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.
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
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:
- 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;
- proteins of infectious agents such as viruses and bacteria;
- 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.
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.