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 al. Antibodies to dietary antigens in
rheumatoid arthritis--possible molecular mimicry mechanism. Clin
Chim Acta 1991;203:153-65.
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