Concepts 2018-01-19T14:49:24+00:00

Science

Concepts

To understand how various environmental factors cause MS, it is helpful to be aware of a number of scientific concepts that are part of the MS story. These concepts are explained in simple language and in some cases links to other websites and to a few scientific papers found in our virtual library.

Leaky Gut

The concept of a leaky gut or as it is more properly called, increased intestinal permeability, is a very important one for understanding why autoimmune reactions occur. The gut can be considered an area which is “outside” of the body and it contains various “foreign” elements such as bacteria and food proteins. It is critical that little if any of these foreign particles reach the circulatory systems (blood and lymph) because if they did they would cause major immune reactions. The gut wall is normally impermeable to large molecules (ie intact folded proteins) and only when a food protein is broken down into amino acids can the molecules pass through the gut wall. However, when the gut wall is damaged larger molecules such as intact food proteins and bacterial products can pass through and set off immune reactions. In genetically susceptible people these foreign proteins can sometimes cause autoimmune reactions by either mimicking self proteins or mimicking viral agents which themselves mimic autoantigens. The bottom line is people with an autoimmune disease want to heal their intestinal wall such that it prevents the passage of foreign proteins.

Here is a link to an excellent essay on the leaky gut and how to heal it: Galland Article

PubMed Abstracts

Dig Dis Sci 1996 Dec;41(12):2493-8

Yacyshyn B, Meddings J, Sadowski D, Bowen-Yacyshyn MB

Department of Medicine, University of Alberta, Edmonton, Canada.

Increased intestinal permeability and the CD45RO isoform expression of the leukocyte common antigen on peripheral blood CD20+ B cells are found in Crohn’s disease. Others have observed that multiple sclerosis (MS) patients may have an increased risk of coacquisition of Crohn’s disease. The aim of this study was to identify an association between these diseases using peripheral blood CD45 isoform expression and intestinal permeability in MS. Lactulose/mannitol permeability and peripheral blood CD20+ B cell CD45RO expression were defined in healthy controls, MS patients, and patients coincidentally affected by MS and Crohn’s or MS and ulcerative colitis (UC). Five of 20 MS patients had increased intestinal permeability, a finding not previously reported. High levels of CD45RO were found on circulating CD20+ B cells from patients with MS. This has not been reported previously in MS and is found in very few other conditions. Eight patients with coincident MS and Crohn’s disease or MS and UC were studied. Coincident MS and UC patients expressed CD45RO on CD20+ B cells, a finding not identified in UC patients alone. A subgroup of MS patients has increased intestinal permeability. These patients express CD45RO CD20+ B cells, also found in Crohn’s disease.

Annu Rev Nutr 1988;8:329-50

Gardner ML

School of Biomedical Sciences, University of Bradford, West Yorkshire, England.

There is now no reasonable doubt that small quantities of intact proteins do cross the gastrointestinal tract in animals and adult humans, and that this is a physiologically normal process required for antigen sampling by subepithelial immune tissue in the gut. It is too small to be nutritionally significant in terms of gross acquisition of amino-nitrogen, but since it has important implications relating to dietary composition it must receive consideration from nutritionists. The process of intact protein absorption occurs without eliciting harmful consequences for most individuals, but it appears likely that a small number of people absorbing these “normal” amounts may react idiosyncratically; also, some individuals may absorb excessive amounts, and they may suffer clinically significant consequences. Likewise, individuals with diminished absorption of intact protein may be at risk. Normal absorption probably occurs predominantly by transcellular endocytosis with some possible contribution by a route between cells; increased net entry of protein to the circulation may reflect (a) increased paracellular (intercellular) passage, (b) increased transcellular passage, and/or (c) decreased lysosomal proteolysis. Tests to distinguish among these possibilities are strongly desirable. Intact protein absorption may be involved in the pathogenesis of inflammatory bowel disease, “food allergies, ” and other diseases, including even major psychiatric disorders, but the current evidence is mainly indirect and suggestive. Great caution and careful objective studies are needed to establish whether such relationships with disease do exist and to unravel the underlying basic physiological mechanisms. Now that interest has developed in the assessment of intestinal permeability to small- and medium-sized molecules, it is hoped that equally simple methods for studying macromolecular permeability will be developed and applied. Therapeutic methods for enhancing intact polypeptide absorption would be valuable for vaccine and peptide drug administration by the oral route. Therapeutic reduction of the process may be relevant in food-sensitive patients.

Pediatr Clin North Am 1975 Nov;22(4):731-46

Walker WA

In this article, I have attempted to summarize the concept of intestinal permeability to antigens such as ingested food proteins, bacterial breakdown products, endotoxins, and enzymes. The mature gut retains the capacity to absorb macromolecules by a pinocytotic mechanism which is more pronounced during the neonatal period. The vast majority of individuals have no ill effects from the intestinal transport of large molecules. However, when increased quantities of toxic or antigenic macromolecules gain access to the body because of a derangement in the intraluminal digestive process or because of a defect in the mucosal barrier, antigen absorption may be altered and result in either local intestinal or systemic disorders. The speculative concepts suggesting that clinical disease states may be associated with altered mucosal permeability have been discussed.

Aliment Pharmacol Ther 1997 Dec;11 Suppl 3:47-53; discussion 53-6

Meddings JB

Gastrointestinal Research Group, University of Calgary, Alberta, Canada.

Measurements of intestinal permeability (IP) may help in determining susceptibility for the development of Crohn’s disease or imminent relapse in patients with the disease. It is now apparent that a subset of patients at high risk for the development of Crohn’s disease have either increased baseline IP or an exaggerated response to environmental agents that increase IP. These, coupled with observations that increased IP in patients at risk for the development of Crohn’s disease is associated with an abnormal immunological phenotype, lend support to the hypothesis that increased IP is a very early event in the genesis of Crohn’s disease.

Molecular Mimicry

The concept that molecular mimicry is an important factor in autoimmune disease was first published in 1985 and since that time substantial evidence has accumulated such that it has become the favoured mechanism for causing many autoimmune diseases including MS.

The concept is simple but entails a lot of understanding of the workings of the immune system. Basically molecular mimicry means that part of a molecule of a given protein closely resembles a part of another totally different protein. Proteins are made up of strings of amino acids and in molecular mimicry one series amino acids (eg~10) in one protein is very similar to a string of ten amino acids in another protein. Given that there are 20 different amino acids it is a rather rare occurrence to find such mimicking arrangements but many examples have been demonstrated.

The main types of proteins which came into play in autoimmune disease are:

  1. self proteins which are part of the human body. An example of this would be myelin basic protein which is the most common protein in myelin;
  2. proteins of infectious agents such as viruses and bacteria;
  3. food proteins. For example over 400 different proteins occur in cow’s milk and most have over 150 amino acids.

To understand how molecular mimicry works in the induction of autoimmunity one must understand the basic mechanisms of an immune response to a foreign invader in the body. The immune system recognizes a part of the protein portion of the invader. It does this with T cells which have receptors which bind to short segments (~10 amino acids) of a foreign protein. It is helped in this task by so called antigen presenting cells such as macrophages. A macrophage will engulf a foreign invader (eg a bacteria or food particle) and break it down into fragments. A special molecule in the macrophage then carries a protein fragment(peptide) to the surface of the cell and “presents” it to the millions of circulating T cells. A T cell which has a matching receptor locks onto the presented protein fragment. The T cell then becomes activated and stimulates other portions of the immune system to begin an immune response against all proteins which contain a similar looking amino acid string. The details of what constitutes a similar looking string are beyond this summary but suffice to say it has been found that a variety of similar, yet somewhat different strings, can be recognized by the same T cell.

Thus, it is easy to understand how molecular mimicry can trigger an autoimmune reaction. If the protein fragment from a foreign invader which is presented to the T cell closely resembles part of a self protein then the activated immune system will not only attack all foreign invaders which have the same string of amino acids but will also attack a very similar string in a self protein. It has been shown that parts of proteins in various foods and infectious agents resemble parts of various self proteins. Sometimes a three-way mimicry occurs with a protein fragment from a food closely resembling that of an infectious agent which in turn closely resembles part of a self protein. In Celiac disease part of the gliadin molecule (found in various grains such as wheat and rye), part of adenovirus 12 and part of a gut protein all closely resemble each other, and the result of such mimicry is an immune attack on the gut when food containing gliadin protein is eaten. A similar three-way mimicry occurs between a cell wall protein in grains and legumes, part of the Epstein Barr virus and part of the collagen in joints. This leads to rheumatoid arthritis in genetically susceptible people. For type 1 diabetes parts of milk proteins and viral proteins mimic proteins in the insulin-producing beta cells of the pancreas.

For MS it has been established that numerous viruses and bacteria have amino acid strings which mimic parts of proteins in the myelin proteins of the central nervous system. Undoubtedly food proteins also contain such mimicking protein fragments and thus two and three-way mimicry is a ready explanation for why the immune system attacks myelin and causes MS.

An important part of molecular mimicry is what exact string of amino acids is presented to the immune system because that will determine if part of a self protein is also mimicked or not. That is why MS and other autoimmune diseases are strongly dependent on genetic makeup and why only a small percentage of the population contracts these diseases. Most people do not have genes which result in mimicking peptides being presented to their immune system. A person’s genes will also determine which self protein is mimicked and thus what specific autoimmune disease that person gets. People, who have genes such that a myelin protein is mimicked by a presented foreign protein fragment, will experience an immune attack on their myelin which eventually leads to clinical symptoms and a diagnosis of MS. Those who present collagen-mimicking fragments get rheumatoid arthritis.

Currently most researchers are concentrating on infectious agents as the main drivers of molecular mimicry despite the strong evidence that food proteins also supply appropriate mimics. In fact, it is likely that food proteins are the main mimics in some cases because the geographical distribution of diseases such as MS and type 1 diabetes closely follows differences in dietary habits rather than differences in infectious agents. Of course, it has been established that food proteins are the driver of Celiac disease, one of the few autoimmune diseases for which the cause is known.

In summary, molecular mimicry is currently the best explanation for why the immune system attacks self tissue in some people. When all is said and done it just comes down to a case of mistaken identity in which the immune system in genetically susceptible people mistakes part of the body for a foreign invader. Below are some Pubmed abstracts on the concept of molecular mimicry.

PubMed Abstracts

FASEB J 1998 Oct;12(13):1255-65

Oldstone MB

Viral Immunobiology Laboratory, Division of Virology, The Scripps Research Institute, Department of Neuropharmacology, La
Jolla, California 92037, USA.

Molecular mimicry has been proposed as a pathogenetic mechanism for autoimmune disease, as well as a probe useful in uncovering its etiologic agents. The hypothesis is based in part on the abundant epidemiological, clinical, and experimental evidence of an association of infectious agents with autoimmune disease and observed cross-reactivity of immune reagents with host ‘self’ antigens and microbial determinants. For our purpose, molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the molecules’ linear amino acid sequences or their conformational fits may be shared, even though their origins are as separate as, for example, a virus and a normal host self determinant. An immune response against the determinant shared by the host and virus can evoke a tissue-specific immune response that is presumably capable of eliciting cell and tissue destruction. The probable mechanism is generation of cytotoxic cross-reactive effector lymphocytes or antibodies that recognize specific determinants on target cells. The induction of cross-reactivity does not require a replicating agent, and immune-mediated injury can occur after the immunogen has been removed a hit-and-run event. Hence, the viral or microbial infection that initiates the autoimmune phenomenon may not be present by the time overt disease develops. By a complementary mechanism, the microbe can induce cellular injury and release self antigens, which generate immune responses that cross-react with additional but genetically distinct self antigens. In both scenarios, analysis of the T cells or antibodies specifically engaged in the autoimmune response and disease provides a fingerprint for uncovering the initiating infectious agent.

Immunology 1995 Oct;86(2):168-75

Ostenstad B, Dybwad A, Lea T, Forre O, Vinje O, Sioud M

Institute of Immunology and Rheumatology, University of Oslo, Norway.

A peptide of 15 amino acids derived from the cereal glycine-rich cell wall protein (GRP), sharing a significant homology with Epstein-Barr virus nuclear antigen-1 (EBNA-1), fibrillar and procollagen, stimulated synovial fluid (SF) T cells from juvenile (JRA) and adult (RA) rheumatoid arthritis patients. An over expression of the V alpha 2 gene family was found in the SF from patients who responded significantly to the peptide. To investigate in more detail the SF T-cell responses to the GRP peptide, we established peptide-specific T-cell lines and clones from a DR8+ positive JRA patient with pauciarticular form. The T-cell clones were phenotyped as T-cell receptor (TCR)alpha beta+/CD4+ and their clonality was investigated by polymerase chain reaction (PCR) and flow cytometric analysis. TCR sequences from different clones demonstrated that the clones were identical and used the V alpha 2. 1/J alpha 6 combined with V beta 5. 5/J beta 2. 7 gene segments. Interestingly, direct sequencing of the V alpha 2 family PCR product obtained from cDNA prepared from freshly isolated SF mononuclear cells identified the same TCR sequence as that used by the clones, suggesting the monoclonality of SF CD4+ T cells bearing V alpha 2. 1/J alpha 6 gene products. The present data suggest a recruitment and expansion of a SF T-cell subpopulation, and also support the hypothesis that autoimmune diseases can be triggered by protein epitopes with crucial amino acids homologous to self-proteins.

Cell 1995 Mar 10;80(5):695-705

Wucherpfennig KW, Strominger JL

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138.

Structural similarity between viral T cell epitopes and self-peptides could lead to the induction of an autoaggressive T cell response. Based on the structural requirements for both MHC class II binding and TCR recognition of an immunodominant myelin basic protein (MBP) peptide, criteria for a data base search were developed in which the degeneracy of amino acid side chains required for MHC class II binding and the conservation of those required for T cell activation were considered. A panel of 129 peptides that matched the molecular mimicry motif was tested on seven MBP-specific T cell clones from multiple sclerosis patients. Seven viral and one bacterial peptide efficiently activated three of these clones. Only one peptide could have been identified as a molecular mimic by sequence alignment. The observation that a single T cell receptor can recognize quite distinct but structurally related peptides from multiple pathogens has important implications for understanding the pathogenesis of autoimmunity.

Mol Med 1998 Apr;4(4):231-9

Honeyman MC, Stone NL, Harrison LC

Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet autoimmunity in type 1 diabetes. T-cell epitope peptides in autoantigens have potential diagnostic and therapeutic applications, and they may hold clues to environmental agents with similar sequences that could trigger or exacerbate autoimmune disease. We identified 13 epitope peptides in IA-2 by measuring peripheral blood T-cell proliferation to 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes relatives selected for HLA susceptibility haplotypes. The dominant epitope, VIVMLTPLVEDGVKQC (aa 805-820), which elicited the highest T-cell responses in all at-risk relatives, has 56% identity and 100% similarity over 9 amino acids (aa) with a sequence in VP7, a major immunogenic protein of human rotavirus. Both peptides bind to HLA-DR4(*0401) and are deduced to present identical aa to the T-cell receptor. The contiguous sequence of VP7 has 75% identity and 92% similarity over 12 aa with a known T-cell epitope in glutamic acid decarboxylase (GAD), another autoantigen in type 1 diabetes. This dominant IA-2 epitope peptide also has 75-45% identity and 88-64% similarity over 8-14 aa to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses, and the bacterium Haemophilus influenzae. Three other IA-2 epitope peptides are 71-100% similar over 7-12 aa to herpes, rhino-, hanta- and flaviviruses. Two others are 80-82% similar over 10-11 aa to sequences in milk, wheat, and bean proteins. Further studies should now be carried out to directly test the hypothesis that T-cell activation by rotavirus and possibly other viruses, and dietary proteins, could trigger or exacerbate beta-cell autoimmunity through molecular mimicry with IA-2 and (for rotavirus) GAD.

Paleolithic Nutrition

The Paleolithic lasted from about 200 000 years ago to about 12 000 years ago and was characterized by a hunting and gathering lifestyle for humans. During this time the food supply consisted almost exclusively of lean wild meats, fish, vegetables and fruits. These provided all the nutrients necessary for a very active lifestyle which involved far more exercise than our current way of living. Most importantly, because humans slowly adapted to this food supply over 2 000 000 years, the human genome was very compatible with all the various types of proteins, fats, carbohydrates and micro-nutrients found in these foods as well as various anti-nutrients that the plants and animals evolved to discourage their consumption. Thus it is very unlikely that the normal constituents of the food supply (excluding bacteria etc) would have caused any common biochemical malfunctions (ie disease) because those not compatible with such foods would have been naturally selected from the gene pool over the hundreds of thousands of years this food supply was consumed. Thus, a diet of lean meat, fish, fruits and vegetables is now considered to represent a Paleolithic Diet and such a diet is basically that to which humans are genetically adapted.

With the rapid increase of the human population and a consequent dwindling of the standard foods, humans added new foods to their diet and these included grains (cultivated grass seed) and milk and meat products from domesticated animals. This change to a “grow your own” food supply of the agricultural revolution began about 12 000 years ago in the Middle East and slowly spread westward, reaching Scandinavia and the British Isles about 6 000 years ago.

There can be little doubt that in the early days of agriculture there must have been a broad spectrum of genetic incompatibilities with these new foods which contained a great variety of new, never-seen-before proteins as well as a much greater abundance of saturated fat than the Paleolithic foods. Such incompatibilities likely varied from very high to minor. Over the last 6000 years most of the genes which were very incompatible with the new foods were probably eliminated from the gene pool because of the biochemical failures (illnesses) which would have hit those with such genes before the age of reproduction. However, those with lesser genetic incompatibilities and who were not affected by adverse reactions until after the age of reproduction (~18-30) have passed on such genes to our current generations. Thus most diseases associated with the new foods of dairy, grains and high saturated fat meats do not appear until later in life. These include heart disease, stroke, some cancers (prostate, breast, colon), many autoimmune diseases and a variety of chronic degenerative diseases (eg Parkinson’s, Alzheimer’s).

Notably a few of these diseases do occur in young people and include juvenile diabetes and arthritis. These “exceptions to the rule” most likely relate to the very recent practice of supplementing babies with the new foods (milk, wheat, soy) in the first year of life. Such a practice will identify another group of individuals with very specific food incompatibilities and who would have probably been fine for a long time if they had not had such an early exposure to the problematic foods.

In summary, it only makes sense that if our genes are compatible with a supply of a great variety of chemicals from lean meat, fish, fruits and vegetables that any deviation from this is going to have a negative effect on part of the gene pool. Thus, it is not surprising that epidemiological studies have shown that the more dairy, grains and high fat meats a society eats the greater the prevalence of all the various non-infectious, “lifestyle” diseases which were listed above. The fact that the people of the outports of Newfoundland who eat mainly fish and home-grown vegetables have one tenth the amount of multiple sclerosis than do genetically similar Albertans whose diet is dominated by red meats, grains and dairy products is a fine example of the relationship between disease prevalence and dietary habits. If your car was built for diesel fuel, don’t be surprised if you have a variety of malfunctions when you start filling it with high octane gasoline!

It can be instructive to compare a Paleolithic diet with a standard North American one to understand where the main problems lie.

Protein – In a Paleolithic diet protein makes up about 25-30% of calories and is derived almost exclusively from lean meats and fish. This contrasts with the NA diet which consists of only 10-15% protein which is derived from high fat meats, grains, dairy products and legumes. Thus, both the amount and sources vary greatly between the two dietary practices. Proteins play a major role in autoimmune disease and thus these new sources of proteins (dairy, grains, legumes) which present the immune system with completely new protein fragments, are very problematic. Celiac disease is a fine example of an autoimmune disease driven by these novel proteins. These newly introduced proteins also play a major role in MS, rheumatoid arthritis, Crohn’s and type 1 diabetes.

Carbohydrates – Paleolithic carbohydrates were gained mainly from fruits and vegetables which have a low glycemic index and which are associated with abundant micro-nutrients and fibre. They made up about 30-35% of the calorie intake. Once again, the contrast with the NA diet is huge. In the NA diet carbohydrates are derived mainly from grains and refined sugars with fruits and vegetables being a minor supply. Furthermore, carbohydrates make up 50-60% of calories, nearly twice that of the Paleolithic diet. These new sources of carbohydrates have a high glycemic index and this, in combination with the great increase in intake, significantly stresses the glucose-insulin system. This results in a myriad of diseases most often led by type 2 diabetes. These new carbohydrates also have much less fibre and micro-nutrients which also has a very negative health effect.

Fats – Fats comprise about 35-40% of Paleolithic calories and consisted mainly of monosaturated and polyunsaturated fats. In the polyunsaturated fats substantial amounts of omega 3 EFAs were included such that the omega 6/omega 3 ratio was less than 4. Saturated fats made up less than 40% of fat supply. The main sources of fat were lean wild animals, fish and nuts. Currently the NA diet contains similar amounts of fat (35-40%) but the amounts of the various types of fats are very different. The main fat types eaten today are saturated fat from fatty red meats and dairy products and trans fatty acids from margarines and processed baked goods. Omega 3 fats are almost non-existent in the diet and the ratio of omega 6 to omega 3 EFAs exceeds 10. The overabundance of saturated fat, the introduction of an entirely new fat type (trans fatty acids) and a major deficiency in omega 3 EFA have resulted in major health problems including heart disease, stroke, hypertension, cancer and chronic degenerative diseases.

Micronutrients – The Paleolithic diet contains many more micronutrients (vitamins, minerals, antioxidants) than does the NA diet. Vitamin consumption was about three times that of today in the Paleolithic due to the high intake of fruits and vegetables. Similarily intake of Zn, Ca, K and Fe was much higher in the Paleolithic. Only sodium and perhaps iodine are consumed much more today. Sodium consumption is about eight times that of the Paleolithic and this overabundance of Na along with an very low consumption of most minerals and vitamins not surprisingly has serious consequences for health.

In summary, our current diet is very different from that consumed in the Paleolithic and with which humans are genetically compatible. These major differences are having a major effect on the health of the NA population and MS is just one of a broad spectrum of lifestyle diseases driven by our radically new dietary habits.

PubMed Abstracts

Am J Med 1988 Apr;84 (4):739-49

Eaton SB, Konner M, Shostak M

Department of Anthropology, School of Medicine, Emory University,

Atlanta, Georgia 30322.

From a genetic standpoint, humans living today are Stone Age hunter-gatherers displaced through time to a world that differs from that for which our genetic constitution was selected. Unlike evolutionary maladaptation, our current discordance has little effect on reproductive success; rather it acts as a potent promoter of chronic illnesses: atherosclerosis, essential hypertension, many cancers, diabetes mellitus, and obesity among others. These diseases are the results of interaction between genetically controlled biochemical processes and a myriad of biocultural influences–lifestyle factors–that include nutrition, exercise, and exposure to noxious substances. Although our genes have hardly changed, our culture has been transformed almost beyond recognition during the past 10, 000 years, especially since the Industrial Revolution. There is increasing evidence that the resulting mismatch fosters “diseases of civilization” that together cause 75 percent of all deaths in Western nations, but that are rare among persons whose lifeways reflect those of our preagricultural ancestors.

Med Hypotheses 1997 Sep;49 (3):247-61

Broadhurst CL

22nd Century Nutrition, Inc., Herbal Vineyard, Inc., Cloverly, MD 20905-4007, USA.

Natural whole foods contain fats as structural components, and have a balance of polyunsaturated fat, monounsaturated fat, and saturated fat. Since we are still a Paleolithic species, adapted to eating only wild foods, it is difficult to justify the consumption of anything other than an overall balance of triglyceride/phospholipid types in an evolutionary sense. No natural fats are intrinsically good or bad–it is the proportions that matter. Variety is recommended in dietary lipid structure, degree of saturation, and chain length. Pathological n-3/n-6 polyunsaturated fat imbalance, obesity, and progressive glucose intolerance are consequences of adopting cereal grain based diets by both humans and livestock. Food processing and refining amplify these problems. Excessive concerns regarding polyunsaturated fat peroxidation in vivo are not warranted when triglycerides are balanced and normal diets are consumed. Numerous phytochemicals present in unrefined oils, fruits, vegetables, and herbs afford significant protection from lipid peroxidation and chronic disease.

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