Monday, September 3, 2012

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.

6 comments:

  1. As a Hashimotos patient I wonder if any therapies will be developed in my lifetime. I would also be happy with a better understanding of a dietary approach to reduce symptoms.

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  2. Katica,
    There is a cure for Hashimoto's thyroiditis. It amounts to changing diet and fixing gut flora.

    Most cases of Hashimoto's result from some form of gluten intolerance/celiac, so the first step is to eliminate grains containing the gluten proteins. This will reduce putting more of the aggravating plant antigens into your system. The next step is to repair the suppressive part of your immune system that is the foundation for your autoimmune disease. You have damaged your gut flora by a combination of diet and antibiotics. Your damaged gut flora no longer stimulates the development of the suppressive part of your immune system and continues to develop the aggressive part that is attacking your thyroid gland. Probiotics from live dairy products can provide temporary support for your immune system, but you also need to replace the dozens of different species of bacteria that you have eliminated by antibiotics.

    You can pick up new types of bacteria by stopping the practices that made you at risk for autoimmune diseases: excessive hygiene and avoidance of activities that provide exposure to dirt bacteria. You would not have this problem it you were in intimate contact with people/animals who have healthy gut flora and/or you constantly introduced new bacteria into your gut by eating vegetables that were only lightly cleaned, i. e. they still retained some live soil bacteria on their surfaces. Your cooking and cleaning habits have prevented you from replenishing your gut flora with the bacteria needed for normal development of your immune system.

    A third component needed for development of Hashimoto's, in addition to wheat and antibiotics/damaged gut flora, is inflammation. The Anti-Inflammatory Diet that I recommend at the top of this page will eliminate most sources of inflammation and should be the foundation for your cure.

    Don't forget to fix your vitamin D deficiency! Don't expect a low dose supplement, e.g. 2,000 IU of D3 per day, to fix your deficiency. Keep measuring your serum levels till you are over 60 ng/ml.

    Hashimoto's cannot be fixed without fixing your vitamin D deficiency, removing gluten and inflammatory components from your diet and fixing your gut flora/immune system.

    Let me know about your progress, you should expect a complete cure, unless you have wiped out your thyroid gland.

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