Helminths, Oligosaccharides and Immunotolerance

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.

Immune Tolerance
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.

reference:
van Die I, Cummings RD.  Glycans modulate immune responses in helminth infections and allergy.  Chem Immunol Allergy. 2006;90:91-112.

Cause of Autoimmunity and Allergies

Inflammation-Induced Presentation by Mannose Receptor

Speculation on how innocuous proteins become the targets of our immune systems, and result in allergies, asthma, celiac, arthritis, lupus, and other inflammatory autoimmune diseases.

Inflammation

It all starts with chronic inflammation. In most cases diet is the predominant source of inflammation, but infections (bacterial, viral, fungal) may also contribute. Inflammation sets the stage for faulty processing of proteins at the focal location where lymphocytes and antigen-presenting cells are congregating.

Antigen Presentation

At this point a major mistake occurs. Cells that have been alerted to danger by inflammatory cytokines, start to internalize and process proteins in the vicinity, so that peptide fragments of the “antigens” can be displayed on their surfaces in the clutches of major histocompatibility complex proteins. The problem arises when self proteins are internalized, processed and displayed as candidate peptides.

Basic Triplets of All Allergens and Autoantigens

I have looked at dozens of allergens and autoantigens, and they all have one peptide sequence in common, a triplet of basic amino acids. The impetus for this article was finding this morning that one of the autoantigens for Hashimori’s thyroiditis is thyroglobulin, the serum carrier of thyroid hormones. I checked the sequence of thyroglobulin and it has two of the rare basic triplets.

Thyroiditis Autoantigen Is Thyroglobulin

I checked the Pubmed literature to see if thyroglobulin is naturally taken up by cells, since I have been trying to figure out the receptor for basic triplets. What I found was an article on the binding of thyroiditis autoantigens to mannose receptor. The idea of the paper was that the autoantigens in this case were heavily glycosylated and maybe the mannose receptor that is involved in antigen presentation of glycosylated antigens, would bind the selected autoantigens as well. I didn’t get much past the title of the paper.

Candidates for Allergen/Autoantigen Receptor

What I put together was the fact that antigen presenting cells use mannose receptor to internalize antigens. This places this receptor in the right place and the right time to be a receptor for basic triplets. But what would a basic triple binding protein domain look like and could mannose receptor be a candidate?

Structure of Thyroglobulin

I downloaded a structure for mannose receptor and began looking for a surface region that would bind carbohydrates, aromatics and basic amino acids. The critical amino acids in all of these cases are aromatic amino acids, phenylalanine, tyrosine and tryptophan. Tryptophan is at the heart of most carbohydrate binding proteins. Since the mannose receptor is a member of the carbohydrate-binding lectins, I expected to find tryptophans on the surface of the mannose receptor. I just looked for the tryptophan that binds the carbohydrates. It was exactly as I predicted. The mannose receptor should be able to form very stable tryptophan/arginine-like ladders with basic triplets.

I made a figure of the mannose receptor bound to a carbohydrate (red and grey). One of the exposed tryptophans (yellow) is bound to the carbohydrate. Several other tryptophans could be exposed and oriented toward a basic amino acid spread over the surface of the tryptophan in place of the carbohydrate. A similar kind of structure is used by importin to transport proteins with nuclear localization sites (NLS, basic quartets) into the nucleus. Many proteins with NLSs are also autoantigens, e.g. lupus.

I think that the peculiar circumstances that lead to allergy and autoimmunity result in the binding of self-proteins or allergens to mannose receptor and result in antibody production.

Why the Mannose Receptor?

Why does the mannose receptor make mistakes? The exposed tryptophan may also bind numerous plant products. In fact, the phytochemicals, e.g. alkaloids, flavonoids and terpenoids, are an abundant and varied group of chemicals that would bind to the exposed tryptophan of the mannose receptor and compete for binding with basic triplets. Protection offered by plant “anti-oxidants” may be due in part to this activity.