Here's Something That May Knock Your Hat In The Creek

[tex]

Hi All,

Linda's post about the "NO/ONOO- Cycle Diseases", as proposed by Dr. Pall, prompted me to do some thinking, and some more research on this topic. I've studied and researched this issue before, and I recall that nitric oxide is not only connected with so-called "autoimmune" issues, but with certain other "natural" processes in the human body, as well. This has nothing to do with the topic at hand, but for your general information, the article at the following link lists some of the natural functions of nitric oxide, in the body:

http://users.rcn.com/jkimball.ma.ultran ... /N/NO.html

As many of you know, I have long believed that MC and the other IBDs are not caused by autoimmune disease, as claimed by conventional thinking in the mainstream medical community. IOW, IMO, autoimmune disease as a concept, only exists in medical literature, and in the minds of medical professionals - not in the real world. I know that Polly tends to agree with me, (and I believe that Dr. Fine also holds this view), that MC is probably caused by a pathogen - either a bacterium or a virus. I have no idea, though, whether either of them believes in the existence of autoimmunity as a disease, otherwise. Personally, I will concede that autoimmunity might exist as a symptom of a disease, rather than as a disease, per se.

Through the years since my symptoms first started, I may have had slightly less than my fair share of cold and flu viruses, but that's probably due to the fact that I almost always take special precautions to avoid catching viruses that regularly make the rounds. So I certainly don't consider my immune system to be "overactive". In fact, I can see no reasons to suspect that it may be, (or might have been, at some point in my life), overactive. Consequently, I see no reason to suspect that my GI issues might have been, (or still are), a result of an overactive immune system.

Consider the article at the following link. Ignore the name of the article, but consider what the researchers discovered about Crohn's disease.

In the UCL study, Professor Tony Segal and colleagues investigated whether the disease is instead caused by impaired innate immunity. They found a defective immune response in Crohn’s sufferers, based on a lack of white blood cells sent to destroy bacteria.

The findings suggest that in CD sufferers, a weak immune response is failing to or severally delaying the elimination of bacteria in the bowel because of an ineffective neutrophil response. Instead, macrophages (another form of white blood cell) are containing the bacteria in granuloma (clumps of debris) which accumulate in the intestines, resulting in secondary, chronic inflammation.

I believe that the word "severally", (which I highlighted in cyan), is probably supposed to be "severely", since that would make more sense.

“Normally, an acute inflammatory response would kick in to remove the bacteria and return the condition of the bowel to normal. But in Crohn’s disease, we think that the acute inflammation fails to kick start, leaving bacteria to fester in the bowel wall which in turn triggers chronic, secondary inflammations.

“Inflammation in our healthy volunteers was associated with the production of nitric oxide, a similar mechanism to that which induces the penis to become erect. We therefore used Viagra to correct the poor response in Crohn’s sufferers, where the drug amplified the effects of nitric oxide to return inflammation levels to nearly normal.”

http://www.ucl.ac.uk/media/library/crohn

Obviously, if sildenafil, (Viagra), can reverse the inflammation, then an autoimmune issue is not the source of the problem, (nor is an overactive immune system implicated). The bottom line is that IBDs, (and probably all autoimmune "diseases", for that matter), are not caused by an overactive immune system, and they are not due to an autoimmune reaction. They are caused by an under-active immune system, in the form of a weak response from the innate immune system.

Since this research supports my position, then naturally I believe that these researchers are on the right track. Note that this article is already almost 5 years old, and yet the obsolete thinking at the leading IBD institutions hasn't changed one iota. They appear to have totally ignored this research as if it never happened. It's almost as if the medical community is steadfastly opposed to making rapid progress in it's treatment methods. They are keen on implementing tiny changes, (and embracing new drugs), but whenever radical changes in their thinking are proposed, they suddenly turn into stone walls.

Tex

[Gloria]

The bottom line is that IBDs, (and probably all autoimmune "diseases", for that matter), are not caused by an overactive immune system, and they are not due to an autoimmune reaction. They are caused by an under-active immune system, in the form of a weak response from the innate immune system.

This begs the question - if IBDs are causes by an under-active immune system, then why do steroids, which suppress the immune system, reduce the symptoms? Also, why does Imuran help Crohn's? Unless the distinction is treating the symptoms vs. determining the cause.

Gloria

[tex]

Gloria,

I was wondering how long it would take before someone asked those questions, but frankly, I thought that Joe would ask first, since he's taking Imuran.

Obviously, I don't have a good answer to your questions, because for one thing, no one knows why steroids resolve the inflammation that's present with IBDs in the first place, (or any other form of inflammation that they're used to treat, for that matter). All we know is that they somehow suppress inflammation. The exact mechanism of action is unknown. True, they can be used to suppress immune systems, but that doesn't happen overnight, and actually, it takes a relatively long time, in the case of budesonide, for example - probably over a year, before any significant degree of immune system suppression is obtained. That suggests that immune system suppression is not the primary mode of control - something else suppresses the inflammation long before the immune system is actually suppressed.

In fact, we don't actually know how most drugs work. They have simply been demonstrated to have certain therapeutic effects, and have been granted FDA approval, on that basis, (after passing efficacy and safety trials). Consider the sildenafil used in the trial cited above, for example. It was originally developed in 1996 in order to treat angina, but have you ever seen anyone's angina treated with it? It can also be used to lower blood pressure, but after research showed it to have a very interesting side effect, all that was forgotten. Of course, it's mechanism of action is well known, for the most commonly used purpose, but most drugs don't receive that much attention, and all we know is that they have a certain level of efficacy when used at the prescribed dosage rate, for the indicated disease. In fact, many drugs are used for their side effects. For example, anti-depressants, and drugs such as bile acid sequestrants, are often used to treat IBS and even MC, because they have the side effect of constipation.

I have no idea why Imuran suppresses the symptoms of Crohn's disease - the actual therapeutic mechanism is surely unknown. Whatever it is, I'm guessing that the mode of action is probably not due to immune system suppression, but rather, it works in spite of immune system suppression. Note that it takes a long time to work up to the proper dose of Imuran needed for effective immune system suppression, and yet, improvement in symptoms are noted long before any significant degree of immune system suppression is achieved, (with Crohn's disease).

Consider this: The anti-TNF drugs, (Remicade, Humira, Embel, etc.), are very powerful immune system suppressants, and they're considered to be very effective for treating Crohn's disease and RA. Theorteically, they should be very effective at treating MC, but for some reason, they are not. We have several members who use an anti-TNF drug for RA or other related issues, but for the most part, this class of drugs seems to make their MC symptoms worse. Remember Rose? Despite all our suggestions, we were never able to help her. There is no doubt in my mind that the anti-TNF drug, (read that immune-suppressing drug), that she was using, was the primary reason why she could never achieve remission with a finely-tuned diet. Remember that Pat gave Imuran a more than fair trial, but in the end, it did not help to resolve her MC symptoms.

Everyone is treating this disease by guesswork, but I'm guessing that suppressing the immune system is not the optimum way to go - at least not with MC, and probably not with any IBD, (or any other autoimmune disease, for that matter). Note that a depleted vitamin D level is a primary contributor to developing an IBD, (because it suppress the immune system).

Tex

[Joefnh]

Hi Tex, I'll weigh in on this one... Its an interesting premise but a tough one to follow. The markers for autoimmune and inflammation are well understood in many disease models from hay fever to rheumatoid arthritis. I am not sure how we can dismiss RA factor and sedimentation rate testing. Although given the premise of the study, it may make sense that a unknown antigen may be the trigger for the immune response, hence why immune suppressants are effective. The overall question here is what is the cause and effect loop in IBDs as a whole.

As far as Imuran, it has definitely addressed multiple issues in my case. As you may remember I have been dealing with CC, Crohns, iritis, uveitis, a touch of Raynauds and the various joint and muscle pains. From what I can tell each of these has a root etiology of inflammation and is generally considered autoimmune in nature. The Imuran has resolved a good 90% of each of these. Certainly in my case Imuran has worked much better than Entocort, most likely due to the systemic difference between the 2 medications.

One reason for the length of time for the Imuran to work may be due to the dosing schedule. For IBD's it is recommended to start at a low dose and slowly work up to the target dose over a period of 6 - 8 weeks while monitoring the WBC and liver enzymes. The goal for the slow titration is to carefully monitor the blood work, while also determining the lowest dosage necessary to achieve the desired result.

I do know on several of the other Crohns boards that I frequent that of the TNF inhibitors that Humira is used successfully in treating Crohns and colitis, seemingly more often than the other TNF drugs. It does seem though that the purine synthesis inhibitors like Imuran are used more often. Some of this is most likely due to the FDA on label usage listings. I believe that Imuran is the only immunomodulator listed for the use in Crohns disease.

There may be a clue as to the popularity and potential efficacy of the Imuran over TNF inhibitors in the mechanisms of the 2 drugs. The Imuran being a purine synthesis inhibitor does tend to directly affect the population of leukocytes (B & T type) directly through the synthesis of the cellular DNA process, while the TNF drugs (alpha & beta) work through the cytokine channel to reduce the B & T types of leukocytes. Overall it seems that the literature does show that Humira does not lower the WBC a much as a Imuran does. I have always wondered what role that would play in the disease mechanisms of Crohns and LC for that matter.

As always Tex you have brought up a though provoking topic here.

--Joe

[Polly]

Interesting thread.

To me, autoimmune (AI) diseases are those in which the body "digests/destroys" itself. Usually this is by making antibodies to "self", as in the case of Hashimoto's disease where antibodies are made to one's thyroid tissue, or in diabetes type I where antibodies are made to one's pancreatic tissue, or in Crohn's where antibodies are made to one's gut tissue . The antibody/antigen complexes that result from this "battle" are what cause inflammation, and thus generalized symptoms and damage to the body. IOW, all of those white cells and chemicals (cytokines, etc.) that are produced in battle wreak havoc on the body, both locally and systemically.

By this definition, MC would be considered an AI disease only if we agree that our resident gut bacteria are "self", since the hallmark of MC is that our bodies start attacking the "good" bacteria in our guts. This is an interesting point in itself, since the resident bacteria are not really body tissue per se. They are apart and separate from tissue actually made by the body. However, there is some special feature about them that occurs when we acquire them from our moms at birth, so they do have some kind of unique, personal "stamp" about them. I guess we could consider them "self".

The food intolerances associated with MC would NOT qualify as AI disease, since those foods are not "self" to begin with. They only get into the body because of a leaky gut and are then treated as any foreign invader would be by the immune system. Antibodies are made to them, complexes are formed, and inflammation occurs.

So, inflammation is "generic" and results from the body's immune system attacking something, anything - bacteria, viruses, its own tissue, a foreign body like a splinter in the skin or food protein in the gut. The same chemicals are produced by these battles, and it is these chemicals that cause the damage. I believe that we probably have "overactive" immune systems that have an "itchy trigger finger" so to speak. It doesn't take much to set them off. And once they take aim, WATCH OUT! The battle is magnified or amplified compared to a "normal" person. We have far more impressive "cytokine storms", so to speak, when our immune systems do react. The best example of this was the flu pandemic of 1918, where the highest mortality rate was in the youngest/healthiest people, like men in their 20s. It was not the flu virus that killed them, it was their overwhelming immune response to the bug that did. Those chemicals produced in battle literally digested their lung tissue. That's what made this flu bug so unique - it caused a huge immune response to occur because it was so virulent. (My internist told me that should I ever be exposed to such a major pandemic flu, I should be sure to take prednisone to help quell my immune response).

Love,

Polly

[tex]

Joe,

Well, of course, with the immune system suppressants, you're treating symptoms by suppressing T-cell development, (among other things), and the inflammation connected with MC is primarily a T-cell event, so theoretically at least, those drugs should be effective for treating MC. (In reality, of course, they don't appear to be, at least not on a consistent basis).

Polly makes some very good points, and if I were convinced that the concept of autoimmune disease actually exists, then I would be in total agreement with the points that she raised, because the evidence points to that as a plausible explanation. However, I'm not sure that the markers have been correctly interpreted. Do any of the tests that supposedly confirm autoimmunity actually test for reactions against normal human tissue?

The TTG antibody test used for screening for celiac disease, tests for antibodies to an enzyme produced by the body, (transglutaminase). A test for autoimmune thyroid disease, (Hashimoto's disease), involves testing for antibodies to thyroid peroxidase, (which is an enzyme normally found in the thyroid gland). Why is it that all "autoimmune" testing appears to be based on the detection of antibodies to enzymes? Is that really "self", ( , admittedly, it's pretty close). If this is actually an autoimmune reaction, then why is it directed only against an enzyme? More importantly, why are all "autoimmune" reactions apparently directed against enzymes? There has to be a reason for that, and the nature of the reason probably holds some vital clues to unlock the mysteries that surround the process. Or, it may hold an explanation for why the process is misinterpreted as an "autoimmune" reaction.

Celiac disease is claimed to be an autoimmune disease, and yet, the reaction is apparently directed against gluten, not against "self". In order to successfully treat the disease, one does not have to avoid "self". Indeed, all one has to do, is to remove all sources of gluten from the diet, and all the symptoms will resolve. So, that means that celiac disease is not actually an autoimmune disease - it's simply a disease of gluten-sensitivity, and the so-called "autoimmune" issues are nothing more than symptoms of gluten-sensitivity. I have a hunch that there is a similar key that will explain/resolve all other so-called "autoimmune" diseases.

The primary problem, IMO, lies in the possibility that while the "markers" for what is called "autoimmune" and "inflammation", may be reasonably well understood, are the concepts of "autoimmune" and "inflammation", themselves, actually as well understood as they are claimed to be? The fact of the matter is, much of what is presented as science in medicine, is actually fallacious, because it's based on shaky assumptions, and "smoke and mirrors" statistical analysis. Studies show that much/most of what is claimed to be understood in medicine is obviously in error, and conflicting studies continue to reverse prior opinions that were previously claimed to be fact, thus confirming that the medical research database is filled with "questionable" findings, to put it politely. Of course, this is occurring to some extent with all the sciences, but this disturbing trend seems to be the most obvious in the field of medical research.

Consider celiac disease, for example. It has probably been plaguing mankind for roughly 10,000 years, and it was originally medically described almost 2,000 years ago, and any celiac doc worth his or her salt will tell you that after all this time, it is certainly a well understood disease. And indeed, after all that time, one would think that it should definitely be well understood. But is it? Obviously not, since only very recently are some of the most prestigious celiac "celebrities" beginning to admit the existence of non-celiac gluten-sensitivity, and recognize that the disease can be diagnosed much sooner, (by alternate markers), than had been previously thought. Only recently have medical researchers "acknowledged" that the same type of inflammation that causes MC, also exists in celiac disease. Maybe, after a few more centuries elapse, celiac disease will actually be well understood. Or maybe not.

Have you ever studied the research findings of Dr. John Ioannidis, concerning the validity of research claims? He has pretty much devoted his carreer to analyzing the accuracy of published research reports, and the results are extremely disturbing, to say the least.

From Why Most Published Research Findings Are False

Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

http://www.plosmedicine.org/article/inf ... ed.0020124

That article is now 5 years old. Here's another, which was published earlier this year:

It’s science’s dirtiest secret: The “scientific method” of testing hypotheses by statistical analysis stands on a flimsy foundation. Statistical tests are supposed to guide scientists in judging whether an experimental result reflects some real effect or is merely a random fluke, but the standard methods mix mutually inconsistent philosophies and offer no meaningful basis for making such decisions. Even when performed correctly, statistical tests are widely misunderstood and frequently misinterpreted. As a result, countless conclusions in the scientific literature are erroneous, and tests of medical dangers or treatments are often contradictory and confusing.

http://www.sciencenews.org/view/feature ... _Its_Wrong

So, while many research conclusions which are thought to be well understood, are not only not well understood, but in fact, blatantly incorrect; by contrast, the extent of the seemingly-overwhelming problem with invalid research conclusions and claims, is indisputable, and, somewhat ironically, well understood.

When science defies logic, it's probably bad science. From a macroscopic perspective, just consider the concept of autoimmunity, on it's own merits. If you want to look at it as a physics or engineering problem, view it as a free-body diagram, but on a macroscopic scale. Does it make sense? How could an organism survive, if it attacked itself? The answer is, "it could not". At least not in the long-term. Therefore, autoimmunity is not a logical concept, so it's not a valid concept. Autoimmunity, IMO, is simply a fabricated concept, created to explain poorly-understood chemical processes that occur in the body, but in the algorithm that defines survival of a species, it fails to meet the essential boundary conditions.

I'm not saying that there is no circumstantial evidence to support the case for autoimmunity. I'm simply saying that IMO, the evidence may be misunderstood, and misinterpreted. At least that's how I see it.

Tex

P. S. Sorry that it took me so long to get this response posted. I posted it earlier, but immediately realized that I needed to make a bunch of additions, and since I was becoming increasingly dizzy, and didn't really feel like working on it, I just removed it, to edit later. I'm feeling better now, so I finished it and re-posted it.

[Polly]

Hiya Tex!

As usual, I enjoy all of your musings. You always raise interesting issues and questions. No wonder you were dizzy yesterday after finishing your above post - that took a lot of brainpower! LOL! Seriously, I hope the dizziness is gone by now.

I certainly can't begin to answer all of your excellent questions, but I thought you'd be interested in the fact that it is not just antibodies to enzymes that occur in AITD (autoimmune thyroid disease or Hashimoto's), for example.

from medscape:

"Pathophysiology

Patients with Hashimoto's thyroiditis have antibodies to various thyroid antigens, the most frequently detected of which include anti - thyroid peroxidase (anti-TPO), antithyroglobulin (anti-Tg), and to a lesser extent, TSH receptor-blocking antibodies. Nevertheless, a small percentage of patients with Hashimoto's thyroiditis (approximately 10-15%) may be antibody negative.

Other antithyroid antibodies found in AITD (including Hashimoto's thyroiditis) include thyroid-stimulating antibody and cytotoxic antibody."

Love,

Polly

[tex]

Polly,

Touché! Obviously, I never should have brought up my thoughts about autoimmune issues in this topic, in the first place, because that sidetracked the entire thread, and I'm not really married to that viewpoint, anyway, I just think that it's a thought-provoking, (though admittedly radical ), possibility. Certainly, I'm not ready to insist that such a concept is ready for "prime time" status.

To get back to the article cited in the lead post of this thread - in your opinion, then, do you feel that Crohn's disease is definitely an autoimmune disease, and contrary to the findings of the article that I cited, it cannot be caused by a weak innate immune system response? (IOW, bearing in mind that MC doesn't seem to be a "card-carrying" autoimmune disease, doesn't that raise some questions about the "autoimmune" status of Crohn's?)

Incidentally, what about the 10 to 15% of Hashimoto's victims who are antibody negative? Does that imply that the NK lymphocytes, (natural killer cells), are running amuck, and destroying the thyroid by misuse of apoptosis, or is some other antibody marker being overlooked?

Love,
Tex

[MaggieRedwings]

Morning All,

Well I love the musings and interesting theories but damn - it will take me forever to digest this (no pun intended) and make sense of it.

Love, Maggie

Thank you all - you are very serious thinkers.