Dukan Diet

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.

The cause of allergies and autoimmune degenerative diseases is inflammation.

As a scientist, I am concerned with how the body works at the molecular level. I try to understand how molecules of cells interact to cause disease. So if you tell me that you have an allergy, I want to understand how you became allergic and I am much less interested in how you avoid triggering your allergy. If you say that your allergy is triggered by ragweed pollen, I want to know the shape and structure of the proteins or carbohydrates of the pollen that actually come in contact with receptors on the surface of your cells and trigger the allergic response, but I also want to trace those interactions back to the original events that started the allergy.

Allergies are mistakes of your immune system. Your body should learn to ignore common food and environmental molecules as it ignores itself. There is an elaborate system used by cells of your body to disassemble and display fragments of dangerous pathogens on the surface of cells for evaluation by the immune system. Inappropriate display of innocuous or self molecules is part of the problem in allergies and autoimmunity.

Ragweed pollen, for example, will cause no reaction unless pollen proteins bind to antibodies (IgE) held in receptors on the surface of mast cells. We know that ragweed pollen binds to anti-ragweed antibodies on the surface of mast cells of allergic individuals and triggers the release of histamine and other molecules that give the symptoms of allergy. That’s why you take antihistamines to remediate the allergic symptoms. The first questions are what are the ragweed molecules to which the antibodies bind, i.e. the ragweed allergens and why is this allergic person producing anti-ragweed antibodies?

We know that the ragweed allergens are common pollen proteins, but why are they particularly prone to producing allergies? I tried to figure out this riddle by asking if there is something about these proteins that make their transport into cells more likely. I had just discovered that a particular amino acid sequence, a triplet of basic amino acids, lysine or arginine, resulted in transport of proteins into cells. This triplet that provides binding to heparin is found, for example in the nasty HIV protein, called TAT that moves on heparan sulfate proteoglycans (HSPGs) from infected to uninfected human cells and paves the way for the spread of infection. This triplet is also found in heparanase, that is first secreted by cells in an inactive form, is brought back into cells by binding to HSPGs, is activated by partial digestion and resecreted for action in the extracellular environment. This heparin-binding triplet can also be added to other proteins, e.g. the fluorescent jellyfish protein, to transport those proteins into cells.

Examination of ragweed pollen and subsequently dozens of other common allergens revealed that each one (or a close relative) possessed the unusual heparin-binding triplet of basic amino acids. The basic charged character of these sequences also determined that these parts of proteins would be present as accessible coils on the surface of the proteins. It is interesting that people suffering from the autoimmune disease of lupus produce antibodies to most of the proteins found in the nucleus of their cells. These nuclear proteins bind to nucleic acids, that mimic the structure of heparin and in many cases have triplets of heparin-binding basic amino acids. Thus, it appears that allergenic proteins enhance the chance of uptake by cells that can display them to the immune system, because of their triplet heparin-binding domains and the immune system subsequently produces antibodies that bind to other regions of the protein allergens. This explains how the antibodies are produced to these allergens, but it does not explain why some people produce antibodies to environmental antigens and healthy people do not.

Allergic people readily expand their allergies to include new allergens. What is it about these susceptible people that makes them allergic? I think that the answer is inflammation. Inflammation leads to a disruption of normal production of heparan sulfate proteoglycans and as a consequence to a change in how external proteins interact with cells involved in processing antigens for presentation to the immune system. This means that people with chronic inflammation, also called the metabolic syndrome, are not only increasingly susceptible to diabetes, arthritis, heart disease, etc. but they are also at risk for picking up new allergies. This also suggests that an anti-inflammatory diet and lifestyle changes would be of great benefit to those with allergies. Unfortunately, because of immunological memory, it will take years to deplete the population of antibody secreting cells that provide the basis for a specific allergy and during this depletion time, the allergen would have to be scrupulously avoided. It might also mean that autoimmune diseases such as type I diabetes might be treated by depletion of anti-beta cell antibodies and their secreting B cells along with a shift to an aggressively anti-inflammatory diet.

It is my belief that many of the genetic components of allergies and autoimmune diseases would not be experienced in the absence of chronic inflammation as a precipitating condition.