Thursday, April 1, 2010
Parasitic worms reverse allergies and autoimmune diseases using oligosaccharides to mimic self and silence immune over-responsiveness.
Helminth therapy, i.e. infection with parasitic intestinal worms to provide remission from allergies, inflammatory bowel and other autoimmune diseases, has been examined as a potential therapeutic model to rehabilitate immunological dysfunction. The surface oligosaccharides of these worms have been found to mimic human oligosaccharides and alter immune responses by binding to carbohydrate-binding, i.e. lectin, receptors.
The essence of allergic and autoimmune diseases is a defect in distinguishing between pathogen, innocuous and self molecules. Heightened immune reactions as a result of inflammation move the immune system toward production of antibody and T cell receptors specific for antigens. Those antigens respond to unique receptors on the surface of each B and T lymphocyte. The lymphocyte population has been previously depleted of cells that can produce receptors that will bind to most self antigens. This depletion makes the lymphocyte population generally non-responsive, or tolerant to self antigens. Thus, the immune system is blind to the body.
Regulatory T Cells and Tolerance
Most of the immune cells of the body are present in the lining of the gut. It is in the gut that various immune cells continue to develop for their various roles, including controlling immune reactions to self antigens and to common food molecules. Immune cells in the gut are exposed to some food molecules and bacteria that leak through the cells of the intestinal villi. Responding to these common antigens by inflammation can lead to inflammatory bowel disease. This pathological over-responsiveness is normally avoided by development of regulatory T cells, Tregs, that suppress immune responses to common food molecules and to surface antigens of common bacteria.
Treg Development Depends on Gut Flora
Gut bacteria are needed for the normal function of the immune system. Oddly, Helicobacter pylori, Hp, the cause of stomach ulcers and cancer, also stimulates the development of Tregs. Thus, the pathology of Hp may result not from its presence, but rather from how it is growing. Since Hp uses hydrogen gas produced by Klebsiella in the lower bowel and hydrogen production is dependent on dietary starch, then it follows that the pathological behavior of Hp may be dependent on dietary starch. A low starch diet may actually result in Treg stimulation from Hp and a reduction in allergies and autoimmune diseases.
Tregs Enhanced by Heliminths
Immunological tolerance is also stimulated by parasitic worms, Helminths. Helminth infestations, therefore, reduce allergies and autoimmune diseases and may contribute to the hygiene hypothesis to explain the prevalence of allergies, autoimmune and other inflammation-based degenerative diseases in modern societies. Examination of worms to find the molecules responsible for inducing immunological tolerance has identified complex surface and secreted oligosaccharides (small sugar chains) as the active molecules. Helminth oligosaccharides mimic human cell surface oligosaccharides and bind to carbohydrate-binding, lectin, receptors on immune cells to stimulate Treg development.
Lectin Receptors Control Tolerance
There are many implications of the modulation of the immune system via oligosaccharides. Note that related oligosaccharides are components of human milk and prepare the gut and develop the immune system. This explains why formula, which lacks these unique oligosaccharides, results in aberrant gut flora, contributes to neonatal necrotizing colitis and supports the development of allergies and autoimmune diseases. In contrast, judicious use of self or Helminth oligosaccharides may provide a means of restoring the function of damaged immune systems and therapy for allergies and autoimmune diseases. Also note that the critical use of lectins, which have oligosaccharide-binding sites rich in aromatic amino acids to bind the hydrophobic faces of the sugars, will also bind and provide entry into immune cells for allergens and autoantigens that have triplets of basic amino acids. The binding sites of lectins should also bind many aromatic phytochemicals. Immunomodulation by phytochemicals may result from interference with or mimicking the binding of oligosaccharides to lectin receptors.
van Die I, Cummings RD. Glycans modulate immune responses in helminth infections and allergy. Chem Immunol Allergy. 2006;90:91-112.