The Human Operating Manual

Immune System & Lymphatic System

Immune System & Lymphatic System

What it is

What it does

How it communicates with the rest of the body

What can go wrong with it

How to look after it

The Immunity Fix notes

Virtually all living organisms, including unicellular organisms and bacteria, have an elementary immune system called the restriction modification system. The most basic qualities of immunity found in plants and eukaryotes include the production of antimicrobial peptides called defensins, engulfing of large particles through phagocytosis and the complement cascade that enhances the effectiveness of antibodies. Humans and jawed vertebrates have more sophisticated mechanisms, such as the ability to start recognizing certain pathogens more efficiently over time and adapt to them better (known as adaptive immunity).

Immune System Classifications

Innate Immune System (IIS) is the one you are born with and comprises the majority of host defense. It is a default quality of the body to identify and react to foreign substances in a non-specific generic way. Innate immunity is usually activated when microbes or pathogens have entered the organism and are recognized by pattern recognition receptors (PRRs) that recognize microbial components. The same can also happen upon injury, damage, or stress. PRRs are used by virtually all living organisms.

Examples of surface barriers that protect against the immediate entry of pathogens include the skin and mucous membranes of animals, the exoskeleton of insects and the outer layer of leaves. There are also chemical barriers such as antimicrobial peptides that get secreted by the skin, antibacterial enzymes in the saliva, tears, breast milk and stomach acid. When particles get in through the body’s openings like the nose or mouth, mechanical reactions like sneezing, coughing or urination will kick in as to eliminate the threat.

Pattern recognition receptors are expressed primarily by cells of the IIS, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells. They recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Extracellular PAMPs are verified partly by toll-like receptors (TLRs). TLRs trigger the secretion of cytokines that turn on other host defense mechanisms.

  • The killing of pathogens by antibodies is called the ‘complement cascade or system’. It contains over 30 different proteins and comprises the major humoral component of the IIS response. Complement triggers phagocytosis, inflammation and membrane attack of cell walls of bacteria.
  • Antibodies or immunoglobulins (Ig) are large Y-shaped proteins produced primarily by plasma cells to neutralize pathogens. They recognize a specific molecule characteristic to a particular pathogen called an antigen, tagging them for destruction. In mammals, there are five isotypes of antibodies (IgA, IgD, IgE, IgG and IgM).

The innate immune system is mediated by white blood cells (leukocytes), which include phagocytes (macrophages, neutrophils, dendritic cells), innate lymphoid cells, mast cells, eosinophils, basophils and natural killer cells. They eliminate pathogens through either physical attacks or by engulfing them. The latter is called phagocytosis. It is considered to represent the oldest form of host defense. Phagocytes move throughout the body to find invaders but they can also be summoned by cytokines.

  • Dendritic cells (DCs) are phagocytes located in the skin, nose, lungs and intestines. They link the body’s tissue with the immune system by presenting antigens to T cells.
  • Natural killer (NK) cells are lymphocytes that do not directly attack intruders. Instead, they eliminate dysfunctional host cells, such as tumor cells, senescent cells or cells infected with a virus by secreting cytotoxic molecules. NK cells recognize infected cells by a condition called ‘missing self’, which describes cells that have a low level of a cell-surface marker called MHC I (major histocompatibility complex class I). Healthy normal cells maintain intact self MCH antigens and the NK cells preserve them.

Inflammation is the innate immune system’s immediate response to an infection. This creates swelling, heat, sweating, pain and increased blood flow to the region of injury. Fever is mediated by prostaglandins that are a group of lipids called eicosanoids that have hormonal-like effects. Inflammation is also produced by cytokines like interleukins that communicate between white blood cells and interferons that regulate cell functions during a viral infection. Cytokines summon immune cells to kill pathogens but also initiate healing.

Adaptive Immune System (AIS) is what you obtain by getting exposed to various pathogens throughout your life. Every previous infection creates an immunological memory that remembers each infectious agent and gives them a signature antigen. It is a more specific response that gets triggered by recognizing non-host antigens during a process called antigen presentation. Adaptive immunity can be acquired naturally through exposure or artificially via vaccination. The first functions of the adaptive immune system arose with the first vertebrates because invertebrates lack them. It is important to note that adaptive immunity seems to have the ability to help fight infections even if you have never been exposed to them before. For example, previous exposure to common cold coronaviruses may provide some protection against SARS-COV2 as there are similarities in their structure. Importantly, T-cell immunity seems to last decades, whereas antibody protection may only last a few months. You need to have well-functioning T cells for your adaptive immunity to work. Unfortunately, T cell function declines with age, poor diet and chronic diseases.

The AIS is composed of lymphocytes like T cells (T killer/helper cells) and B-cells (antibody producers), which are derived from hematopoietic stem cells in the bone marrow. T-cells are implicated in the cell-mediated immune response, whereas B-cells are involved with the humoral immune response. Once an invading pathogen has entered a cell it has escaped antibody defense, which is known as humoral immunity, and this is when the body utilizes T cells to eliminate pathogens.

  • Killer T cells eliminate infected, damaged or dysfunctional cells by recognizing antigens coupled to MCH I molecules. This process is assisted by co-receptors on T cells called CD8. Once contact is made, T cells release cytotoxins that penetrate the target cell’s membrane and induce apoptosis or programmed cell death, which helps to stop viral replication.
  • Helper T cells or CD4 T cells modulate both innate and adaptive immunity, helping to determine what kind of an immune response is appropriate to deal with a particular pathogen. They have no cytotoxic or direct pathogenic properties. However, upon activation, resting helper T cells release cytokines that enhance the microbicidal effect of macrophages and activity of killer T cells. Helper and regulatory T cells recognize antigens coupled to MCH II molecules by expressing T cell receptors (TCR).
  • Gamma delta T cells have the same qualities as killer T cells, helper T cells and NK cells. They have an unconventional T cell receptor (TCR) that is made of one γ (gamma) chain and one δ (delta) chain as opposed to αβ (alpha beta). The highest abundance of gamma delta T cells can be found in the gut mucosa and they link adaptive and innate immune responses. Gamma delta T cells recognize intact antigens bound to no MCH receptors.

On B cell surfaces there are B cell antigen-specific receptors that recognize entire pathogens without the need for antigen processing. They bind to foreign antigens and process them into antigenic peptides through proteolysis. These peptides are then showcased on the B cell’s surface MCH II molecules that attracts helper T cells. Helper T cells release lymphokines that activate the B cell. As a result, the B cell divides, and its descendants begin to secrete millions of antibodies that begin to circulate the blood and lymph to recognize pathogens that express the particular antigen in question. They then bind to those pathogens and mark them for destruction. Every B cell lineage expresses a distinct antibody; thus, the entire B cell antigen receptor complex represents all the antibodies the body can produce

Pathogens have developed many mechanisms that enable them to successfully enter and infect a host without getting detected or destroyed by immune cells.

  • Bacteria break down surface barriers by secreting digestive enzymes through the type II secretion system.
  • Using the type III secretion system, they can penetrate the host cell with a tube and direct their infectious proteins inside that turn off host defenses.
  • Some pathogens like Salmonella, which causes food poisoning, and Plasmodium falciparum, the parasite responsible for malaria, hide inside host cells to avoid detection.
  • Mycobacterium tuberculosis resides in a protective capsule.
  • Other bacteria like Pseudomonas aeruginosa and Burkholderia cenocepacia, found in cystic fibrosis, form biofilms that protect them from immune cells.
  • Some pathogens produce surface proteins and compounds that render antibodies ineffective.

When we have prior exposure to infections, the body knows how to fight similar pathogens better. However, there are cases where the opposite happens. For example, measles is able to eliminate the immune system’s acquired memory, making the person more vulnerable to diseases. Getting a little bit sick is good for an adaptive response, but getting too sick may deplete the body’s resources for immunity.

Immune System Disorders

Immunodeficiencies or immunocompromised states are conditions in which the body’s ability to fight infections is compromised. They happen when one or more parts of the immune system is inactive. For example, there is humoral immune deficiency, including B cell deficiency, T cell deficiency, complement deficiency, granulocyte deficiency or spleen dysfunction.

  • In most cases, immunodeficiencies are acquired through extrinsic factors like malnutrition, aging, specific medications, chemotherapy, heavy metal toxicity, mercury poisoning, alcoholism, smoking or a HIV infection, which are called secondary immunodeficiencies. Some people are born with compromised immune systems, which is called primary immunodeficiency. The exact genes responsible for this are unknown. Immunodeficiencies increase the vulnerability to opportunistic pathogens and decrease cancer immuno-surveillance.
  • With age, the body’s ability to mount an immune response decrease, which is called immuno-senescence. This primarily affects the adaptive immune system rather than the innate immune system, impairing the production of T cells that would recognize pathogens. There is also a decline in the cytotoxicity of NK cells, B cell production and total number of phagocytes. The ability to develop long-term immune memory, including through vaccination, is compromised. Age-related immunodeficiency is found in virtually all species, which is a major contributor to mortality and increased morbidity. However, it appears to be more determined by biological age instead of chronological age. Continuous exposure to pathogens and viruses can also speed up immuno-senescence.

Autoimmunity describes a situation where the body mounts an immune response against its own healthy cells and tissue. The immune system fails to differentiate between self and non-self, thus attacking the host. Conditions that create this kind of a response are called autoimmune diseases. Examples include celiac disease, type 1 diabetes, Hashimoto’s thyroiditis, Grave’s disease, Addison’s disease, rheumatoid arthritis and multiple sclerosis (MS).

  • There are multiple mechanisms thought to cause autoimmunity. They include discordant T and B cell activity, which creates autoreactive B cells, or infections bypassing T cells, creating super-antigens that activate B and T cells. An extrinsic antigen can also have similarities with host antigens, making antibodies attach to some host antigens, exaggerating the immune response. Defective apoptosis in dendritic cells can activate lymphocytes in a dysfunctional way, leading to a decline in self-tolerance. Genetic abnormalities in T cells, immunoglobulins and the MCH complexes are associated with risk factors for developing autoimmunity.
  • Women tend to be more susceptible towards certain autoimmune diseases because they mount a much larger inflammatory response upon activation than men. Pregnancy appears to create increased risk of autoimmunity due to the direct exchange of cells between the mother and child.
  • There is an inverse relationship between infections and autoimmunity. In some studies, parasite infections are associated with reduced autoimmune diseases, such as type 1 diabetes, autoimmune brain inflammation and multiple sclerosis. Hypothetically, different pathogens can promote the increase of regulatory T cells and anti-inflammatory molecules that will also provide protection to the host. In any case, manic hygiene and elimination of all bacteria and pathogenic agents in your environment will weaken your immune system.
  • Many immunodeficiencies have characteristics of autoimmunity. Compromised immunity can promote autoimmunity through chronic immune system activation. An example would be common variable immunodeficiency (CVID), where several autoimmune diseases are manifested, such as inflammatory bowel disease, autoimmune thrombocytopenia and autoimmune thyroid disease.

Hypersensitivities are another example of immune disorders that damage the body. There are four categories of hypersensitivity, depending on their mechanisms and time lapse:

  • Type I hypersensitivity causes immediate allergy like rashes, swollen throat, vomiting or shortness of breath, which is mediated by IgE. It can range from mild symptoms to death. Manifested disorders include asthma, atopy (exaggerated IgE response), and swelling.
  • Type II hypersensitivity, mediated by IgM and IgG, happens when antibodies bind to host cell antigens, marking them for elimination. Manifested disorders include thrombocytopenia, Grave’s disease, autoimmune hemolytic anemia and rheumatic heart disease.
  • Type III hypersensitivity is triggered by IgG antibodies that bind to soluble antigens to create an immune complex. This then gets deposited in different tissues like joints and kidneys, causing a local inflammatory reaction. Manifested disorders include rheumatoid arthritis, systemic lupus, membranous nephropathy and serum sickness.
  • Type IV hypersensitivity is a delayed response that takes several days to kick in. Helper T cells get activated by an antigen presenting cell, activating macrophages during future exposure and causing inflammation. Manifested disorders include contact dermatitis (poison ivy rash), multiple sclerosis, coeliac disease, Hashimoto’s thyroiditis, and chronic transplant rejection.

Immunity and autoimmunity can be manipulated by immunosuppressive and anti-inflammatory drugs. They are used to control inflammation and autoimmune attacks or prevent organ transplant rejection. Unfortunately, some of them, like glucocorticoids, can have negative side-effects that include hyperglycemia, weight gain and osteoporosis. Cytotoxic drugs, like methotrexate and azathioprine, inhibit the immune response by killing activated T cells, which affects other cells and organs as well, creating toxic side-effects. Immunosuppressive drugs, such as cyclosporin, block T cells from responding appropriately.

The Body’s Immune Defense

Hormones and their by-products can function as immunomodulators, affecting overall resilience. Female sex hormones like estrogen have immune-stimulating properties, whereas male sex hormones such as testosterone appear to be immunosuppressive. Other hormones like thyroid hormones, human growth hormone, IGF-1 and prolactin can also regulate the immune system. Furthermore, vitamins and minerals are necessary for the functioning of enzymes that produce hormones.

These are the factors you would want to keep in order for the sake of optimal immunity:

  • Bone marrow is where our immune cells originate from. Stem cells are produced from bone marrow, which can then differentiate into immune cells. The immune system then sends T cells from your bones to the thymus to mature.
  • The thymus is the primary organ of the lymphatic system that is most influential on immunity. It is located in the upper front chest region behind the sternum and in front of the heart. The thymus helps to mature T cells, which are essential for adaptive immunity. Abnormalities in the thymus can lead to autoimmune disorders. To prevent that, you need to stimulate thymic functioning by promoting lymph flow, eating a healthy diet and avoiding chronic stress.
    • With age, the size of the thymus begins to decrease, which might explain why aging leads to immuno-senescence. Decreased thyroid functioning that results from aging contributes to immune dysfunctions as well. Hypothyroidism lowers thymic activity, reduces the size of the spleen and lymph nodes, and suppresses the humoral immune response. Administrating T4 to old animals promotes the regrowth of the thymus, repairs endocrine function and age-related immune dysregulation. Giving growth hormone and IGF-1 together to old animals promotes thymic restoration.
  • The spleen is the second largest organ of the lymphatic system and is located in the upper left abdomen. In-utero, it regulates hematopoiesis or the formation of blood cellular components such as red blood cells. The spleen’s primary function is to filter blood and to remove old or damaged red blood cells and platelets. It can then store some of these breakdown materials, such as iron, or return the iron to the bone marrow to make hemoglobin. Antibody-tagged bacteria are also metabolized and removed in the spleen. The spleen also stores blood, red blood cells and platelets in case of emergency. The spleen can detect pathogens and help release white blood cells in response to infection. Through lymph flow, the spleen stores monocytes that promote tissue healing by transforming into dendritic cells and macrophages. Conditions like sickle cell anemia, malaria, leukemia, Hodgkin’s disease, cysts and tumors can enlarge the spleen, reducing its ability to effectively filter blood cells. It appears that the spleen is controlled by the brain in a top-down fashion via the autonomic nervous system, which aids with antibody production. The two key areas in the brain that are connected to the spleen are the amygdala and the hypothalamus and they control fear and stress responses. Glucocorticoids, which get released during stress, are immunosuppressive and generate antibodies during moderate stress.
  • The thyroid gland regulates energy metabolism and cellular homeostasis. Thyroid hormones: thyroxine (T4) and triiodothyronine (T3) are produced by thyroid cells that absorb iodine from food and combine it with the amino acid tyrosine. Once released into the bloodstream they affect body temperature, metabolic rate, breathing and heartbeat. Thyroid functioning can affect immunity by regulating the amount of fat and fat-free mass you have, maintenance of lymphocytes, mediating the inflammatory response, controlling immune cells, and preventing autoimmunity. Importantly, two molecules of sodium are required to drive one molecule of iodide into the thyroid gland. Thus, maintaining appropriate sodium status is needed for optimal thyroid and immune health.
    • Hyperthyroidism appears to decrease the proinflammatory effects of monocytes and macrophages, whereas hypothyroidism increases reactive oxygen species and phagocytosis. Involution of the spleen and lymph node due to hypothyroidism decreases cell-mediated immune responses, which can increase the severity of viral infections and sepsis. Thyroid hormones also modulate natural killer cells and low thyroid function depresses NK cell activity. Increasing T3, which is the active thyroid hormone, seems to reverse this phenomenon.
    • Low thyroid function can also make you more susceptible to other immunocompromised and disordered states like diabetes, obesity, autoimmunity and inflammation. With a lower metabolic rate, it is easier for you to gain weight and harder to conduct other important processes of defense. An abundance of energy production helps to provide enough resources for all immune functions, whereas a depletion in energy lowers immune function. However, hyperthyroidism can also cause problems related to autoimmunity, such as Graves’ disease and an increase of pro-inflammatory cytokines.
    • Thyroid hormones convert cholesterol into steroid hormones like testosterone, vitamin D, DHEA and progesterone. These hormones have many benefits, such as muscle growth, faster metabolic rate, bone density, increased fertility, etc. People with low thyroid tend to have higher cholesterol because they do not have enough thyroid hormones to convert it into other hormones. High thyroid stimulating hormone (TSH) can raise cholesterol, whereas hyperthyroidism lowers cholesterol and cause hormonal imbalances.
    • Stress lowers thyroid functioning through adrenal insufficiency. Inflammatory cytokines like interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and tumor necrosis factor (TNF) alpha reduce the conversion of T4 into T3. IL-6 lowers serum T3 directly. Stress-induced low thyroid can cause stress to the body, suppressing thyroid function even further. At the same time, the state of hypothyroidism itself can initiate this stress-induced cascade.
    • Low thyroid function = spleen size reduction, hormonal dysfunction, lower thymic activity -> reduced adaptive immunity, lower metabolism -> weight gain, metabolic syndrome, decreased NK cell activity, risk of autoimmunity, suppressed immunity accelerated immuno-senescence.
  • The liver is the center for all metabolic reactions inside the body. It filters out toxins, promotes the body’s own detoxification systems, conducts immuno-surveillance, eliminates pathogens and manages energy balance. Many immune cells, including NK cells, complement components, cytokines and chemokines are located in the liver. With transforming growth factor-β, the liver inhibits immunoglobulins, T and B lymphocytes as needed. Transforming growth factor-β has many important roles during all phases of the immune response in converting immune cells.
    • The liver is the primary detoxification organ that removes pathogens, heavy metals, and environmental toxins. Heavy metal toxicity can reduce immune function, cause autoimmunity, cancer, hypersensitivities and other health problems. Liver cirrhosis or dysfunction can increase susceptibility to bacterial infections, reduce immuno-surveillance and increase inflammation. Fatty liver from drinking too much alcohol or non-alcoholic fatty liver disease from the overconsumption of refined carbs, sugars and seed oils will also inhibit liver function. The key is to avoid imbalances between the body’s maintenance immunological function and excess inflammation.
    • Glutathione (GSH) is the body’s main antioxidant produced in the liver. It protects against free radicals, heavy metals and helps to eliminate lipid peroxides as well as toxins through Nrf2-mediated M1-like macrophage polarization. Immune cells work best with optimal glutathione levels that balances redox status. GSH is more powerful and practical than regular antioxidant supplements because the body self-regulates it in conjunction with the immune system. Glutathione will either stimulate or inhibit immune response to control inflammation, thus protecting against autoimmunity as well, by priming T cells for inflammation. However, endogenous glutathione not only limits inflammatory reactions but fine-tunes the innate immune response towards antiviral pathways in response to an infection independent of GSH’s antioxidant properties.
      • Compounds that boost glutathione include N-acetyl cysteine (NAC), glycine, alpha-lipoic acid, broccoli sprouts (sulforaphane), magnesium, selenium and glutathione.
    • Nrf2 or Nuclear Factor Erythroid 2-Related Factor 2 is a transcription factor that binds to DNA to express various genes. It is one of the primary regulators of our body’s own antioxidant systems by activating the antioxidant response element (ARE), which increases antioxidants like glutathione, NADPH, bilirubin, thioredoxin and cell protection, producing major anti-inflammatory changes and lowering oxidative stress. Nrf2 is a critical regulator of both innate and adaptive immunity, especially during inflammation. In mice, the Nrf2 antioxidant response element pathway controls fibrosis and autoimmunity in scleroderma. Absence of Nrf2 exacerbates autoimmune encephalomyelitis in mice.
      • Compounds that activate NRF2/ARE include broccoli sprouts (sulforaphane), curcumin, coffee (chlorogenic/caffeic/ferulic acid and diterpenes such as cafestol), red wine (quercetin and resveratrol), whole grains (ferulic acid), olive oil, green tea (EGCG), garlic, onions, cinnamon, hops plant (xanthohumol), spirulina (heme-oxygenase 1, phycocyanin), astaxanthin, berberine, berries (especially blueberries), nuts (pterostilbene), grapes, passion fruit, white tea, Japanese knotweed (piceatannol), buckwheat and asparagus (rutin).
  • Energy Metabolism. An active immune system requires a lot of energy, which is why the body is always trying to do a cost/benefit analysis whether or not it is worth it to maintain heightened immunity in various situations. During life-threatening circumstances like starvation or running away from predators, immunity is not as important as mere survival. That is why intense physical exertion leads to a short-term drop in immune system functioning. The benefits of activating an immune response are protection against pathogens, but the costs include potential autoimmunity or inflammation. Manufacturing immune cells and antibodies are energy demanding. Infected animals and humans cover that increased energy demand by reducing their physical activity, feeling fatigue, and being less sociable. Therefore, an abundance of energy in the form of ATP and other molecules is also needed for optimal immunity. Building muscle helps stimulate the production of more mitochondria (and hence more ATP production) and magnesium helps to activate ATP. Thus, exercise, especially weightlifting, and magnesium supplementation are great “energy boosters”, whereas overconsuming refined carbohydrates and sugars depletes ATP.
    • NAD+ or Nicotinamide adenine dinucleotide is a paramount co-enzyme that is involved with virtually all cellular processes and energy production. Decreasing NAD+ is linked to aging, disease and weaker immune system functioning. It is required for supporting every defensive response as well as recovery. NAD-biosynthetic pathways regulate immune cells and innate immunity. During an immune response, macrophages upregulate nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B-cell colony-enhancing factor 1 (PBEF1), which governs the NAD salvage pathway to control inflammation and cell survival. NAD also regulates cytokines, blood lymphocytes and monocytes. 
    • NADPH or nicotinamide adenine dinucleotide phosphate (NADP+) is a cofactor for anabolic processes such as cellular growth and nucleic acid synthesis. The extra phosphate group gets added during the salvage pathway of NAD+. NADPH is the reduced form of NADP+. It protects against excessive reactive oxygen species (ROS) and enables the regeneration of glutathione.
    • Autophagy, or self-eating, is a major cleaning maintenance system of the body. It modulates the immune system, eliminates pathogens, removes dysfunctional cell components, supports DNA repair and lowers inflammation. Autophagy gets ramped up during physiological stress, fasting, exercise or infections but there are always some small amounts of it happening. Autophagy plays a role in shaping immune system development, fueling the host’s immune responses and directly controlling intracellular microbes as a cell-autonomous innate defense.
  • Uric Acid is the most concentrated antioxidant in the human blood that mitigates oxidative stress, especially under hypoxia. In low amounts, it can be beneficial, but in excess it causes gout and fibromyalgia. You obtain uric acid from purine-rich foods like meat, fruit, fish and grains but accumulate it during exercise and with the overconsumption of fructose.
  • Strong gut lining. Intestinal permeability or leaky gut is associated with autoimmune diseases and the development of several inflammatory diseases. Increased low-grade inflammation makes one more prone to infections. Bone broth, tendons and ligaments have collagen and glycine that promote tissue rejuvenation. Butyrate is also essential as the main source of energy for cells in the large intestine. You can get butyrate mainly from the fermentation of fiber like beans, vegetables and legumes but also ghee and butter. Microbial metabolites through the Nrf2 pathway have shown to enhance gut barrier integrity.
    • Diversity of the gut microbiota is linked to stronger immunity because microbes have an important role in modulating our body’s defense systems. They also help the host adapt to the microbial and pathogenic environment they’re in.
    • Skin integrity is another essential component to immunity through enhanced barrier strength. The skin is constantly exposed to various pathogens and internal reactive oxygen species. Nrf2 plays a crucial role in modulating that oxidative stress.

Factors that reduce immunity:

  • Low thyroid
  • Stress/Glucocorticoids
  • Reduced lymph flow
  • Thymic/Spleen/Liver dysfunction
  • Suboptimal micronutrient status
  • Suboptimal hormone status
  • Heavy metal overload
  • Refined sugar, carbs, and seed oils
  • Suboptimal glutathione levels
  • Intestinal permeability (Leaky gut)

Factors that boost immunity:

  • Thyroid hormones
  • Lymph flow
  • Micronutrients (vitamins/minerals)
  • Exercise
  • Hyperthermia
  • Glutathione/Glutathione boosters (see above)
  • NRF2 activators (see above)
  • Autophagy
  • Collagen/Glycine

Interferons and Anti-Viral Defense

A virus-infected cell will release interferons to signal neighboring cells to tighten their defenses. Interferons (IFN) are a collection of signaling proteins that get released by cells in response to a virus or infection. They also bind to specific receptors and activate many immunomodulating and antiviral pathways. For the antiviral effects to be established, other “effector” proteins need to be produced.

Interferons belong to the cytokine class of proteins and are grouped into three major categories: alpha, beta and gamma. The difference between them is their origin and antiviral action. Interferon-alpha and beta are in the same type I sub-class, whereas interferon-gamma is separate in type II. Interferons activate immune cells, such as natural killer cells and macrophages and they increase antigens and other cytokines that can create a fever. Muscle pain and flu-like symptoms are caused by the production of these cytokines.

  • Type I Interferons include IFN-α, IFN-β, IFN-ε, IFN-κ and IFN-ω. They’re produced by fibroblasts and monocytes when the body detects the presence of an invading virus. After production, they bind to the receptors of targeted cells and express proteins that prevent viruses from replicating. IFN-α can be effective against hepatitis B and C, whereas IFN-β is effective for multiple sclerosis.
  • Type II Interferon in humans is IFN-γ, which is also known as the immune interferon. It’s activated by interleukin-12 and released by T cells. However, type II interferons can inhibit the proliferation of type two T helper cells. This lowers the Th2 immune response and induces an additional Th1 immune response, leading to the development of diseases like multiple sclerosis.
  • Type III Interferons consist of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3 and IFN-λ4. They all have antiviral effects and immune response against viruses and fungal infections.

Protein kinase R (PKR), as well as RNAse L, are both induced by IFN activity and they inhibit protein synthesis in the cell of both viral and host genes. PKR is a suicide enzyme that shuts down all protein synthesis in the cell, killing the cell and the virus at the same time. Interferon also signals neighboring cells that are in close proximity to virally infected cells to produce PKR to be ready for viral infection. Once PKR detects the presence of double-stranded RNA from a virus, it kills the cell along with the virus.

  • Some viruses, like H5N1 bird flu, fight back against interferons. They can evade detection by having a protein called Non-Structural protein (NS1) bind to its own double-stranded RNA hiding it from PKR’s suicide detection and preventing the self-kill mechanism.

Interferon-stimulated genes (ISGs) limit the spread of infections by increasing p53, which kills infected cells through apoptosis.

Interferons also upregulate major histocompatibility complex molecules (MHC I and MHC II) and increase activity of immunoproteasomes. Elevated MHC I promotes peptides that help recognize and remove malignant cells. MHC II expression increases peptides that help T helper cells co-ordinate the actions of other immune cells. Interferons can also inhibit tumor cells by suppressing angiogenesis, or the growth of new blood vessels, to the malignant source. This reduces proliferation of endothelial cells, decreases vascularization and overall growth.

Many viruses have developed ways to resist or evade interferon activity. They avoid the response by blocking signaling events that produce IFNs, thus preventing them from being produced again and by impeding the function of IFN-induced proteins.

  • Viruses that interfere with IFN signaling include Japanese Encephalitis Virus (JEV), dengue type 2 virus (DEN-2), herpesviruses like human cytomegalovirus (HCMV) and Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV8).
  • Viral proteins that affect interferons include EBV nuclear antigen 1 (EBNA1) and EBV nuclear antigen 2 (EBNA-2) from Epstein-Barr virus, the large T antigen of Polyomavirus, the E7 protein of Human papillomavirus (HPV) and the B18R protein of vaccinia virus.

Interferons are mainly produced in response to viruses, bacteria, fungi or the identification of their presence. Recognizing microbial material like viral glycoproteins, viral RNA, lipopolysaccharide endotoxin, CpG motifs and bacterial flagella can trigger the release of IFNs. Cytokines like IL-1, IL-2, IL-12, TNF-alpha and others can do the same.

Here’s how to increase interferons naturally:

  • Astragalus is a Chinese herb that enhances antibodies and autophagy. In patients with asthma, astragalus promotes the production of T helper cells and IFN-gamma. Astragalus root and elderberry extract has been shown to increase IFN-beta.
  • Chlorella and Chlorophyll. Plants obtain their dark green pigment thanks to chlorophyll. It has anti-oxidant and deodorizing effects. Supplementing chlorella has lowered liver enzyme levels in patients with chronic hepatitis C infection. Chlorophyll has been shown to reduce inflammation caused by lipopolysaccharide.
  • Echinachea is a commonly used herb for respiratory infections. It modulates cytokines and interferon-gamma.
  • Licorice root – Glycyrrhizin, an active component of licorice root, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. This effect did not happen when administered together with anti-gamma interferon monoclonal antibody.
  • Melatonin is the sleep hormone that modulates the immune system during sleep. It’s also a powerful antioxidant that regulates T cell receptors that lead to the activation of interferons.
  • Medicinal Mushrooms like chaga and reishi have powerful antioxidant and immunomodulating properties. Chaga extract has been shown to increase the secretion of Th1 and Th2 cytokines, which regulate antigens and interferons.
  • Ginseng – Mice given Korean red ginseng extract showed increased immunoglobulin G2a and interferon-gamma production accompanied by reduced IL-4.

Nutraceuticals that may have potential for boosting the type 1 interferon response to RNA viruses:

  • Glucosamine – increases O-GlycNAcylation of mitochondrial antiviral-signaling protein (MAVS) activating interferon regulatory factor 3 and increasing the production of type 1 interferons. An estimated dose in humans would be approximately 3 grams of glucosamine three times daily, which is about 3-times higher than typically used doses for osteoarthritis.
  • Spirulina – Inhibits NADPH oxidase and oxidative stress improving Toll-like receptor 7 activation and type 1 interferon production. 15 grams per day has been estimated as a dose that may provide benefits during acute RNA viral infections.
  • Ferulic acid or Lipoic acid – increases phase 2 enzymes and boosts endogenous antioxidant systems helping to increase type 1 interferon production. Ferulic acid 500- 1,000 mg per day or lipoic acid (alpha or R lipoic acid) 600 mg 2-3 times daily may have some utility against RNA viruses.
  • N-acetylcysteine (NAC) – 600 mg 2-3 times daily increases glutathione and has mucolytic effects.
  • Selenium – 50-200 mcg daily improves glutathione peroxidase and immune cell proliferation.
  • Zinc – 30-50 mg daily, with an additional 2-3 milligrams of copper, helps support immune function. Usually, a 20/1 ratio is used when supplementing with zinc/copper.
  • Yeast beta-glucan – 250-500 mg for overall immune support.
  • Elderberry extract – 600-1500 mg per day (standardized to 10-15% anthocyanins).

Immunity and Stress

Stress is an imbalance in the body’s homeostasis that imposes physiological as well psychological challenges.

Chronic stress is one of the major contributors to an imbalanced immune system and predisposition to diseases. Patients with viral infections show elevated cortisol. Symptoms of irritable bowel syndrome are linked with elevated cortisol. Sustained stress can increase the risk of developing autoimmune diseases. Chronic stress also activates dormant viruses that can undermine the immune system, thus leaving you more vulnerable to additional infections.

There’s many studies illustrating how your psychology and nervous system affect immunity (see book for links):

  • A 2016 review found that childhood stress and trauma increase the release of cytokines by the immune system. Research shows that individual characteristics such as age, personality traits, level of neuroticism, childhood experiences, past trauma determine the final effect of the stress on an individual.
  • Psychological stress has been shown to increase the susceptibility to various infections and immune-related diseases like cancer and HIV and it also increases the risk of cardiovascular disease.
  • In rats, exposure to different stressors releases different proinflammatory cytokines with differences between physical injury and social stress.
  • People with psoriasis have higher levels of cortisol, which is the main stress hormone and this may worsen symptoms.
  • Psychological stress is also implicated in rheumatoid arthritis. Systemic inflammation also affects a person’s psychology and physiology. It promotes sickness, pain, stress and acute phase reactions.
  • Increased cytokine levels and inflammation are linked with major depression, stress and suicidal thoughts.
  • There’s also a link between breast cancer, depression and social support. A 2013 review found that women with higher genetic risk factors for cancer showed immune system abnormalities in response to stress.

Stress can change your behavior and psychology by causing anxiety, depression, delusions, sadness, anger, social isolation, panic attacks and headaches. The hippocampus can also atrophy, which decreases the body’s ability to respond appropriately to stressors.

Brain-Derived Neurotrophic Factor (BDNF) helps us recover from chronic stress by promoting neuroplasticity and making the brain more malleable.

Here are ways to boost BDNF:

  • Sleep plays a huge role in BDNF production and stress adaptation. If you’re sleep deprived, then your emotional bandwidth decreases substantially.
  • Stress depletes magnesium by activating the sympathetic nervous system. The majority of people are already deficient in magnesium and it’s hard to obtain it from food.
  • Exposure to sunlight also raises BDNF and circadian rhythm alignment is crucial in mood regulation and all metabolic processes.
  • Acupuncture therapy improves neurological recovery after traumatic brain injury by activating the BDNF/TrkB pathway. Using a simple acupuncture mattress can help you to relax and improves sleep.
  • Music can increase BDNF by lifting mood and getting you out of fight or flight.
  • Exercise dramatically increases BDNF. However, too much exercise may cause chronic stress, so you need to keep exercise at a moderate level.
  • Curcumin can reverse the negative effects of chronic stress on the HPA axis and BDNF expression. It lowers inflammation and promotes relaxation.
  • Cold and heat thermal regulation require BDNF developmental plasticity. It’s also critical to not over-react to these stressors as it may embed a negative memory into your psyche.

Optimism is associated with a stronger immune system. However, when circumstances are too difficult or uncontrollable, optimism is associated with weaker immunity. This might be because coping with harder stressors imposes higher energy demands on optimists when maintaining optimism itself is already energetically costly. During brief, acute stress, optimists have better immune function than pessimists but this relationship gets reversed under more difficult stressors.

Acute stress mobilizes immune cells and raises pro-inflammatory cytokines. Episodic stressor, like taking an exam, suppresses cellular immunity but preserves humoral immunity. Chronic stress, however, raises inflammatory markers like CRP and IL-6. Inflammation is needed for eliminating pathogens, initiating healing and adaptation, however, when elevated chronically it will promote stress-related diseases like atherosclerosis or osteoporosis. Psychological stress is also found to be involved with rheumatoid arthritis.

Examples of hormesis include:

  • Exercise
  • Sunlight
  • Heat Exposure
  • Cold Exposure
  • Intermittent Fasting
  • Intermittent Hypoxia
  • Low Level Radiation
  • Dietary Phytonutrients
  • Acute Stress

COVID-19 and an Overactive Immune System

Symptoms of COVID-19 include fever, coughing, exhaustion, shortness of breath and loss of taste or smell that differs from the common cold. Disease outcome can range from mild to severe, progressing towards acute respiratory distress syndrome (ARDS), septic shock or hypoxemia. The cause of death is mainly respiratory failure, including organ failure, by invading the central nervous system. Respiratory organs are affected the most by COVID-19 because the virus enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is concentrated in the lungs. The virus uses a spike glycoprotein to dock to the ACE2 receptor and enter the host cell.

SARS-CoV2 can cause acute myocardial injury and permanent cardiovascular damage because there is a significant amount of ACE2 receptors in the heart as well. Clot formation and blood vessel dysfunction are noted to lead to pulmonary embolisms and ischemic events, which contribute to its mortality.

One of the main symptoms of COVID-19 patients is systemic inflammation, particularly the ‘cytokine storm.’

  • This pathological cytokine release is caused by an imbalance between immune cells (too many effector immune cells and too few regulators) like in autoimmune diseases. The cytokine storm is common among severe-to-critical COVID-19 patients, characterized by reduced lymphocytes, NK cells and elevated D-dimer, C-reactive protein (CRP), ferritin and procalcitonin.
  • Elevated CRP and ferritin are associated with the onset of a cytokine storm in patients receiving chimeric antigen receptor T cell therapy.
  • There is a lot of evidence that COVID-19 causes a drop in circulating T and B lymphocytes, especially during severe stages of the infection. This dysregulates the immune response and compromises defense against the infection.
    • Decreased CD4+ and CD8+ T cells are linked to COVID-19 disease severity. Several studies have noted that there is a negative relationship between elevated inflammatory cytokines and reduced circulating T cells in SARS-CoV2 patients.
    • B cells are also lower in severe COVID-19 patients compared to mild patients, with the amount of B cells being negatively associated with the viral burden.
    • Despite the reduced lymphocytes, there is still an abnormal increase in monocyte/macrophage/neutrophil recruitment. Inflammatory activated monocytes are observed in the peripheral blood of COVID19 patients. Both monocytes and macrophages have a high number of ACE2 receptors, which can get infected with SARS-CoV2, resulting in the activation of pro-inflammatory genes.
    • ACE2 expression has been found on the CD68+ and CD169+ macrophages in spleen and lymph nodes of COVID‐19 patients as well, which further jeopardizes the immune system function.
    • SARS-CoV2 has been found to generate proinflammatory cytokines in the spleen and lymph nodes through macrophages, which contributes to the cytokine storm. Autopsy reports reveal that the lungs of COVID-19 patients are accumulated by inflammatory macrophages. The dysregulated activation of inflammatory monocytes/macrophages is orchestrated by delayed type I interferon (IFN-I) signaling.
    • It is possible that glycine and vitamin D/magnesium may help to reduce this cytokine release from macrophages.

Another proinflammatory molecule that gets activated during an infection is HMGB1 (high mobility group box 1), which is a damage-associated molecular pattern (DAMP) protein with cytokine capacity. It binds to chromosomal DNA, toll-like receptor 3 (TLR3), TLR4 and the receptor for advanced glycation end products (RAGE), which activates NF-kB and NLRP-3 inflammasomes. HMGB1 is found to be involved in obesity, insulin resistance, diabetes, thrombosis-related diseases and polycystic ovary disease, which are all characterized by low-grade inflammation.

  • Excess extracellular HMGB1 increases pro-inflammatory cytokines, such as TNF, IL-1 and IL-6[663]. This causes tissue damage and dysfunction that can complicate many diseases. Because of its strong bipolar charge, HMGB1 is prone to bind with other pro-inflammatory molecules like IL-1α, IL- 1β, lipopolysaccharides (LPS) as well as DNA, RNA, histones and nucleosomes. This amplifies their pro-inflammatory effects in a synergistic manner. Magnesium deficiency upregulates NF-kB and HMGB1 secretion from LPS-treated macrophages.
  • Only RAGE and TLR4 are confirmed to function as HMGB1 receptors. Via RAGE, HMGB1 mediates β- amyloid accumulation triggered by sepsis in central nervous system diseases that are associated with impaired cognition and neurodegeneration.
  • Preclinical and clinical studies have demonstrated that respiratory infections like influenza and human respiratory syncytial virus (HRSV) generate a lot of extracellular HMGB1 in pulmonary inflammation and HMGB1-specific antagonists ameliorate these effects. In one clinical study, the mortality of bacterial pneumonia in acute respiratory distress syndrome (ARDS) was greatly predicted by plasma HMGB1 levels.
  • Experimental studies show that HMGB1 has a crucial role in mediating acute lung injury by recruiting leukocytes into the lungs. Hyperoxia increased the accumulation of HMGB1 in lower respiratory fluids before the injury. Patients of long-term mechanical ventilation and ventilator-associated pneumonia have high levels of HMGB1 in their bronchoalveolar lavage fluids. HMGB1 is also seen to be a mediator of the lung inflammation seen in COVID-19.

In cytokine storms, it is not known which comes first – NFkB/NLRP3 inflammasome activation or HMGB1/DAMPs/PAMPs. During COVID-19, HMGB1 is likely to be the initiating factor for damaging cytokine storms coming before NF-kB activation.

The overall course of events during infections that leads to pathological cytokine storms seems to look like this:

  1. Cells experience damage/senescence or get infected with a virus
  2. Those cells release damage associated molecular patterns (DAMPs) or pathogen associated molecular patterns (PAMPs), which activate immune system receptors
  3. DAMPs, like HMGB1, signal the production of the inflammatory response
  4. HMGB1 binds to TLR2/TLR4/RAGE receptors to begin mobilizing pro-inflammatory cytokines
  5. Activation of NF-kB/NLRP3 inflammasomes ensues
  6. Release of pro-inflammatory cytokines like IL-1, IL-6, IL-1B, IL-18, IL-17, IL-22 and others occurs
  7. Onset of the cytokine storm and pyroptosis, which describes a highly inflammatory programmed cell death, damaging other tissues
  8. Reduction in T cells and B cells and their function due to the pro-inflammatory cytokines
  9. Increased susceptibility to viral replication and spread throughout the body
  10. Monocytes and macrophages get infected with the virus, activating more pro-inflammatory genes and jeopardizing immune function
  11. The number of circulating neutrophils and neutrophil extracellular traps increases, causing organ damage and injury
  12. As the cytokine storm continues, the body’s immune organs and cells become continuously more damaged, weakening the ability to resist the virus even further and eventually leading to sequential organ failure or death

Hyperglycemia and diabetes mimic the same HMGB1 response by increasing RAGE expression and creating oxidative stress. Anything that inhibits RAGE and improves glycemic control would reduce HMGB1 expression and its pro-inflammatory effects.

Therefore, there is a big difference in the course of events between minor and severe COVID outcomes:

  • Minor COVID – Well functioning immune system, active CD8 T cells + type 1 interferons-> reduced viral replication + lack of inflammation -> increased viral clearance -> lack of cytokine storm -> recovered patient
  • Severe COVID – Immunosenescence + senescent cells -> dysfunctional CD8 T cells + reduced Type 1 interferons -> cells more susceptible to viral infection -> increased viral replication -> cytokine storm -> acute respiratory distress/organ failure/thrombosis/sepsis -> death

Nutraceuticals that can inhibit HMGB1, TLR4, LPS, NLRP3 inflammasome, RAGE, NF-kB and the cytokine storm:

  • Nicotinamide riboside (NR) inhibits HMGB1, which has been shown to prevent oxidative stress and organ injury in sepsis. It is also a precursor to NAD+, which is a critical enzyme needed for all physiological processes in the body, including immunity.
  • Glycyrrhizin is a direct HMGB1 antagonist shown to lower its expression. It is the main sweet-tasting compound of licorice root. In vitro, glycyrrhizin has been used to inhibit the replication of SARS-CoV1. The results were more effective than 6-azauridine and pyrazofurin and equally as effective as ribavirin and mycophenolic acid, which are antiviral medications. Glycyrrhizin should be tested further to see if it can be considered an effective alternative therapeutic agent for COVID19 due to its ability to bind to ACE2 as well.
  • Ferulic acid has been shown to reduce HMGB1, IL-6 and IL-8 in response to human umbilical vein endothelial cell radiation injury in vitro. It also inhibits the production of macrophage inflammatory protein-2 (MIP-2) in a respiratory synthetical virus. Derivatives of ferulic acid have inhibitory effects against influenza H1N1. Ferulic acid is a phenolic compound found in plant cell walls. Foods with ferulic acid include many vegetables, the bran of cereal grains, barley, flaxseed, legumes and beans. Flaxseed lignans can also reduce HMGB1 and other pro-inflammatory cytokines.
  • Ginseng, rich in ginsenoside, reduces LPS-induced HMGB1 release. Angelica sinensis (dong quai) protects mice against lethal endotoxemia and sepsis by lowering HMGB1. Ginsenosides have also been shown to inhibit influenza A virus. Korean red ginseng decreases HMGB1 by suppressing pro-inflammatory cytokines.
  • Green tea may reduce LPS-induced release of HMGB1 and other pro-inflammatory cytokines in sepsis patients. Green tea extract supplementation inhibits HMGB1 release in rats exposed to cigarette smoke. EGCG, the main polyphenol in green tea, reduces HMGB1/RAGE expression and alleviates lung injury in PM 2.5-exposed asthmatic rats. EGCG also stimulates autophagy and reduces HMGB1 in endotoxin-stimulated macrophages. At higher concentrations, EGCG has ACE2-inhibitory effects. Other flavonoids are also able to inhibit ACE2. EGCG is known to inhibit the viral entry of hepatitis C and Zika virus, which are in the same class of viruses as SARS-CoV2.
  • Lactobacillus rhamnosus and Bifidobacterium Breve suppress HMGB1 and pro-inflammatory cytokines on cigarette smoke activated macrophages. Lactobacillus rhamnosus GG has also anti-inflammatory effects in asthma, by balancing Th1/Th2 cells. Brown alga phlorotannins can down-regulate TNF-alpha, IL-6 and HMGB1, suppressing septic shock.
  • DHA (docosahexaenoic acid) supplementation can prevent the accumulation of macrophages in LPS exposure and hyperoxia. It also lowers HMGB1. Long-chain fatty acids like DHA and EPA may function as ACE enzyme inhibitors with anti-inflammatory properties. Dietary omega-3s also inhibit TLR4 receptor recruitment, which lowers pro-inflammatory pathways.
  • Chloroquine, dexamethasone and gold sodium thiomalate inhibit extracellular release of HMGB1 in a dose-dependent manner. In mice, chloroquine suppresses HMGB1 inflammatory signaling and protects against lethal sepsis. In vitro, chloroquine inhibits SARS-CoV2 replication, but it has not seen great success against other viruses in humans. Chloroquine phosphate has shown efficacy in treating COVID-19-induced pneumonia. Twenty studies involving over 105,000 patients from nine countries suggest that if given early enough, chloroquine and its derivatives like hydroxychloroquine are effective in improving COVID-19 outcomes, reducing mortality by a factor of 3.
  • Hydroxychloroquine (HCQ) is an antimalarial agent that is being used to treat COVID-19. Combining HCQ with azithromycin may reduce mortality and increase frequency of being discharged home. There is a theoretical increased risk of QT prolongation and arrhythmias with combined HCQ and azithromycin (although it does not appear to be seen very often in the community), thus, some doctors use doxycycline instead. In vitro, HCQ reduces SARS-CoV2 replication in clinically significant concentrations. By inhibiting endosomal NADPH oxidase complexes, HCQ has anti-inflammatory and antiviral effects. Through the same NADPH pathway, hydroxychloroquine, as well as glycine and spirulina, may also reduce the elevated risk of thrombosis seen in COVID-19.
  • Suggested dose schedules for drugs/nutraceuticals with antithrombotic potential in COVID-19. Taken from DiNicolantonio and McCarty 2020:
    • Hydroxychloroquine—200 mg, 2 times per day
    • Spirulina—15 g (rounded tablespoon), one time per day
    • Glycine powder—5 g, 2–3 times per day
    • Lipoic acid—600 mg, 2–3 times per day
    • Ferulic acid—500 mg, 2 times per day
    • Broccoli sprout powder—5 g, 1–2 times per day (providing 20–40 mg of sulforaphane)
    • N-acetylcysteine—600 mg, 2–3 times per day
    • Citrulline powder—2 g, 2 times per day
    • Folic acid—40 mg, one time per day
    • Biotin—10 mg, 2–3 times per day
  • Azithromycin (the antibiotic found in a Z-pak) is mostly used for bacterial infections. In combination with hydroxychloroquine, azithromycin has been shown to clear SARS-CoV2 in 93% of patients after 8 days. Azithromycin has anti-inflammatory and antibacterial properties, including the ability to eliminate senescent cells. Senescent cells are more susceptible to viral replication and are more prevalent in immunocompromised states.
  • Colchicine, which is traditionally used to treat gout and rheumatoid arthritis, shows promise in moderate to severe COVID-19 patients, by increasing time to clinical deterioration and preventing complications. It inhibits neutrophil chemotaxis, inflammasome signaling and reduces neutrophil-platelet aggregation. In coronary heart disease, colchicine reduces the risk of major cardiovascular events.
  • Ivermectin has been used to treat parasitic infections for decades. Anecdotally, a single 9 mg dose of ivermectin has been found to lead to rapid clinical resolution in severe COVID-19 patients. Amongst 173 COVID19- patients, mortality was significantly lower in those who received ivermectin (15% vs 25.2 %, p=0.03). In vitro, ivermectin is reported to inhibit SARS-CoV2 proliferation. However, this anti-viral effect requires 35-fold higher dosage than the 9 mg administered to humans. This had casted doubt whether or not ivermectin could be an effective drug for COVID-19, unless very large doses are used. Nevertheless, ivermectin pre-treatment before a lethal LPS injection has been shown to reduce mortality by 50% with a 4 mg/kg dose. In vitro, ivermectin can block cytokine production by LPS-infected macrophages.
  • Spironolactone – SARS-CoV-2 uses the ACE2 receptor for entry and the transmembrane serine protease TMPRS22 for fusion. The expression of both is driven by androgens (like testosterone) and thus spironolactone, which is an androgen receptor inhibitor, may be of some utility early on in COVID. Spironolactone also increases plasma ACE2 (not membrane bound ACE-2) which may bind to SARSCoV2, hence reducing its binding to membrane ACE2. Contrary to regular ACE inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), that raise lung membrane-located ACE2, spironolactone leads to a more favorable expression of ACE2, which includes a more extended elevation of circulating ACE2 compared to membrane-bound ACE2, theoretically providing enhanced protection against SARSCoV-2. This process might also downregulate TMPRSS2 because of the antiandrogenic activity of spironolactone without affecting male hormones negatively. Additionally, spironolactone has been shown to alleviate the harmful effects of obesity on renin angiotensin- aldosterone (RAAS) along with RAAS hyperactivation due to increased angiotensinogen production by the adipose tissue, and several publications have suggested this may reduce obesity-related COVID-19 complications and inflammatory lung injuries.
  • Quercetin prevents LPS-induced HMGB1 release and proinflammatory function. It was found to help with SARSCoV1 by blocking viral entry into the cells. Vitamin C combined with quercetin may have additional antiviral effects against SARS-CoV2 and may help with the treatment of COVID-19 patients. In mice, quercetin attenuates liver fibrosis through HMGB1/TLR2/TLR4/NF-kB signaling.
  • Vitamin D deficiency is associated with increased HMGB1-mediated inflammation in coronary arteries. Deficient vitamin D status is also linked to a higher risk of severe COVID-19 outcomes and mortality in African Americans. Early vitamin D treatment (calcifediol, a partially activated vitamin D analog) in hospitalized patients significantly reduced intensive care unit necessity.
    • A study done in April 2020 claimed that vitamin D supplementation could reduce risk of COVID-19 infections and deaths. The mechanisms include cathelicidin recruitment, lower viral replication, reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines. The researchers recommended that people at risk of influenza/COVID-19 should consider taking 10,000 IUs per day for a few weeks to raise 25(OH)D concentrations above 40-60 ng/mL (100-150 nmol/L).
  • Riboflavin (vitamin B2) deficiency causes pathological activation of macrophages, expressing excessive HMGB1 and TNF-alpha. Foods high in riboflavin include liver, eggs, dairy, salmon, mushrooms, meat, spinach and almonds. Riboflavin combined with UV light has effectively inactivated the Middle East respiratory syndrome coronavirus (MERS-CoV) in human plasma.
  • Natural compounds that reduce NLRP3 inflammasome include curcumin, sulforaphane, quercetin, EGCG, ginseng, genipin, mangiferin, propolis, resveratrol and other polyphenols. They can be obtained from various vegetables and plant foods. However, the amount of those compounds is exceedingly small in whole foods, which is why supplementation might be necessary to see a significant effect. At the same time, taking these ingredients in large doses all the time can have negative side-effects. Hence, eating whole foods is a safer option long-term.

Intense physical exertion makes cells release danger molecules or alarmins, which leads to a short-term elevation of HMGB1 and other alarmins. This signals the body to adapt and stimulate growth. After recovery, these biomarkers will be lowered down again. At the same time, the acute rise in inflammatory damage molecules can have a beneficial effect through preconditioning hormesis. Exogenous HMGB1 pretreatment has been shown to protect against hepatic ischemia/reperfusion injury. HMGB1 has also promoted the migration and proliferation of regenerative cells to the sites of injury. Thus, regular moderate exercise both aerobic and anaerobic can be effective for lowering basal HMGB1 as well as stimulating preconditioning hormesis, which can attenuate damage from future exposure because the body has gotten more resilient.

Preconditioning hormesis also occurs with heat exposure and the sauna by upregulating heat-shock proteins. Exogenous administration of heat-shock protein 70 (HSP-70) 18 hours before administration of endotoxins increases tolerance to an endotoxin challenge. HSP-72 has also been shown to have protective effects on oxidative stress, LPS and TNF stimulation in murine macrophages. HSP-27 inhibits HMGB1 translocation and protects cells against pro-inflammatory stress. Therefore, a regular sauna may also attenuate the damage that may occur from cytokine storms.

Foods That Strengthen the Immune System

Here are specific foods and compounds that can fortify the immune system:

  • L-Glutamine is the most abundant amino acid in the human body. You get it from primarily animal protein like meat, eggs, fish, poultry, but also from legumes, beans and vegetables. We can synthesize glutamine, which makes it a non-essential nutrient, but our demand for glutamine increases during stress, physical activity, and when under different medical conditions.
    • Glutamine is used by activated immune cells. It supports lymphocyte proliferation and helps to produce cytokines by lymphocytes and macrophages. Additionally, glutamine may help people with food hypersensitivities by reducing inflammation on the gut surface. Glutamine is used mostly by cells of the intestine. It can thus protect against and repair leaky gut, hence improving immunity. Getting enough glutamine from the diet or by using a supplement helps protect intestinal epithelial cell tight junctions, which prevents intestinal permeability.
  • Sulfur-Rich Foods. Sulfur is needed for the synthesis of glutathione. Sulfur can be derived from methionine and cysteine. You can raise glutathione by eating sulfur-rich foods like eggs, beef and dark leafy greens. Cruciferous vegetables, such as broccoli and cauliflower have sulfur which elevates glutathione. Additionally, broccoli and cruciferous vegetables can raise glutathione by activating the Nrf2 pathway via the production of sulforaphane. Dairy, cereal and grains are low in glutathione; fruit and veggies are moderate; and fresh pastured meat is high in glutathione.
  • Collagen is the main building block for connective tissue, skin, tendons, bones and cartilage. It makes up 25-35% of our whole-body protein content. You need collagen for skin elasticity, wound healing, tissue regeneration and scaffolding. Collagen consists of various amino acids like glycine, proline, alanine, arginine and others to form a triple helix. Glycine makes up nearly 1/3rd of collagen and proline about 17%.
    • Collagen-containing C-type lectins (collectins) located in the liver, lungs, placenta and kidneys have been found to mediate the innate host defense against influenza and prevent secondary infection. Collectins are a vital component of the innate immune system in the lungs. They clear pathogens via the complement system.
    • Chicken drumsticks, tendons, ligaments, cartilage, and collar bones have collagen. They also have less methionine, which is usually found in muscle meat, and more glycine. This prevents homocysteine from rising too high and causing inflammation. Restricting methionine is linked to extended lifespan because of reduced IGF-1 and mTOR signaling. However, glycine supplementation has been found to have the same effects on life-extension as methionine restriction. That’s why getting more of these tendons, and ligaments is healthier than just eating muscle meat. Although bone broth soup is the most known food with collagen, it is unlikely to have enough collagen precursors to have a significant effect compared to supplemental collagen sources. Nevertheless, cooking up bones to make broth or soup is still great for not wasting food, and balancing the methionine/glycine ratio.
    • Other foods that can help with collagen production are fish skin, chicken skin, eggs and protein in general. Vitamin C is also important for procollagen synthesis and recycling. That is why vegetables, berries and fruit are also great for maintaining skin and bone health.
  • Lactoferrin is a globular glycoprotein found in milk, saliva and tears. It is found the most in human colostrum also known as the “first milk”, human breast milk, and cow’s milk. Many studies have shown lactoferrin has antiviral effects against viral pathogens. Lactoferrin can inhibit the virus from attaching to the cells, prevent it from replicating and enhancing immune system functioning. Lactoferrin-derived peptides are actively being researched as potential therapeutic inhibitors of influenza virus infections. Furthermore, hydrolyzed whey protein, which contains lactoferrin and many other bioactive peptides, has been shown to induce macrophage activity and activate anti-inflammatory pathways. Whey protein is also high in cysteine helping to boost glutathione levels. Fermented dairy like kefir and cheese have been shown to reduce respiratory infections in both adults and children thanks to the bacteria Lactobacillus GG.
  • Fruits and Vegetables. Regular consumption of fruits and vegetables may be useful for the immune system. A higher intake of fruit and vegetables has been shown to reduce proinflammatory mediators and enhance immune cell profile. For example, one 2012 study found that increased fruit and vegetable intake improved antibody response to a vaccine that protects against Streptococcus pneumonia in older people. However, whether these benefits would be found in someone who has an overall healthy diet (i.e., not consuming the Standard American Diet) and sourcing quality pastured animal foods is uncertain.
  • Elderberries and Dark Berries. Dark pigmented berries have polyphenols and antioxidants that strengthen the immune system by modulating the gut microbiota. Raspberries, strawberries, blueberries, blackberries, cherries and cranberries are all great berries with low sugar content. In a study of 60 people, taking 15 ml of elderberry extract 4 times per day 48 hours after the onset of influenza virus A and B relieved the symptoms on average 4 days earlier. Elderberries have also been shown to reduce symptoms of the flu. A meta-analysis of randomized, controlled trials found that elderberry supplementation can effectively reduce the duration of the cold and flu.
  • Probiotics and Probiotic Foods. Bacteria like Lactobacilli and Bifidobacteria have been shown to improve gut health and immunity. You can get them from fermented foods such as sauerkraut, kimchi, kefir and fermented dairy. Lack of fermented foods in the diet has been shown to cause a fall in innate immune response. Akkermansia has also shown to protect against obesity and type-2 diabetes. You can get them from polyphenol-rich foods.
    • A 2017 systematic review and meta-analysis of randomized controlled trials found that probiotics and prebiotics improve efficacy of influenza vaccination. Experimental studies show that probiotics may have direct antiviral effects through probiotic-virus interaction or by stimulating the immune system.
    • Probiotic supplementation enhances immunity in the elderly. Older people can benefit from long-term use of an oral blend of probiotics including Lactobacillus plantarum, Lactobacillus rhamnosus, and Bifidobacterium lactis, which enhance secretory immunity and increase IgA antibodies. In another study, a probiotic strain Bacillus subtilis was shown to stimulate IgA in the elderly to reduce the frequency of respiratory infections by 45%. Lactobacillus plantarum has been found to enhance human mucosal and systemic immunity as well as prevent NSAID-induced (such as ibuprofen) reduction in T regulatory cells.
    • Prebiotics are foods that the bacteria in our gut will eat. They can improve the integrity of the gut lining and reduce inflammation. Resistant starch, which is a type of prebiotic, improves glucose control and insulin sensitivity, which are risk factors for worse outcomes in viral infections. Cooking and cooling starch like potatoes or rice creates resistant starch. Other prebiotic foods include asparagus, leeks, onions, green bananas, artichoke, dandelion greens and garlic, which have all beneficial effects on the immune system.
  • Allium Vegetables like onions, leeks, and shallots promote glutathione. Garlic is a known natural antibiotic and antimicrobial food that kills viruses directly. To activate garlic’s beneficial compounds, primarily allicin, you have to crush it and consume lightly heated because overheating destroys these ingredients. Alternatively, you can take an allicin supplement daily. Aged garlic is also effective and has slightly different immunomodulatory effects.
    • Black garlic is created by fermenting fresh garlic, which enhances its bioactivity. It contains more antioxidant compounds than fresh garlic. Black garlic extract supplementation has been shown to have immunomodulatory effects, impeding TNF-alpha, IL-6, and interleukin-1 β (IL1β) and preventing mice from dying to LPS infection.
  • Herbs and Spices. Oregano and oregano essential oil are effective antifungal and antibacterial compounds. Other herbs like thyme, rosemary, clove, lemon balm and cat’s claw have similar properties. Spices like cayenne pepper, chili pepper (containing capsaicin) and black pepper can also kill pathogens directly. Using various herbs and spices in your cooking is a great way to get polyphenols and antioxidants.
  • Teas. Green tea, black tea and herbal teas have medicinal properties, such as polyphenols, that boost antioxidant defense systems and fight infections. Catechins in green tea have antiviral effects against influenza virus.
  • Raw Honey and Bee Pollen. Honey has antimicrobial peptides and medicinal properties that strengthen the immune system. It has also been shown to inhibit the growth of pathogens such as E. coli and salmonella. Raw honey is a great natural alternative to sugar and syrups. Bee pollen is a powerful modulator of immune system function, but you should be careful with not taking too much. Honey is an effective treatment for cough caused by an upper respiratory tract infection. Be wary of giving honey to infants as it can cause botulism

Foods That Weaken the Immune System

Here are the foods/beverages you should avoid or limit because they weaken the immune system:

  • Excessive Alcohol. Consumption of excess alcohol impairs the immune system and increases vulnerability to lung infections. In folk medicine, small amounts of strong spirits like vodka and herbal tinctures are used to kill pathogens locally as a disinfectant. There might be a hormetic response similar to plant phytonutrients. However, having several drinks is probably too much and damaging. Sugary alcohol like cocktails, cider, and beer do not strengthen the immune system.
  • Inflammatory Oils and Rancid Fats. Canola oil, margarine, sunflower oil and omega-6 seed oils, in general, are highly inflammatory and derail the body’s immune system and metabolism. Most processed foods have added vegetable oils and they are used in restaurants as well. Even healthy fats like olive oil or roasted nuts can become rancid. Use minimal heat when cooking with fats or meat to avoid lipid peroxidation and creating carcinogens.
  • Refined Grains. Pastries, cookies, cake, donuts and conventional bread products are high in carbs and have no real nutritional value. They can also damage the gut lining and cause inflammation. Gliadin, which is a protein found in wheat, raises another protein called zonulin, which makes the gut more permeable. Zonulin is a substance that regulates the blood-brain barrier and gut tight junctions. Serum zonulin has been found to be much higher in people with celiac disease compared to healthy controls. Reducing the consumption of grains may improve gut health and lower inflammation, especially if you are sensitive to gluten. Traditional sourdough bread is not harmful for most people because it has bacteria that essentially pre-digest the gluten and contains other enzymes that improve digestion.
  • Processed Carbs and Added Sugars. Candies, syrups, chips, fries, soda, etc. will weaken the immune system by causing systemic inflammation and insulin resistance. Of course, there is a certain amount you can get away with and physical fitness can also negate some of the side-effects, but you should avoid processed carbohydrates and added sugars as much as possible. Excessive amounts of carbohydrates can also promote chronic inflammation, type 2 diabetes and make one more prone to infections, for example by increasing nuclear factor-κB activation.
  • Poultry. Chicken, turkey and poultry, in general, have quite an unfavorable fatty acid profile. They are predominantly high in omega-6 fats, especially if the animals have been fed corn or grains. It’s not an issue if poultry is your only source of omega-6 but if the diet is already high in omega-6, then it can make things worse. A high omega-6 to omega-3 ratio has been linked to increased inflammation. Factory-farmed birds are also more prone to infections and viruses due to living in confinement.
  • Processed Meat. Bacon, sausages, dumplings, canned meat and other processed meats should be avoided and often have preservatives added to them which can be pro-inflammatory. Nitrates present in processed meats can cause harmful compounds such as nitrosamines to form in the gut in the absence of vitamin C.
  • Certain Seafood. Certain seafood can be high in mercury and other pollutants. Environmental toxins such as dioxins and PCBs can concentrate in fish fat. Toxins become concentrated in long-lived and large predatory fish. Therefore, avoid eating large fish like tuna, shark, pike, halibut and trout because they accumulate more heavy metals due to their size and eating habits. Smaller fish/seafood like salmon, pollock, krill and sardines are lower in heavy metals. Farmed fish can be fed antibiotics, as well as grains, and other inflammatory foods that produce an unfavorable fatty-acid profile.
  • Heavy Metals Such as Cadmium. Environmental pollution in the form of cadmium (Cd) has been shown to disrupt mitochondrial function and potentiate pulmonary inflammation in animal studies. Cadmium elevates inflammatory IL-4 levels and alters metabolites associated with fatty acid metabolism, leading to increased pulmonary inflammation during viral infection. Oysters and scallops tend to be high in the toxic heavy metal cadmium and should be kept to only 2 oz. or less per day.

Adaptogens for Boosting Immunity

Adaptogens are plant compounds that support homeostasis inside the body. If you’re low in energy or vitality, they can be a boost, but if you’re over stimulated, they can help calm you down. For something to be called adaptogenic, it has to be nontoxic, non-specific and have a physiological effect.

Here’s a list of the most common and effective adaptogens:

  • Chaga Mushroom (Inonotus obliquus): Chaga grows on birch trees and it lowers cholesterol, triglycerides, inflammation, and oxidative stress. The polysaccharides from Chaga’s fruiting body have been shown to activate macrophages through MAPK and NF-κB signaling. In the form of a water extract, chaga has been shown to stimulate white blood cells and anti-inflammatory cytokines. At the same time, it can inhibit the production of inflammatory cytokines. You can take chaga as a powder, tincture, extract, or make tea out of it. Optimal daily dose is estimated to be around 1-2 teaspoons as chaga can be fairly high in soluble oxalates that can bind with calcium and cause kidney stones. The oxalate levels of chaga depend on the source and it would be a good idea to get the level of soluble oxalates contained in a supplement prior to taking. The estimated levels of oxalates in chaga have been around what would be found in almonds, peanuts, cereal grains, and chocolate but less than foods with extremely high levels, such as spinach, rhubarb, and beet greens. However, insoluble oxalates do not seem to be the problem as they are excreted out in the feces, thus it is the soluble oxalate levels that matters most. There was one case-report in a 72-year-old woman with liver cancer who consumed 4-5 teaspoons of chaga for 6 months that caused liver damage and complete irreversible kidney failure. Thus, you want to make sure you are not consuming high amounts of chaga and consider avoiding high-oxalate foods like spinach, rhubarb, nuts, seeds, beans, chocolate, beets, tea, raspberries, etc. when taking chaga.
  • Reishi Mushroom (Ganoderma lucidum): Reishi is a fungus that grows in humid areas. It supports the immune system and red blood cells, which improves the body’s ability to fight disease. In a study of over 4000 breast cancer survivors, 59% of the subjects consumed reishi regularly. Reishi contains a wide variety of bioactive polysaccharides, beta-glucans, and over 120 different terpenoids. It increases HDL-cholesterol, decreases TNF-alpha, and fights fatigue. Daily dose would be similar to chaga i.e. 1 to 2 teaspoonfuls.
  • Shiitake Mushroom (Lentinula edodes): Shiitake is a dark brown fungus that grows on decaying trees. It contains polysaccharides, terpenoids, and sterols that strengthen the immune system, lower cholesterol, and combat cancer. Regular shiitake mushroom consumption (1 to 2 teaspoonfuls or 5 to 10 grams) has been shown to reduce inflammation and improve immune function in young adults. The trial showed reduced c-reactive protein, increased gamma-delta T cell and natural killer cell proliferation and increased secretory IgA indicating improved gut immunity.
  • Turkey Tail (Coriolus/Trametes versicolor): Turkey tail has been shown to decrease leukemia cells in vitro and improve the immune system of chemotherapy patients. It contains 35 different polyphenols and flavonoids like quercetin, which are potent antioxidants. Turkey tail also contains other substances, such polysaccharide peptide (PSP), that activates macrophages and modulate the immune response. In vitro, turkey tail extract has been found to inhibit the growth of Staphylococcus aureus and Salmonella enterica.
  • Ashwagandha: Animal studies find that ashwagandha has immunomodulatory effects by upregulating Th1 and macrophages. In humans, ashwagandha has been shown to reduce stress and balance the immune system. Amongst 5 people, ashwagandha upregulated the expression of CD4 and CD3+ T cells 96 hours after consumption.
  • Ginseng: Asian and American ginseng regulate immune cells and have antimicrobial properties. Fermented wild ginseng root has anti-inflammatory and antioxidant effects. Traditionally, ginseng has been used to treat chronic fatigue and erectile dysfunction. In a study on 30 people, 200 mg of ginseng a day improved mental health and mood, but the effects returned to baseline after 8 weeks. In another study, a 200 mg dose was more effective in promoting mental performance and time to exhaustion during a test compared to a 400 mg dose. So, more is not always better.
  • Ginger: Ginger is known for its ability to lower inflammation, treat infectious agents, and protect against environmental stressors, such as smoke and chemicals. One of its active ingredients gingerol is a potent anti-inflammatory substance. Consuming 2 grams of ginger a day has been shown to reduce muscle pain. Among 247 people with osteoarthritis in the knee, subjects who took ginger extract had less pain and needed fewer medications. Women who took 1 gram of ginger powder for the first 3 days of their menstruation reduced their pain as effectively as ibuprofen. In type 2 diabetes, 2 grams of ginger powder per day lowered fasting blood glucose by 12% and reduced oxidized lipoproteins by 23%. Three grams of ginger per day can also lower cholesterol significantly.
  • Turmeric: Curcumin, one of several active compounds in turmeric, has anti-inflammatory properties that can help chronic pain and infections. It also helps to boost glutathione levels in the body and inhibit NF-kB activation. Curcumin also has antibacterial, antiviral, and antifungal qualities in humans. You can get it from just using curry or other Indian spices on your food, but the greatest benefits come from turmeric supplements that either contain the fat soluble curcuminoids or the water soluble turmerosaccharides. Typical doses of turmeric from supplements are usually around 500 mg taken two to four times daily with food.
  • Astragalus (Astragalus membranaceus): Research shows astragalus protects against gastrointestinal inflammation and has immune system strengthening properties. In one study, a combination of astragalus, echinacea, and licorice herbal tincture stimulated immune cells within 24 hours of consumption and kept them elevated for the following 7 days. Test tube studies have found that Astragalus extract turns on the immune response in macrophages.
  • Licorice Root: Also known as sweet root, is a common sweetener in candies and sweets, which has been used as medicine for centuries. It’s most often used to treat coughs, digestive problems, and colds. Licorice has been shown to reduce H. pylori, alleviate ulcers, promote immune system functioning, and fight viral infections such as SARS or influenza. Isoliquiritigenin (ILG) – one of the main active compounds of licorice root – has been shown to inhibit influenza virus replication and inhibit inflammatory cytokines. Administration of ILG reduces the morbidity of mice infected with the H1N1 virus. Glycyrrhizin, an active compound of licorice root, has also been used to block the replication of SARS-associated coronavirus. However, excess glycyrrhiza can cause headaches, fatigue, hypertension, and even heart attacks. It’s also not recommended during pregnancy or breastfeeding. Licorice can interact with many medications, such as diuretics, anti-arrhythmia drugs, blood pressure medications, blood thinners, statins, and non-steroidal anti-inflammatory drugs (NSAIDS). Doses of licorice should be limited based on its glycyrrhizin content, which should not exceed more than 100 mg of glycyrrhizin per day.
  • Schisandra chinensis (five flavor fruit): A fruit vine that grows purple-red berries. A 2013 animal study found that Schisandra reduced liver damage and protected against lipid peroxidation. It has also shown to alleviate symptoms of menopause in women, block excessive beta-amyloid in Alzheimer’s disease, and reduce depression in mice. A safe dosage is 1.5-6 g/day as a powder or 3 g/day of the actual fruit. Excessive doses can cause heartburn, ulcers, reflux, and allergies.
  • Moringa (Moringa oleifera): Moringa contains vitamin C, beta-carotene, quercetin and chlorogenic acid that lowers inflammation. Human studies have shown it can decrease blood sugar and lipids. It also inhibits lipid peroxidation and improves kidney functioning. Moringa root intake has reduced urinary oxalate and reduce kidney stone formation. Other benefits include reduced stress, anxiety, and regulation of thyroid hormones. Daily dosage should stay between 1/2-2 tsp/day of moringa powder or 1,500-3,000 mg/day.
  • Holy Basil (Ocimum sanctum): Otherwise known as tulsi, has antiviral, antibiotic, fungicidal, germicidal, and disinfectant qualities. A 2017 review showed that holy basil has potential in treating cardiovascular disease thanks to its antioxidants. Due to the antibacterial effects, you can use it for oral health as well.
  • Andrographis: A genus of plants in the acanthus family. They are known as waterwillows, including other names. Andrographis Paniculata has been used for cough, the cold, and influenza in traditional Chinese and Indian medicine. It is deemed to be safe for relieving acute respiratory tract infections and shortening the length of symptoms. There seems to be efficacy in reducing symptoms of upper respiratory tract infections as well.
  • Artemisinin: Also known as wormwood, inhibits the replication of flaviviruses by promoting the production of type I interferon.

Most adaptogens are generally not recommended to be taken all the time because the body can potentially build up a tolerance to them. For most of the above, take them to help with stress, inflammation or during times of higher risk for infections.

Here are some supplements that appear to have no effect for improving immunity and may even make infections worse:

  • Paracetamol and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Painkillers are commonly used to treat the flu, but they are not remarkably effective. Acetaminophen or paracetamol has been shown to increase the duration of colds because it decreases the natural antibody response. In pneumonia, NSAIDs impair neutrophil functioning, their recruitment to the site of inflammation, and the resolution of inflammatory processes after acute pulmonary bacterial challenge, which slows down recovery from the disease. A 2014 study discovered that suppressing fever with NSAIDs or other pain killers may increase influenza cases and deaths in the U.S.
  • Multivitamins: Supplementation of B-vitamins, vitamin E, folate, and vitamin C has not been shown to protect against common infections. However, it may be beneficial for overcoming some nutrient deficiencies. Vitamin C has been shown to reduce the duration and severity of the common cold, but it does not seem to be a preventative.
  • Echinacea is known for its immune strengthening properties, especially in treating upper respiratory infections. However, recent systematic reviews have found the health claims to be lacking in statistical relevance.
  • Cough Medications: Coughing is a protective mechanism that clears the airways of mucus and pathogens. None of the common over-the-counter drugs such as codeine, dextromethorphan (DXM) or antihistamines have been found to be effective against the flu or coughing.

Here are the fundamentals of a strong immune system:

  • Optimize Your Sleep – Sleep is probably the most essential thing for the body’s recovery and adaptation. It also governs adaptive immunity, vaccine efficacy, antioxidant defense systems, physical repair, and the immune response. Sleep deprivation and poor sleep is detrimental for the body’s ability to deal with stress and external stressors because all the resources are being depleted on self-maintenance.
  • Fix Metabolic Syndrome – Poor metabolic health is like a fire in your kitchen that begins to spread throughout the rest of the building. It causes chronic inflammation that burns through the body’s magnesium, glutathione, and immune cells. Hyperglycemia, hyperinsulinemia, diabetes, and hyperlipidemia promote oxidative stress and the onset of the cytokine storm. Obesity and insulin resistance make it more likely for you to carry viral particles around and be sick for longer. 
  • Eat a Nutrient Dense Diet – You may lose weight and improve your biomarkers with a low nutrient diet, but this can compromise your immune system. The body needs certain nutrients to mount a sufficient antiviral response and conduct other processes of immunity. To avoid malnutrition, eat a mix of plant and animal whole foods (or at the very least certain plant compounds in addition to animal foods). The most important nutrients for the immune system are vitamin D, magnesium, selenium, zinc, copper, vitamin A, vitamin E, vitamin C, vitamin K, and the B vitamins. Other beneficial nutrients are omega-3s, glutamine, collagen, glycine, and astaxanthin.
  • Supplements to Fix Your Nutrient Deficiencies – A lot of people may still have nutrient deficiencies despite eating a whole food-based diet. This is the result of soil erosion, poor farming methods, pesticides/herbicides/fertilizers and just the decline in the nutritional value of our food. The most common deficiencies are vitamin A, vitamin D, choline, magnesium, omega-3s, zinc, vitamin K, and B vitamins, especially riboflavin (B2). Supplementing them may be effective but be sure to discuss this with your doctor beforehand.
  • Forest Bathing – Spending time in nature is beneficial for stress management, overall health, mindfulness, and the immune system. In Japan, the term ‘forest bathing’ translates from ‘Shinrin-yoku’ and it has been shown to lower inflammation, reduce stress, promote anti-cancer killer cells, improve cardiovascular disease risk factors, and decrease blood glucose. Exposure to the natural particles and bacteria when in nature builds up your microbial diversity and enhances immunity against various pathogens. Living in a hyper-sterile disinfected environment reduces your body’s resilience because it’s not receiving enough experience to different microbes. Getting your hands dirty with gardening, hiking or mountain climbing is also beneficial.
  • Regular Exercise – The body needs physical activity to stay healthy and maintain its defense system integrity. Exercise is a hormetic stressor that causes a positive response given enough time for recovery. The mild increase in inflammation and oxidative stress is a form of preconditioning that enhances your resilience to stressors in the future. Overtraining, however, will weaken immunity and increases susceptibility to illness.
  • Hot/Cold Hormesis – Hyperthermic conditioning with saunas as well as cold therapy are similar to exercise in the way they affect the immune system. In moderation they are great for enhancing immunity but in excess can be harmful. It is hard to over-do the sauna, but you should be careful if you have hypertension or are already sick. Going into an ice bath or a cold shower with symptoms of illness is also not useful. Hot/cold preconditioning ought to be used primarily for maintaining or improving metabolic and immune health.
  • Intermittent Fasting – Intermittent fasting is also a form of hormesis that has a beneficial effect on the immune system by upregulating glutathione, autophagy and Nrf2. Although extended fasting can cause an acute drop in immunity, it rebounds back up after breaking the fast. Thus, regular time-restricted eating is safer, especially if you are already sick.


The Mind & Immune System, New Findings: Acupuncture & Fascia

By stimulating the body at particular sites, they could liberate cells and molecules that enhance the function of the immune system.

By stimulating fascia, in particular locations on the body, there’s a pathway leading out to the adrenal medulla that could liberate particular chemicals that could lead to an anti-inflammatory effect.

Foundational Tools & Practices for a Healthy Immune System

Adequate sleep (deep and high quality, timed well and consistently), sunshine (set circadian rhythm for genes and cells to function at appropriate times), exercise (150–180-minute zone 2 per week), quality nutrition, social connection, hydration, etc.

Immune System Basics: Skin/Mucous, Innate & Adaptive Immune System

3 layers of defense: physical barrier (skin), innate, and adaptive immune system.

The skin is the primary barrier. You also have openings (eyes, ears, nose, mouth) which invasive organisms can get into. This is why they are lined with mucus, which traps/filters/kills bacteria and viruses. The chemistry of that mucus is also important for doing its job.

Killer Cells, Complement Proteins (“Eat Me!” Signals), Cytokines (“Help Me!” Signals)

Innate immune system is very fast. We tend to wipe the chemicals from other people to sample them. When something enters our body that our immune system doesn’t recognize the innate immune system takes charge. White blood cells (neutrophils, macrophages, NK cells) surround and kill whatever the invader is. They work with complement proteins, which travel through blood to mark/tag invaders so that WBCs can go kill them. Cells that are damaged from the injury or parasite or suffering from the bacteria/parasite itself will release an alarm signal in the form of cytokines. Inflammatory markers like IL-1, IL-1, TNF-alpha, etc., communicate with the WBCs.

The Adaptive Immune System: Antibodies

The adaptive immune system creates antibodies against bacteria, viruses, parasites, and even physical invaders. It attaches to and creates an imprint of the invader and then uses that imprint to create antibodies for future attack. Leukocytes are WBCs that are derived from the same origin cell/stem cell, which reside in the bone marrow and go to sites of infection, when called out, to create the antibodies.

Ig = immunoglobulin, part of adaptive immune response in creating antibodies

IgM = the first of the adaptive immune responses, comes on earlier (recent infection if a person is immuno-positive for a certain viral or bacterial invader).

IgG = more stable form of specific antibody

Something gets into the system, into the mucus, and/or bloodstream, innate response to contain, the adaptive to generate antibodies (IgM then IgG).

The mucus lining needs to be kept in good shape. Maintain a healthy microbiome, nasal, mouth, eyes, all along the digestive tract (mouth, throat, stomach, intestines, rectum), urethral, and vaginal.

Tool 1: Nasal Microbiome and “Scrubbing” Bacteria & Viruses; Nasal Breathing

Nasal breathing is good for scrubbing bacteria to prevent infection. Use its natural filter by nasal breathing. The best way to dilate a deviated septum or collapsed sinus is actually to just breathe through it more.

The nasal microbiome has a particular species of microbiota that are good at fighting infection. Oxygenation of the environment is good for enhancing their effect.

Tools 2 & 3: (Not) Touching Your Eyes; Gut Microbiome & Fermented Foods

Try not to touch the eyes after shaking hands with or touching people. The crust in your eyes in the morning is the accumulation of dead bacteria that you have successfully battled through the night.

Enhance the proliferation of good gut microbiota by ingesting 2-4 servings of fermented foods per day. This reduces the number of inflammatory cytokines, due to less cells being infected.

Natto, sauerkraut, kimchi, pickles, etc.

Some Interleukins Are Anti-Inflammatory

IL-10 is anti-inflammatory.

Sickness Behavior

A suite of response that we all undergo when we begin getting sick. Slowing of usual levels of activity, lethargy, people and animals stop grooming (overall suppression of certain activity), loss of appetite (possibly to discourage vomiting or diarrhea or to harbor more resources for the sake of repair), slowed circulation (lymphatic system can ramp up activity when we are immobile).

Some People Seek Care When Sick, Others Want to be Alone

Psychologically can go into a vulnerable state (50% want help from others, whereas 50% want to be left alone – possibly an adaptive response to reduce infection spread).

Sickness Behavior & Depression: Cytokines

The sickness state mimics the major depression state. Robust increases in IL-6 and TNF-alpha. Sickness behavior is what provides a bridge between the nervous system and the immune system. Healthy behavior also points to a clear bridge in a different way.

Reduced Appetites When Sick: Protein, Iron, Libido

Reduced appetite of protein rich food may be an attempt to reduce iron levels, as many bacteria seem to thrive in high iron level environments.

Loss of libido, not necessary usage of energy.

Vagus-Nerve Stimulation: Fever, Photophobia, Sleepiness

The vagus nerve signals to particular brain sites to engage in this sickness behavior. The fast pathway by which an infection in the body is signaled to the brain (hypothalamus), to increase body temperature/fever.

LPS causes inflammation in the gut, it secretes IL-6 and IL-1, killer cells migrate to the gut (sometimes stomach ache during flu), neural signal to the hypothalamus, fever to kill off invader.

The vagus also sends a message to the brain to change the perception of the outside world, such as photophobia. Most people when they are sick get light aversive. Light from eye, to anterior thalamus, to meninges, creating photophobia and a headache. Triggering you to go to a dark, safe place to rest.

Also, the drive to rest. The supraoptic nucleus promotes the desire to sleep, even during the daytime.

Humoral (Blood-Borne) Factors, & Choroid Change Your Brain State

The slow pathway. If you have an infection for multiple days, the IL-6, IL-1, and TNF-alpha levels are high enough in the blood that it is communicated to the brain. The choroid (fluffy tissue in the ventricles) starts releasing and responding to the cytokines and the brain changes in response to the inflammation to neurons (memory gets poor, cognition gets poor).

Tools 4, 5: Reducing Sickness: Glymphatic Clearance, Pre-Sleep Serotonin, 5HTP

When we feel the first signs of sickness (tickle in throat, run down, etc.), we can do a few things.

The sleep associated with early-stage infection is associated with elevated levels of serotonin in the brain. Enhancing the immune function and fighting infection. So, we can consume foods that increase serotonin production naturally, leading to better quality sleep with a robust immune response.

The glymphatic system is also much more active, especially during deep sleep, clearing debris from the brain. Increased serotonin levels in the brain have been shown to increase the amount of circulation in the glymphatic system. Possibly leading to more rapid recovery.

If you elevate your heels by 12 degrees (head below legs) there is more glymphatic clearance during sleep. Could be used during periods of rest too, as the glymphatic system is also active during certain periods of the day.

Probably shouldn’t take 5-HTP normally as it disrupts typical sleep stages. Maybe taking it when you’re sick would be okay as you won’t be undergoing typical sleep stages.

The glymphatic system has also been tied to the iron deposition system. “Dysfunction of the glymphatic system might be related to iron deposition in the normal aging brain”

Tool 6: Hot Showers, Saunas, Baths & Cortisol, Heath-Cold Contrast

1 x 96-degree 15-minute sauna session can increase WBC profiles and can adjust cortisol levels that were beneficial for combatting infection.

If you are already running a fever, so you probably shouldn’t get in a sauna unless you want to kill off your neurons. Use at the beginning of a potential infection.

A 15-minute sauna followed by a cooling period and back in can be beneficial. The hypothalamus is forced to go through repeated pulses instead of shutting off after adjusting the temperature the first time.

Feed a Fever & Starve a Cold (?), Adrenaline

Eating can increase body temperature. Fasting increases the amount of adrenaline, which has a powerful effect on inflammatory cytokines and the immune system in general.

Tool 7: Activating Your Immune System w/Cyclic-Hyperventilation, Alkalinity

Compared to control and meditation subjects, plasma levels of IL-10 (anti-inflammatory) increased after endotoxin administration, triggered by adrenaline increase with cyclic breathing (WHM breathing – similar to Tummo). Levels of proinflammatory cytokines lower and flu-like symptoms were lower too.

Deliberately employing the SNS to enhance the immune system with adrenaline release. Blood oxygenation drops and pH of body goes up (7.4 to 7.6) too, but it seems the epinephrine release is what is causing the immune response.

The hyperventilation and the breath retention are both important (hyperventilation and hypoxia combine to increase adrenaline levels).

Brain Chemicals & Cyclic-Hyperventilation; Catecholamines, Dopamine

Catecholamine concentrations (dopamine, epinephrine, and norepinephrine) were measured during the breathing protocol experiment. Short term stress can be beneficial and it is typically recognized by the release of these catecholamines increasing alertness and driving motivation. When the dopamine system is activated, you see effects such as reduction in tumor growth.

Mindsets & Immune Function; Yes, You Can Worry Yourself Sick

The corticolimbic-hypothalamic pathway (dorsal peduncular cortex, dorsal tinea tecta (DP/DTT)) is a pathway that originates insights to the brain that are associated with thinking, with emotion and with prior history, and feeds into an area of the brain involved in basic physiological subconsciously controlled processes.

The way to think about something changing our core physiology. If you expose somebody to a psychological stress you can activate this pathway, creating fever and illness-like behavior.

Tool 8: Healthy Mindsets, Hope, Dopamine; Tool 9: Tyrosine; Tool 10: Cold Exposure

When cancer patients reported a sense of hope, their rates of recovery were much higher. A sense of future is tightly tied with the dopamine system. Stimulating the dopamine system, purely with a sense of hope for the future, via activating the mesolimbic pathway, could accelerate wound healing, accelerate the passage from a state of illness to health and wellbeing.

Augmenting the dopamine system may also increase wellbeing, within reason (not overwhelming the system with drugs), and accelerate recovery. The reward pathway liberates the system making inflammatory cytokines go down and anti-inflammatory cytokines go up.

Cold water exposure increases dopamine status massively. Combined with sauna therapy this cold-heat contrast therapy could be a powerful tool for both increasing catecholamines for immune regulation and recovery as well as destroying potential pathogens.

The catecholamines are the bridge of activation between the nervous system and the immune system. Activating the deployment of many more immune cells too.

Once You’re Already Sick: Accelerating Recovery; Tool 11: Spirulina, Rhinitis

Some cold/flu drugs dehydrate you and interfere with sleep. One of the hallmarks of REM sleep is that epinephrine levels are low, which is counter to how these over-the-counter medications (Sudafed) often target the epinephrine system to employ their effects vasodilating and reducing congestion.

Spirulina can reduce rhinitis symptoms (nasal congestion, decreased sense of smell, sleep issues, inflammatory cytokines), with 2g.

Histamines, Mast Cells

Spirulina can inhibit the formation and/or activity of histaminergic mast cells, which usually cause swelling and inflammation at the site of injury or infection, which then cause the recruitment of innate immune cells.

Spirulina can carry side effects in those with a genetic mutation (PKU – sensitive to phenylalanine).

Tool 12: Acupuncture: Mechanism for How It Reduces Inflammation; Fascia, Rolfing

Stimulation with electroacupuncture at specific sites that can lead to increasing inflammation (abdomen) and lowering it (lower limbs) by stimulating the vagal-adrenal reflex. The activation of nerve ending that reside in fascia.

A specific population of neurons (PROKR2 neurons) that send a deep connection to the limb fascial tissue, then out to the spinal cord and the hind brain (DMZ), then to the adrenal gland to release catecholamines. Their release causes a reduction in inflammation. Meaning, activation of the deep fascial tissue causes a chain of neural reactions that leads to the release of norepinephrine, epinephrine, and dopamine – lowering inflammation. Similar to the cyclic breathing hyperventilation study (WHM).

Rolfing involves the separation of muscle from fascia somewhat. Very deep tissue massage.

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