I would like to respond to Moira's post which indicated improvement in
symptoms in an Autistic child following adoption of a paleodiet.
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 auto-immune
in nature. Reed Warren's group (1) 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 (2). 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, circulatingT-lymphocytes can mount an immune response on
the cell or cells which present, via the MHC, that foreign peptide 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*401 and
DRB1*0101 (2). 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 (3).
The QKRAA or QRRAA amino acid motif also occurs quite frequently
in pathogens which reside in the human gastro-intestinal tract including
Escherichia coli, Proteus mirabilis, lactobacillus lactis, Brucella ovis
and many other anaerobic gut bacteria (3). The QKRAA or QRRAA
sequences are found specifically in a particular type of protein
contained in gut bacteria, called DnaJ proteins. DnaJ proteins
normally have a bacterial partner/ligand protein called heat shock
proteins (HSP70). It is the QKRAA or QRRAA amino acid sequence of
DnaJ which allows it to bind HSP70.
When the MHC presents endogenously derived DRB1 alleles which
contain the QKRAA or QRRAA amino acid motif, then circulating HSP70
proteins (which normally bind DnaJ proteins) can bind the body's own MHC
presented QKRAA or QRRAA sequences. Circulating CD4+ T-lymphocytes
recognize this HSP70/QRRAA sequence as foreign and mount an immune
response on all cells presenting this (HSP70) amino acid motif.
We believe that myelin basic protein contains an amino acid
sequence that is homologous to an A.A. sequence found in HSP70, and it
is this three way mimicry between DRB1 peptides, bacterial peptides and
self peptides which causes self tolerance to be broken.
So, how does a paleodiet have anything to do with this process?
Paleodiets are characterized by their lack of cereal grains, legumes,
dairy products, and yeast containing foods. Both cereal grains and
legumes contain glycoproteins called lectins which bind intestinal
epithelial cells and change the permeability characteristics of these
intestinal cells (4,5). Not only do these lectins cause an increase of
the translocation of gut bacteria to the peripheracy, they cause an
increased overgrowth of gut bacteria as well as a change in the gut
flora (4,5). Further, cereal and legume derived lectins (WGA, PHA
respectively) cause increased expression of intracellular adhesion
molecules (ICAM) in lymphocytes (6) which allow bacterial/immune
complexes to move from gut to the affected tissue. Additionally,
cereal and legume lectins increase lymphocytic expression of common
inflammatory cytokines such as tumor necrosis factor alpha (TNFa),
interleukin 1 (IL-1) and IL-6 which are known promoters of autoimmune
disease.
The cell walls of cereals and legumes contain a storage protein,
GRP 180, which also can act as a ligand to self presented MHC peptides
(7). Further, peptides contained in dairy proteins (bovine serum
albumins - BSA, among many) also may contain peptide sequences which can
interact with endogenously presented peptides (8). Cereal, legume,
dairy and yeast free diets potentially have therapeutic benefit in many
autoimmune related disorders via their ability to reduce gut
permeability and decrease the exogenous antigenic load both from
pathogenic bacteria and from potentially self mimicking dietary
peptides.
REFERENCES
1. Singh VK et al. Antibodies to myelin basic protein in children
with autistic behavior. Brain, Behavior and Immunity 1993;7:97-103.
2. Warren RP et al. Strong association of the third hypervariable
region of HLA-DR beta 1 with autism. J Neuroimmunol 1996;67:97-102.
3. Auger I et al. A function for the QKRAA amino acid motif:
mediating binding of DnaJ to DnaK. J Clin Invest 1997;99:1818-22.
4. Liener IE. Nutritional significance of lectins in the diet.
In: The Lectins: Properties, Functions, and Applications in Biology and
Medicine. IE Liener (Ed), Academic Press, Orlando, pp 527-52.
5. Pusztai A. Dietary lectins are metabolic signals for the gut
and modulate immune and hormone functions. Eur J Clin Nutr
1993;47:691-99.
6. Koch AE et al. Soluble intercellular adhesion molecule-1 in
arthritis. Clin Immuunol Immunopathol 1994;71:208-15.
7. Dybwad A et al. Increases serum and synovial fluid antibodies
to immunoselected peptides in patients with rheumatoid arthritis. Ann
Rhem Dis 1996;55:437-41.
8. Perez-Maceda B et a. Antibodies to dietary antigens in
rheumatoid arthritis--possibel molecular mimicry mechanism. Clin Chim
Acta 1991;203:153-65.
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