Allergy, Asthma, Autoimmunity Start the Same Way

Inflammation is the current medical buzzword. Name the disease and inflammation is there.

Reproduction Requires Controlled Inflammation
Aspirin blocks many of the steps in triggering inflammation and thus, aspirin administration can be used to reveal a role of inflammation in many unexpected places. Aspirin is effective in blocking some forms of infertility, inhibiting miscarriages and ameliorating postpartum depression. So inflammation is a critical part of reproduction. But, also notice that depression is a symptom of chronic inflammation.

Cancer Requires Inflammation
High dose (IV) aspirin has been successfully used to treat cancer. Inflammation is required for cancer growth, because both use the same transcription factor, NFkB. The aberrant signaling of cancer cells would normally lead to programed cell death, apoptosis, but inflammation blocks apoptosis. Aspirin can in turn block NFkB and in the absence of inflammation, cancer cells die by apoptosis.

Inflammation is Self-Limiting
Aspirin also transforms the COX/lipoxidase system to produce anti-inflammatory prostaglandins/eicosinoids. Inflammation normally progresses into anti-inflammation. Blocking this progression leads to chronic inflammation and a shift from local to systemic inflammation with the rise of inflammatory interleukins in the blood stream.

Immune Response Requires Inflammation
The signal molecules (IL-1, IL-6, TNF) and transcription factor, NFkB, associated with inflammation were all initially identified in the development of lymphocytes. Hence, IL stands for interleukin, a hormone that triggers leukocyte (literally white blood cells or cells associated with the lymphatic immune system, i.e. lymphocytes) development. The nuclear factor, i.e. transcription factor, involved in expression of the large chain, kappa, of immunoglobulins in B cells, was called NFkB.

Genes Expressed by NFkB Cause Symptoms of Inflammation
About five dozen genes are under control of NFkB. Among these are COX-2, the enzyme that converts omega-6 arachidonic acid to inflammatory prostaglandins; iNOS, the enzyme that produces nitric oxide that dilates blood vessels to produce hot, red skin; and the inflammatory interleukins, IL-1, IL-6 and TNF, associated with autoimmune disease, fatigue and cachexia (wasting).

Autoimmunity and Allergy Start with Inflammation
Medical treatments focus on symptom abatement and ignore cause. What causes obesity, allergy or autoimmune disease? The answer appears to be chronic systemic inflammation plus exposure to unusual proteins. The unusual proteins are immunogenic, i.e. interact with the immune system to produce antibodies or reactive T-cell receptors, and are subsequently recognized as autoantigens or allergens, that are the targets for immune attack. Inspection of these autoantigens and allergens shows that they all have one thing in common, they bind to heparin via a strong heparin-binding protein domain that is typically a triplet of adjacent basic amino acids.

Heparin is a Short, Highly Sulfated Fragment of Heparan Sulfate
Commercial heparin is purified from the intestines of hogs and cattle. Heparin is released from mast cells (made fluorescent for microscopy using berberine) along with histamine and is released into the intestines to block pathogens from binding to the heparan sulfate that is part of the intestine surface. The heparin is anti-inflammatory and it contributes to minimizing the inflammatory response of the intestines to food.

Inflammation Reduces Heparan Sulfate Production
Pathogen-generated inflammation of the intestines reduces heparan sulfate production and increases immune response to food antigens. NFkB activation by inflammation turns off the production of some genes needed for heparan sulfate proteoglycan (HSPG) synthesis. Since HSPG is a major component of the basement membrane that holds tissues together, the reduction of HSPG results in protein loss (proteinuria) from kidneys, leaking of intestines, and disruption of the blood/brain barrier.

Reduction of HSPG Results in Immunological Presentation of Autoantigens/Allergens
Proteins are brought into cells by specific binding to protein receptors. In many cases, particularly involving signaling or growth factors, both the signal molecules and the receptors bind to heparin. In addition, there is a robust circulation of HSPG, which is secreted and internalized with a half-life of approximately six hours. The sweep of the HSPGs take heparin-binding proteins with them for internalization, e.g. HIV-TAT, heparanase, tissue transglutaminase. I think that this HSPG sweep under inflammatory conditions also internalizes basic autoantigens and allergens with strong heparin-binding domains. This internalization is the first step toward immunological presentation and the immune response to autoantigens and allergens.

Autoantigen/autoantibody/HSPG Complexes Kill Cells
Antibodies against self-antigens, autoantigens form antigen/antibody complexes that also bind to and cross-link HSPGs, because of the heparin-binding domains of the autoantigens. The large complexes may disrupt HSPG circulation and trigger apoptosis or abnormal physiology. There are many other examples of heparin-based complexes that are toxic, e.g. Alzheimer’s amyloid plaque, diabetic beta cell antibody complexes, celiac gluten/tRG antibody complexes, multiple sclerosis myelin antibody complexes, atherosclerotic plaque.

Anti-Inflammatory Diet and Lifestyle Protects
Dietary and lifestyle adjustments that minimize inflammation, e.g. low starch, no HFCS, low vegetable oil (except olive) and supplements of vitamins D & C, fish oil (omega-3) and glucosamine, reduce the risk of allergies/asthma, degenerative diseases and cancers. Simple, high level supplements with fish oil reduce numerous mental disorders, e.g. depression, ADHD; infertility, pre-eclampsia and postpartum depression; allergies, asthma; arthritis, atherosclerosis; burn recovery, septicemia and head injury.

Reducing Inflammation is a Panacea for Modern Diseases
Most modern diseases have an inflammatory component, because modern diets are rich in inflammatory components, e.g. starch/sugar, corn/soy oil, HFCS, trans fats, and exercise is minimal. The medical industry has not successfully promoted healthy eating and exercise; and in fact has promoted the devastating replacement of saturated fats with inflammatory polyunsaturated vegetable oils. Meat production has moved away from grazing on omega-3-rich plant vegetation to omega-6-rich corn and soy. Replacement of the corn/soy based agricultural economy would have predictably immense beneficial impact in reducing inflammation-based degenerative autoimmune diseases and cancers.

A Paleolithic Perspective on Biomedical Literature

Homo sapiens seems to be inflammation prone, based on its assortment of biochemical deficiencies. All of the following lead to inflammation: hyperglycemia, vitamin C deficiency, fish deficiency, vitamin D deficiency, grilling meat. Is this an adaptation to agriculture and high population/communicable disease risk?

I was just visiting Diet Rosso and his article on the paleolithic diet flashed me back to some thoughts that I had on the evolutionary benefits of inflammation. So, Rosso made me think about this.

Inflammation is a big health problem in the US. All of the major diseases are inflammatory and all are exacerbated by the inflammatory US diet. But why is the fast food diet so inflammatory? Why is our corn/soy agricultural economy so hazardous to our health?

Corn and soybeans provide a good balance between carbohydrates, fats and protein. The amino acid composition of the combo is also fairly good, and corn and soy oils are high is unsaturated fats. So why does a corn/soy diet lead to degenerative and autoimmune diseases?

I think that the answer is that inflammation is getting a bad rap; as long as our immune system produces effective local responses to pathogens, we are pleased, but when the immune system cranks it up in response to a deluge of disease, we complain. I argue that our current inflammatory response to fast food is just a slight embellishment of the first dietary-based increase in inflammation that provided adaptive protection against the dangers of agriculture.

As I see it, agriculture had a series of dramatic impacts on the evolution of plants, animals and humans, in particular. Taming of plants and animals altered the human diet. Agriculture also institutionalized grilling and grouling, which meant bringing together carbs and protein at high temperatures. The result was an increase in dietary starch, seed/grain oils and advanced glycation endproducts (AGEs). There was also a decrease in fish, leafy vegetables and complex carbohydrates/fiber. Agriculture also led to a dramatic increase in population density.

I imagine that the first villages or very large family groups that resulted from sustained planting of harvestable crops resulted in plagues. Lots of people in close proximity with minimal hygiene is a prescription for infectious disease. Agricultural development required an immunological adaptation to higher loads of communicable diseases. That adaptation was inflammation triggered by agriculturally-associated diets high in starch and low in browsed veggies.

Hunting/gathering, especially along coasts, provided dietary vitamin C, as well as a high ratio of omega-3 to omega-6 fatty acids. Early humans defective in the ability to synthesize vitamin C or omega-3 fatty acids, would not suffer if they ate plenty of leaf veggies. Wild fish and game, as well as leafy veggies, have a high ratio omega-3 to omega-6 fatty acids, so these people would be safe from inflammation-based disease and infertility.

Agriculture focused on seed harvest results in a dramatic shift in diet and disease. Communicable disease was not a problem for hunter/gatherers, because of the necessarily widely distributed small population groups. Agriculture concentrates populations around the crop lands and increases the benefits of physiological energy expenditures on heightened immune activity to provide consistent protection against pathogens. Agriculture required chronic inflammation for disease protection.

Inflammation triggered by cues in the agricultural diet would have a high selective advantage. Individuals who increased their chronic level of inflammation in response to high blood sugar, compounds produced during cooking, i.e. AGE, vitamin C deficiency, vitamin D deficiency (low exposure to sun) and/or omega-3 oil deficiency, would have survival advantage in high population densities associated with agriculture.

The fast food diet is nothing more than an exaggeration of the agricultural diet and it produces and an exaggeration in the human adaptation to agriculture, high chronic inflammation and a suite of inflammatory diseases. Metabolic syndrome is another name for high chronic inflammation. Obesity is inflammatory. A sedentary lifestyle is inflammatory and aging is a suite of symptoms associated with inflammation. Hunter/gatherers didn’t show the same signs of aging as modern humans, and probably had comparable longevity (although there were many other risks.)

Lastly, I want to ponder the modern decline in fertility. Fertilization and implantation requires suppression of inflammation in the female reproductive system. Semen is uniquely rich in omega-3 oils and women who have a high frequency of unprotected coitus with a man with a high level of omega-3 in his semen, are much more likely to become pregnant and carry a pregnancy full term. The fetus requires high levels of omega-3 fatty acids for brain development and can rapidly deplete the omega-3 fatty acid a mother with a deficient diet. Omega-3 deficiency is associated with preeclampsia.

Early males and females with an inflammatory agricultural diet would tend to be infertile, because of omega-3 oil deficiencies and chronic elevated inflammation. Periodic exposure to an abundance of omega-3 fatty acids, such as feasting on migrating salmon, would synchronize fertility and subsequent births. It is humbling that a current research program in land-locked regions of South America uses cans of anchovies to remedy the same pregnancy problems that plague North America and its inflammatory fast food diets.