Evolutionary Discordance of Grains/Legumes in Diet - PART B

Evolutionary Discordance of Grains/Legumes in Diet - PART B

Evidence of genetic discordance as seen in autoimmune diseases


Up to this point, we have only briefly touched upon the role cereal grains have in inducing autoimmune disease (except for a brief look at celiac disease). There is substantial evidence (both epidemiological and clinical) showing the role cereal grains may play in the etiology of such diverse autoimmune diseases as multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis, sjogrens syndrome, dermatitis herpetiformis, and IgA nephropathy.

Although this proposal may at first seem preposterous, there is strong data to suggest that cereal grains may be involved in all of these diseases through a process of molecular mimicry whereby certain amino acid sequences within specific polypeptides of the gramineae family are homologous to (have the same structural form as) a variety of amino acid sequences in mammalian tissue. These homologous amino-acid (AA) sequences can ultimately confuse our immune systems so that it becomes difficult to recognize "self" from "non-self." When this happens, T-cells, among other immune-system components, launch an autoimmune attack upon a body tissue with AA sequences similar to that of the dietary antigen.

It seems that grass seeds (gramineae) have evolved these proteins with similarity to mammalian tissue to protect themselves from predation by mammals, vertebrates, and even insects. This evolutionary strategy of molecular mimicry to deter predation or to exploit another organism has apparently been with us for hundreds of millions of years and is a quite common evolutionary strategy for viruses and bacteria. It has only been realized since about the mid-1980s [Oldstone 1987] that viruses and bacteria are quite likely to be involved in autoimmune diseases through the process of molecular mimicry. Our research group has put together a review paper compiling the evidence (and the evidence is extensive) implicating cereal grains in the autoimmune process, and with a little bit of luck it should be published during 1998. [Editorial note as of June 1999: The paper has now been published; the citation is: Cordain L (1999) "Cereal grains: humanity's double-edged sword." World Review of Nutrition and Dietetics, vol. 84, pp. 19-73.]

Without the evolutionary template and without the evidence provided us by the anthropological community showing that cereal grains were not part of the human dietary experience, the idea that cereal grains had anything to do with autoimmune disease would probably have never occurred to us. This new electronic medium has allowed instant cross-fertilization of disciplines which probably would have rarely occurred as recently as five years ago.

How peptides in cereal grains may lead to molecular mimicry and autoimmune disease

In the human immune system, there are a number of individual mechanisms which allow the body the ability to determine self from non-self so that foreign proteins (i.e., bacteria, viruses, etc.) can be recognized, destroyed, and eliminated. Perhaps the most complex system which nature and evolution have engineered to accomplish this is the human leucocyte antigen (HLA) system. This system was discovered when early physicians found out that tissue from one human could not be grafted to another without rejection. The physiological function of this system was not to foil the efforts of transplant surgeons, but to initiate an immune response to parasites (viruses, bacteria).

All cells of the body manufacture HLA proteins, whose function is to bind short peptides (protein fragments) and display them on the cell surface. Most of the peptides are derived from the body's own proteins (self-peptides). However, when the body is infected by a virus or bacteria, the HLA molecules pick up peptides derived from broken-down proteins of the virus or bacteria and present them to T-lymphocytes. The purpose of T-lymphocytes is to continually scan the surfaces of other cells to recognize foreign peptides while ignoring self-peptides.

Once a T-cell receptor "recognizes" a foreign peptide, a complex series of steps is set into play which ultimately destroys the cell presenting the foreign peptide as well as living viruses or bacteria in the body which also have peptide sequences similar to those which were presented. When the HLA system loses the ability to recognize self (self-peptides) from non-self (foreign peptides), T-lymphocytes attack self-tissue, resulting in what is known as an autoimmune disease (i.e., celiac disease, IDDM, multiple sclerosis, dermatitis herpetiformis, ankylosing spondylitis, etc.).
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As mentioned previously, the incidence of a variety of autoimmune diseases follows a southeasterly gradient from northern Europe (highest incidence) to the Mideast (lowest incidence). This gradient occurs because the incidence of susceptible HLA haplotypes increases as one moves northwesterly from the Mideast. This gradient--which occurs for both the incidence of autoimmune diseases and HLA haplotypes--is not a serendipitous relationship, but occurred as a result of the spread of agriculture from the Mideast to northern Europe [Simoons 1981]. Consequently, as agriculture spread into Europe there were environmental elements associated with this demic expansion ("demic" means the spread of genes through either the migration or interbreeding of populations) which progressively selected against HLA haplotypes (combinations of HLA genes inherited from the two chromosomes in each cell) that were originally present in the pre-agrarian peoples of Europe.

Now, the question is, what were those environmental selective elements? In the case of celiac disease, it doesn't take a rocket scientist to determine that it was wheat. Increasing consumption of wheat caused increased mortality from celiac disease--thus, the incidence of celiac disease and its susceptible HLA haplotypes (HLA-B8, HLA-DQ, HLA-DR) are lowest in those populations with the most chronologic exposure to wheat (Mideasterners and southern Europeans) and greatest in those populations with the least exposure (northern Europeans). Similar arguments can be made for IDDM and a host of other autoimmune diseases. There are a substantial number of animal studies showing that consumption of wheat by rats increases the incidence of IDDM [Scott 1988a; Scott 1988b; Scott 1991; Elliott 1984; Hoofar 1993; Storlien 1996; Am J Physiol 1980;238:E267-E275; Schechter 1983].

How is it that wheat can wreak such havoc with the autoimmune system? Our research group believes that wheat contains peptide sequences which remain undigested and which can enter into systemic circulation. These peptide sequences are homologous to a wide variety of the body's tissue peptide sequences and hence induce autoimmune disease via the process of molecular mimicry. E.g., macrophages ingest the circulating wheat peptides. HLA molecules within the macrophage then present amino-acid sequences of the fragmented peptide to circulating T-lymphocytes, which through clonal expansion create other T-cells to "attack" the offending dietary antigen and any other self-antigen which has a similar peptide sequence--i.e., the body's own tissues.

The original non-agricultural HLA haplotypes conferred selective advantage in earlier evolutionary times because these genotypes provided enhanced immunity from certain types of infectious diseases. However, with the advent of cereals in the diet they represented a liability. Thus, the genetic data clearly shows that a recently introduced food type has resulted in genetic discordance between our species and those from the gramineae family.

Possible autoimmune connection between dietary peptides and some forms of autism


Autism in children is a neuro-developmental disorder characterized by few or no language and imaginative skills, repetitive rocking and self-injurious behavior, and abnormal responses to sensations, people, events, and objects. The cause of the syndrome is unknown, but there is increasing evidence that it may be autoimmune in nature.

Reed Warren's group [Singh 1993] found that 58% of autistic children maintained antibodies to myelin basic protein (a protein found in the myelin sheaths of nerves and suspected of being the target protein [self-antigen] for T-lymphocytes in the autoimmune disease multiple sclerosis). Additional support for the concept that autism may be autoimmune in nature comes from work showing that 46% of autistic children maintain major histocompatibility complex (MHC) alleles associated with the disease [Warren 1996]. The function of the MHC is to present self- and foreign peptides to circulating T-lymphocytes at the surface of all cells throughout the body. Thus, if foreign peptides are presented by the MHC, circulating T-lymphocytes can mount an immune response on the cell or cells that present, via the MHC, those foreign peptides, and destroy them.

The MHC not only presents foreign peptides, but it also presents peptides derived from the proteins of genes comprising the MHC itself. The susceptiblity genes for autism are: DRB1*0404, DRB1*0401, and DRB1*0101 [Warren 1996]. In a particular portion of these genes (the third hypervariable region [HVR-3]), there is a common amino-acid sequence shared by all three genes. This amino-acid sequence is either QKRAA (glutamine-lysine-arginine-arginine-alanine-alanine) or QRRAA. Thus, either the QKRAA amino-acid motif or the QRRAA amino-acid motif can be presented to circulating T-lymphocytes. This particular shared epitope increases the susceptibility to a number of autoimmune diseases, including rheumatoid arthritis [Auger 1997]. (An epitope is the part of an antigen recognized by an antigen receptor, i.e., a specific amino acid sequence of a protein.)