searches are more worthwile Jonathan (especially the link to the transplantation piece is great, I will respond to this later).

A citation from the Ringrose abstract:
"In the 45 studies demonstrating autoimmune reactions in SpA patients proper controls matched for HLA-B27, sex and age were nearly always lacking. Therefore, it is concluded that the frequency of increased autoreactivity in sera from patients and controls is not significantly different".

Don't you think this is an insult on the researchers that wrote this 45 articles and on the papers that thoroughly checked this research before publishing. (especially from someone that did almost no research in this field). Notice also the word nearly. So there were also proper studies that did not lack proper controls even in his view. Nonetheless he concludes without any reservation that there are no significant differences: Blaahh.

Mister Ringrose goes on in his abstract with this:
"Furthermore, the regions of the B27 molecule that are supposed to be crossreactive with bacteria, differ in one or more amino acids among the distinct B27 subtypes. Although these differences strongly influence the binding of antibodies to the B27 molecule, there was no relation between the degree of crossreactivity of certain subtypes and the association of these subtypes with SpA."

Here he should have read his papers better. Because just before this was published:

Differences in endogenous peptides presented by HLA-B*2705 and B*2703 allelic variants. Implications for susceptibility to spondylarthropathies.

Boisgerault F, Tieng V, Stolzenberg MC, Dulphy N, Khalil I, Tamouza R, Charron D, Toubert A.

The title says it all. Notice also that in protein chemics the exact amino sequence is not always important it is the 3 dimensional structure that is.

A more recent study on B27 subtypes is even more clear on the role of subtypes on AS:

"The peptide repertoires of HLA-B27 subtypes differentially associated to spondyloarthropathy (B*2704 and B*2706) differ by specific changes at three anchor positions.

Sesma L, Montserrat V, Lamas JR, Marina A, Vazquez J, Lopez de Castro JA.

Centro de Biologia Molecular Severo Ochoa, Universidad Autonoma de Madrid, Facultad de Ciencias, 28049 Madrid, Spain.

"HLA-B*2704 is strongly associated with ankylosing spondylitis. B*2706, which differs from B*2704 by two amino acid changes, is not associated with this disease".
.

So Ringrose was clearly wrong on this point. Please give me a better con article.

Best regards, Gerard




" Support bacteria - they're the only culture some people have."
-Stephen Wright-

Gerard,

Those citations reflect very detailed research into HLA-B27 subtypes. This seems to be quite a hot area of research.

Here is another one for the Pro side:

Molecular mimicry between bacterial epitopes that cross-react with self-B27 peptides is the most persuasive explanation for the pathogenesis of SpA.

Lopez-Larrea C, Gonzalez S, Martinez-Borra J. The role of HLA-B27 polymorphism and molecular mimicry in spondylarthropathy. Mol Med Today 1998 Dec;4(12):540-9.

Curious, too, that one of our world renown dummies (dummy herein defined as someone foolish enough to dispute the Klebsiella Konspriacy) is involved with this research:

It is important to investigate which of them are and are not associated with AS and related SpA, and whether certain subtypes show any preferential association with some of the clinical features or forms of these diseases among the various ethnic/racial populations and geographic regions of the world. This is expected to provide clues as to the mechanism of disease association, and one of the strongest reasons to study the B27 subtypes is to learn the effects of the sequence variations on the peptide-binding specificity of the molecule.

Ball EJ, Khan MA. HLA-B27 polymorphism. Joint Bone Spine 2001 Oct;68(5):378-82.

Obviously, there must be something to it. Please excuse me for being dense; I still am having problems with how HLA-B27 polymorphism supports a molecular mimicry hypothesis?

Best regards,

Gogo-B01

Gerard,

The following is taken from a Khan article, but is it a better Con article than Ringrose?

HLA-B27 contributes only 16 to 50% of the total genetic risk for the disease, clearly indicating that other genes must be involved. However, no other putative disease genes have yet been absolutely proven. Potential genes include MHC (HLA class II, low molecular weight proteasome [LMP], transporter associated with antigen processing (TAP), tumor necrosis factor [TNF]-alpha, and major histocompatibility complex class I chain-related gene A (MICA), as well as non-MHC genes (IL-1RA, IL-6, IL-10, and CYP2D6). Genome-wide screens have identified other chromosomal areas of interest: 1p, 2q, 6p, 9q, 10q, 16q, and 19q. However, different studies have given conflicting results.

Reveille JD, Ball EJ, Khan MA. HLA-B27 and genetic predisposing factors in spondyloarthropathies. Curr Opin Rheumatol 2001 Jul;13(4):265-72.

Best regards,

jcwinnie


Muhammad Asim Khan, FRCP, FACP
Professor of Medicine
Case Western Reserve University School of Medicine
Cleveland, Ohio, USA

Gerard,

Now this one, I would put under the Con heading:

The human major histocompatibility complex (MHC) class I allele HLA-B27 bears a striking association with the spondylolarthritic group of inflammatory arthritides, yet despite extensive studies its role in the disease process remains obscure. As an MHC class I protein, the primary function of HLA-B27 is to complex with beta(2)-microglobulin forming a structure that presents short antigenic peptides for recognition by cytotoxic T lymphocytes (CTL). It has been proposed that the role of HLA-B27 in spondyloarthropathy involves this process of antigen presentation, and of the numerous theories proposed to explain the association, the most popular have involved the binding and presentation of "arthritogenic" peptides. Transgenic rodent studies directly implicate HLA-B27 heavy chains in disease pathogenesis, but suggest that the mechanism may be distinct from their primary function. The recent demonstration that HLA-B27 heavy chains can form stable homodimers may thus be of relevance.

Allen RL, Bowness P, McMichael A. The role of HLA-B27 in spondyloarthritis. Immunogenetics 1999 Nov;50(3-4):220-7.

Best regard,

jcwinnie


Fractal image: Dave Makin

Jonathan,
The difference between Kahn and Ringrose is that Kahn reads his literature a lot better. He also doesn't do a lot of research himself but he makes nice overviews. What is said here is what everyone already knows. HLA-B27 is not the only factor that is responsible for the disease. It is a multiple step process in which B27 can but not always plays an important role. Otherwise we would have no B27 negative AS patients and we would have no B27 positive ones without the disease. This facts makes that explanations based on the role of B27 always at least should be made with the reservation: in cases in which the B27 plays the leading role.
I would however not describe this piece as a con article. It is only con Klebsiella if the interaction between this bacteria and B27 was stated as the only explanation for the disease in Ebringer's articles.
Best Regards,
Gerard

" Support bacteria - they're the only culture some people have."
-Stephen Wright-