Autoimmune Diseases, Bacteria and GALT (Gut Associated Immune System)

Celiac, Oxidative Stress, Peroxiredoxin, Alopecia

Grain/gluten intolerance, celiac is an immunological attack on the small intestines with increased risk for numerous autoimmune diseases.  Hashimoto’s thyroiditis is a common sequela of celiac and the two diseases share the same autoantigen, tissue transglutaminase (tTG).  Thus, the development of celiac and the production of antibodies to the tTG produced in the intestines, results in a subsequent immunological attack on other tissues that produce lots of tTG, e.g. the thyroid.  Gluten intolerance, because of its attack on the intestines and the proximity of a major part of the immune system (GALT), may play a major role as the foundation for autoimmune diseases.

Gluten Intolerance First Step in Autoimmune Diseases

Celiac may also lead to herpatic lesions of the skin, dermatitis herpetiformis and loss of hair, alopecia.  In these cases, the autoantigen is peroxiredoxin, an enzyme that eliminates hydrogen peroxide produced as a result of accumulation of reactive oxygen species, e.g. superoxide, associated with inflammation.  Peroxiredoxin is also implicated as an autoantigen in periodontal disease, suggesting that celiac may also contribute to dental gum inflammation.

Peroxiredoxin 5 Gene Associated with Alopecia Risk

A recent study (see ref. below) of genes associated with alopecia identified genes involved in Treg and Th-17 development, as well as peroxiredoxin 5 as contributors.  As expected, several genes involved in antigen presentation (HLA-DRA, HLA-DQA)  were also identified.  Th-17 lymphocytes are involved in immune attacks on self tissue, i.e. autoimmune diseases, such as alopecia, in which hair follicles are attacked by the immune system.  Tregs control immune attacks on self tissues.  Peroxiredoxin is an autoantigen and is produced in elevated amounts around hair follicles attacked in alopecia.

Basic Amino Acids of Peroxiredoxin as Expected for Autoantigen

I checked the amino acid sequence of human peroxiredoxin 5 and found an alternative (-nrrlkrfsmv-) to the triplet of basic amino acids that I expect for an autoantigen.  In this case there are two adjacent pairs of basic amino acids (blue rr and kr) that I think precipitate immunological presentation of peroxiredoxin.  Peroxiredoxins are produced in response to oxidative stress at sites of  inflammation and the presence of celiac compromises the gut associated immune system (GALT) that provides Tregs to restrict autoimmunity, so celiac sets the stage for peroxiredoxin presentation to the immune system and for subsequent production of anti-peroxiredoxin antibodies, autoimmunity and destruction of hair follicles, alopecia.

Anti-Inflammatory Diet Should Avoid and Treat Autoimmunity

Control of autoimmune diseases mediated by peroxiredoxin should benefit from a reduction in the conditions that spawned the diseases:

• Th-17 elevation -- celiac inflammation stimulated by grain/gluten
• Treg loss -- GALT inactivation due to inflammatory diet and inappropriate gut flora
• Autoantigen (basic amino acid concentration) presentation -- oxidative stress stimulation of peroxiredoxin

Treatment would be supported by dietary changes:

• anti-inflammatory diet to control gut inflammation and minimize celiac symptoms (vitamin D, low carb/high saturated fat, high omega-3 to -6 fatty acid ratio, no grains)
• probiotics and soluble fiber (e.g. pectin, inulin) to re-establish gut flora (cure dysbiotic constipation) and GALT function, and development of Tregs
• supplements to compensate for depletion of vitamin C and glutathione by oxidative stress, e.g. vitamin C and acetylcysteine (NAC)

Th-17 and Tregs in HIV Infections

Th-17 cells are also reduced by HIV infection, producing susceptibility to infection, but this infection should also reduce autoimmune disease.  The reduction in Th-17 also may be a consequence of problems in the GALT.  Therapy for HIV infection should also include diet considerations to increase Th-17 and also Tregs to reduce autoimmune diseases due to unbalanced Th-17.

ref.

Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y, Kim H, Singh P, Lee A, Chen WV, Meyer KC, Paus R, Jahoda CA, Amos CI, Gregersen PK, Christiano AM.  2010. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.  Nature. 466(7302):113-7.

Humans vs. Naked Mole Rats

Blood Sugar, Insulin, Superoxide, Couch Potatoes

(Thanks to my loyal readers for the inspiration for this article.)
There is a lot to be learned by sticking one's head in the sand.  Mole rats of East African deserts are just as naked as humans, but beyond the lack of hair and complex social structures, we are as different as night and day.  These differences explain some of our unusual physiological characteristics.  Maybe our health problems are linked to our sweaty skin, predatory nature and our need to run, just as the naked mole rats (NMRs) are adapted to their dark, high carb, climate-controlled burrows.

Mole Rats:

• low metabolic rate controlled by eating
• live in low oxygen burrows
• poor temperature regulation
• live in the tubers that they eat -- sweet potatoes with legs
• no insulin or superoxide dismutase
• vitamin C and D production (in darkness)?
• no pain sensors in skin, no stress, no sweat
  
• mostly vegetarian, starch

Humans:

• high metabolic rate controlled by physical activity
• live in high oxygen
• temperature regulation by sweating
• hunters, runners, farmers
• no vitamin C production, vitamin D via sunlight
• insulin used to regulate blood sugar, insulin resistance by superoxide
• oxidative stress leads to inflammation and disease
• carnivores, fat

Naked Mole Rats Are as Unique as Humans

Naked mole rats and humans are odd compared to most mammals.  Those oddities may explain a lot about modern human diseases.  The biggest difference between humans and NMRs is the control of blood glucose.  It seems that NMRs control their metabolism by their eating.  In times of starvation, the NMRs eat less and their metabolic rate lowers.  At the cellular level, this must mean that fat stores are converted to blood glucose to modestly regulate blood sugar as it drops, but the lack of insulin does not permit control of high blood sugar.  Thus, a rise in blood sugar must lead to cessation of eating.  This would make sense, because NMRs husband their resources -- they typically encounter few, very large, starchy, underground tubers/roots, eat into them and continue to live off of them for their lifetimes.  They are underground farmers.  They do not wolf down their slow moving prey and hunt for more.

NMRs Know When to Stop

Individual cells of NMRs regulate their metabolism without apparent recourse to adjusting their surface glucose transporters, since their blood glucose levels are constant or unmanipulateably low.  There is no mechanism for blocking influx of glucose by insulin stimulation when intracellular glucose is too high.  It would be expected that intravenous injection of excess glucose could kill NMRs by producing excess intracellular glucose spilling excess high energy electrons of the electron transport chain into superoxide damage.  Of course low tissue oxygen levels would provide protection, since the rate of superoxide formation is proportional to oxygen concentration at the mitochondrial surface.

Humans Are Runners

Humans are adapted to running down prey during the heat of the day, which means that they produce high metabolic rates, high demands for cooling, high tissue oxygen levels and high glucose/fat utilization.  In a lengthy chase, glycogen is rapidly depleted and fat metabolism ensues.  Human brains are adapted for access to lots of oxygen and nutrients.  Human tissues are adapted to low serum glucose and high levels of oxygen.  Moderate levels of serum glucose lead to increased cellular metabolism via insulin production and increased glucose transport into cells.  Low serum glucose leads to lipid mobilization and liver gluconeogenesis.

Humans Kill for Fat

Physical activity regulates human cellular activity.  Depletion of celllular ATP leads to an increase in cell surface glucose transporters.  Inadequate serum glucose, low intracellular glucose (phosphates) and low ATP lead to lipid utilization.  Lipids are all metabolized in mitochondria and require oxygen as the last, low energy electron acceptor in the electron transport chain.  Brain evolution in humans was adapted to high metabolism and intelligence is associated with intense brain vascularization, oxygen supply and lipid utilization.  It could be argued that glycogen storage is a way for humans to handle excess blood sugar during sleep inactivity, since humans are adapted for handling fats and tolerating carbohydrates.

Sweet Tooth Is Deciduous

Why do humans have a sweet tooth?  A group of early humanoids stumbling onto a cache of cookies made by elves, would quickly eat themselves into a stupor as their blood was diverted from brain to belly, their blood sugar rocketed, insulin surged, glucose gushed into cells, cellular metabolism peaked, cellular ATP pegged over, and superoxide spilled high energy electrons out of the saturated mitochondrial ETC.  Cookies would be killers for humans, if superoxide production didn’t block insulin-based transport of glucose into most cells and channel the high blood glucose into fat deposition. 

Marauding Naked Mole Rats

Cookie-fed humans become fat, lethargic and start to look like potatoes with legs, i.e. NMRs.  Unfortunately, unlike NMRs, humans don’t have off switches for carb glutting.  Humans evolved to run on fats, and can exploit occasional carb caches, because of an adaptive sweet tooth, but lack of evolutionary experience with gigantic carb caches, e.g. agriculture and supermarket cereal aisles, left humans maladapted for high carb diets.  We can’t pull out the HFCS intravenous line and instead become couch potatoes waiting as potential victims for giant marauding NMRs (the healthcare industry).  Fortunately, NMRs can keep the potatoes fat and feed on them indefinitely.

Superoxide Causes Insulin Resistance, Type 2 Diabetes

Intracellular Nutrient Excess Produces Mitochondrial Electron Accumulation
 (Article referenced below was brought to may attention by Cristian Stremiz - thanks)

Insulin resistance blocks insulin-based transport of glucose into cells that are already overloaded with nutrients. The spilling-over of excess high energy electrons in the mitrochondrial electron transport chain onto oxygen produces superoxide. Superoxide is the trigger to block the import of still more glucose. Thus, insulin resistance is a cellular defense against sudden death by superoxide and other reactive oxygen species (ROS).

High Energy Electrons of Glucose Are Used to Make ATP

Cells are biochemical machines that turn on genes to produce enzymes to convert the high energy electrons on the carbon and hydrogen atoms of glucose into ATP energy and molecular components of the cell. The high energy electrons are systematically depleted of energy, protons are pumped to produce a proton gradient across the inner mitochondrial membrane, ATP is made using the proton gradient and the low energy electron are passed off to oxygen molecules to make water. That is a quick summary of cytoplasmic glycolysis, the tricarboxylic acid cycle (mitochondrial matrix) and the mitochondrial electron transport chain. The final step of transferring the depleted electrons to oxygen to make water is how oxygen is consumed in respiration. Note that if everything works well, the high energy electrons of glucose, which could suddenly release all of their energy directly interacting with oxygen and start a fire, just produce water. Another bad alternative would be for the high energy electrons to bind to molecular oxygen making superoxide.

Cells Adjust their Glucose Individually to Match ATP Use

If the supply of ATP from the mitochondrial electron transport chain of a cell gets low, this triggers the migration of vesicles with glucose transport proteins to the cytoplasmic membrane. Since the number of transport proteins determines the rate of import of glucose, then more transporters means an increase in glucose and more ATP. Type 2 diabetes and insulin resistance represents the others extreme, i.e. what happens when cells get too much glucose, max out their capacity to make ATP and high energy electrons build up in the electron transport chain.

High Blood Sugar Triggers Insulin Production to Import the Glucose into Cells

Cells can also participate in body-wide metabolism coordinated by hormones, such as insulin. A sudden increase in blood glucose concentration triggers the pancreas islet cells to release insulin into the blood. The insulin binds to insulin receptor proteins on the surface of cells and that signal brings more glucose transport proteins to the cytoplasmic membrane. The cells import additional glucose and their metabolism increases and more ATP is produces. This lowers the blood glucose level. Some cells can continue to accumulate glucose in the form of glycogen or fat droplets, but other cells do not have this storage capacity. If glucose is supplied beyond the capacity of the cell to use it, then the mitochondrial electron transport chain begins to produce superoxide.

Superoxide Is a Reactive Oxygen Species (ROS)

Oxidation stress is the reason that plant antioxidants, vitamin C and N-acetyl-cysteine are recommended to avoid inflammation. One of the major sources of oxidation stress is the production of superoxide. Cells produce an enzymes, superoxide dismutase, to convert superoxide into hydrogen peroxide, and catalase to convert hydrogen peroxide into oxygen and water. Superoxide can also interact with nitric oxide to produce the nitric oxide radical. Unfortunately, superoxide can also produce hydroxyl radicals that can react with unsaturated lipids to produce lipid peroxides. Thus, superoxides can contribute to the production of many ROS, cause oxidation damage and trigger inflammation.

Many Different Processes that Produce Insulin Resistance all Produce Superoxide

The trigger for insulin resistance appears to be mitochondrial superoxide accumulation. A recent article used numerous mouse models of insulin resistance that mimic the typical human risk factors for insulin resistance and type 2 diabetes, e.g. excess nutrition, physical inactivity, pregnancy, polycystic ovarian syndrome, metabolic syndrome, inflammation, oxidative stress, anti-inflammatory corticosteroids, etc. and demonstrated that in each case mitochondrial superoxide accumulated. Moreover, mutant mice with lowered superoxide dismutase were more susceptible to insulin resistance and mutants producing an overabundance of superoxide dismutase were resistant to insulin resistance.

Insulin Resistance Is a Natural Defense Against Energy Excess

Superoxide sensing and insulin resistance protect cells against too much energy input and oxidative stress, but without the ability to reduce blood sugar, hyperglycemia leads to the suite of degenerative reactions that provide the symptoms of type 2 diabetes.

reference
Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, Richardson AR, James DE.Insulin resistance is a cellular antioxidant defense mechanism.Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17787-92. Epub 2009 Sep 30.