It is clear from this[4] and other studies that the immune response in hospitalized patients with severe COVID-19 is characterized by lymphopenia and the expression of molecules associated with ongoing inflammation,[5] whereas these same molecules are expressed at a lower level in people with mild or moderate disease.
Figure 1. Immune responses to COVID-19 infection (source: [4])
a) Higher IFN-α in in people with severe disease (cf. moderate disease)
b) Higher expression of IFN-λ only in people with severe disease
c) Level of TNF-α (a inflammation-promoting cytokine) correlated with viral load in the nasal passages
d) Viral load declined over time in people with moderate disease (cf. severe disease)
e) IL-5 upregulated as people developed severe disease (cf. moderate disease)
f) Levels of CD4 and CD8 T cells were lower in people with moderate or severe disease (cf. healthy controls)
Immune Responses to COVID-19 Infection
A dysregulated immune response, a cytokine storm and cytokine-release syndrome[8,9] are some of the terms used to describe the overexuberant defense response that is thought to contribute to disease severity in certain people who become seriously ill with COVID-19.
Based on [4], people with severe disease have (see also Figure 1):[4]
Higher expression of IFN-α (Interferon type I) & IFN-λ(Interferon type III) (cf. ppl. w/ moderate disease)
Beyond antiviral control, type I IFNs are known to have anti-inflammatory functions, particularly through the negative regulation of IL-1 and IL-18 and of inflammatory TH17 cells
Type III interferons (IFNs) (or IFN-λ) can be induced in response to viral infections, and lead to JAK and STAT activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription.
Viral load NOT declined over time (cf. ppl. w/ moderate disease)
Higher level of IL-5(cf. ppl. w/ moderate disease)
which aids defense against parasitic worms, not viruses
Lower level of CD4 and CD8 T cells (cf. healthy controls)
which are key immune cells involved in viral clearance
Higher level of pro-inflammatory cytokines (cf. healthy controls)
Higher levels of other cytokines (cf. ppl. w/ moderate disease)
IFN-λ, thrombopoietin (which is associated with abnormalities in blood clotting), IL-21, IL-23 and IL-33
Higher levels of cytokines associated with activation of inflammasome (cf. ppl. w/ moderate disease)
which is a component of the immune response that is a driver of inflammation
Higher Th1 cells (cf. ppl. w/ moderate disease)
Elevated cytokines associated with immune responses to fungi (cf. ppl. w/ moderate disease)
which are cytokines released by Th17 cells
Elevated cytokines associated with immune responses to parasites or with allergic reactions (cf. ppl. w/ moderate disease)
which are cytokines released by Th2 cells
Figure 2. Type I and type III interferons are among the most potent anti-viral cytokines produced by the immune system. Are they friends or foes? (Source: [13])
Internal Immunity (IgG) vs Mucosal Immunity (IgA)
Vaccination will dramatically reduce your likelihood of serious illness or death if you’re exposed to SARS-CoV-2. This largely protects vaccinated people from being overwhelmed by the coronavirus, unless they have an immunodeficiency or are exposed to an unusually large amount of the virus.
There’s two kinds of immunity:[14]
Internal Immunity
Vaccines injected into our muscles provide internal immunity
They are highly effective at stimulating internal immunity, which protects the inside of the body, including the lungs
This occurs by release of antibodies of the Immunoglobulin G type, or IgG, into the blood and production of T-cells
Mucosal Immunity
Mucosal immunity provides the first line of defense by protecting the nose and mouth, and by doing so also reduces spread to others
The mucous membranes secrete a particular form of antibodies of the Immunoglobulin A type (IgA)
Vaccines administered via nasal spray provide mucosal immunity
They’re still under development for Covid-19
Vaccines administered via nasal spray exist for other ailments, including polio
They can supplement existing shots with mucosal immunity
Note that:
Vaccines injected into our muscles—including all the approved inoculations against Covid—are largely ineffective at stimulating the secretion of IgA into our noses that occurs after actual infection with a virus.
For the previously infected, who thanks to natural mucosal immunity are likely at less risk than never-infected vaccinated people of spreading the virus to others
Cytokines are a broad and loose category of small proteins (~5–20 kDa) important in cell signaling. They are key players in the regulation of the immune response, particularly during infections, inflammatory joint, kidney, vessel and bowel diseases, or neurological and endocrinological autoimmune diseases.
but not hormones or growth factors. Unlike hormones, cytokines are not stored in glands as preformed molecules, but are rapidly synthesized and secreted by different cells mostly after stimulation.
Figure 1. Cytokines act in networks or cascades. They are a category of signaling molecules that mediate and regulate immunity, inflammation, hematopoiesis, and many other cellular processes.
Cytokine Network
Cytokines act in networks or cascades. Several different cell types coordinate their efforts as part of the immune system. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted cytokines.
A given cytokine may be produced by more than one type of cell. They act through cell surface receptors.
Cytokines are produced by a broad range of cells, but the predominant producers are helper T cells (Th) and macrophages, including immune cells like:
Macrophages are phagocytic cells that are produced during an injury or infection.
Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types.
Unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines.
However, there are a large number of cytokines that act on B cells that play significant roles in the development, survival, differentiation and proliferation of B cells.
The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well (see Figure 1).
Summary of cytokines and their functions
Th1 cytokines
Cytokines produced by Th1 T-helper cells
Include IL-2, IFN-γ, IL-12 & TNF-β
IFN-γ is the defining cytokines for Th1 cells, which enhances inflammatory functions that support viral clearance
Innate mediators of Th1-driven pathology are powerful across diseases.[14]
Scientists found that liver-resident Kupffer cells induced neutrophil-mediated liver toxicity by producing IL-12 and responding to IFN-γ. Inhibition of the neutrophil response limited liver toxicity.
Th2 cytokines
Cytokines produced by Th2 T-helper cells
Include IL-4 , IL-5, IL-6, IL-10, and IL-13
IL-4 is the defining cytokines for Th2 cells
Th17 cytokines
include IL-17, TGF-beta, IL-6
IL-17 is the defining cytokines for Th17 cells
Th17 cells play a role in host defense against extracellular pathogens, particularly at the mucosal and epithelial barriers, but aberrant activation has been linked to the pathogenesis of various autoimmune diseases.[13]
Anti-inflammation; Central regulator in IgE synthesis,
goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness,
fibrosis and chitinase up-regulation; Also, a mediator of allergic inflammation
and different diseases including asthma.
TNF-α
TNF
Macrophages, NK cells, CD4+lymphocytes,
adipocyte
Pro-inflammation, cytokine production, cell
proliferation, apoptosis, anti-infection, play a damaging role in many inflammatory diseases
Pro-inflammation, macrophage activation,
increase neutrophil and monocyte function
TGF-β
TGF
Macrophages, T cells
Anti-inflammation, inhibition of
pro-inflammatory cytokine production
Inflammation and Pain
Inflammation is part of the body’s defense mechanism and plays a role in the healing process.
The cardinal signs of inflammation include: pain, heat, redness, swelling, and loss of function.
While the sensation is a very individualized experience, inflammation typically causes pain because the swelling and buildup of tissue starts pressing against nerve endings. This pressure sends pain signals to the brain, causing discomfort.
There is significant evidence showing that certain cytokines/chemokines are involved in not only the initiation but also the persistence of pathologic pain by directly activating nociceptive sensory neurons. Certain inflammatory cytokines are also involved in nerve-injury/inflammation-induced central sensitization, and are related to the development of contralateral hyperalgesia/allodynia.
Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction. Their functions also include:
Modulate the balance between humoral and cell-based immune responses
Regulate the maturation, growth, and responsiveness of particular cell populations
Enhance or inhibit the action of other cytokines in complex ways
Pro-Inflammatory vs Anti-Inflammatory
There are both pro-inflammatory cytokines and anti-inflammatory cytokines:
Proinflammatory cytokines
Inflammatory cytokines play a role in initiating the inflammatory response and to regulate the host defense against pathogens mediating the innate immune response.
Some inflammatory cytokines have additional roles such as acting as growth factors.
They are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions.
There is abundant evidence that certain pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved in the process of pathological pain.
Anti-Inflammatory cytokines
Major anti-inflammatory cytokines include IL-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13.
IL-10 is considered a prototypical anti-inflammatory cytokine, and is the most widely studied of the anti-inflammatory interleukins.
Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals.[4]
Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme.[5]
As a result, TNFα levels rise and result in inflammation.[6]
TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.
LIF, IFN-α, IL-6, and TGF-β are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances.
Is cholesterol really the bad guy? The answer is yes-and-no: it depends. In this article, we will discuss the myths and facts of cholesterol.
The Cholesterol Myth: What Really Clogs Our Arteries (YouTube link)
Is Cholesterol Really the Bad Guy?
In [1], Dr. Dwight Lundell said:
As a heart surgeon with 25 years experience, having performed over 5,000 open-heart surgeries,today is my day to right the wrong with medical and scientific fact.
In a nutshell, here are his statements:
What Was Wrong?
Heart
disease resulted from the simple fact of elevated blood cholesterol.
The only accepted therapy was prescribing medications to lower
cholesterol (hint: statins) and a diet that severely restricted fat intake.
What Is the Answer?
Inflammation
in the artery wall is the real cause of heart disease.[1,16,22,25] Without
inflammation being present in the body, there is no way that cholesterol
would accumulate in the wall of the blood vessel and cause heart
disease and strokes.
If cholesterol alone were the bad guy, then the pill named evacetrapib would be the miracle cures for most heart diseases because evacetrapib can:
Substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity
But, based on a research, it concludes that:[23]
Treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease and the trial was terminated early because of a lack of efficacy.
Figure 1. Healthy Heart for all
What is Cholesterol?
Cholesterol[3,6] is a lipidic (or fatty), waxy steroid found in the cell membranes and transported in the blood plasma. Here are the facts of cholesterol:
Body needs cholesterol
For its structural role in the cell membrane—to maintain membrane permeability and fluidity
As a precursorfor the biosynthesis ofsteroid hormones, bile acids, vitamin D, and the adrenal gland hormonescortisol and aldosterone[4]
No cholesterol, no sex
As a precursor for synthesizing the sex hormones progesterone, estrogens, and testosterone and their derivatives.[4]
For muscle mass buildup
The research at TAMU revealed that following relatively vigorous workouts, individuals who had the most muscle mass gain also had the highest LDL cholesterol levels.[20]
For skin protection
In the skin, cholesterol is secreted by glands just below the surface to protect against dehydration and the wear and tear of sun, wind, and water.[3]
For healing wounds and protecting against infections.[5]
Almost every cell in the body manufactures cholesterol
In vertebrates, the liver typically produces greater amounts than other cells.
Even you eat foods with little cholesterol ingredients, your body will still manufacture at least 1,000 mg of pure cholesterol each day.
Figure 2. Main target organs of oxysterols during ageing and aged-related diseases
Cholesterol may act as an antioxidant[7]
It can stand in to perform an antioxidant function when certain vitamins and minerals are in low supply.
However, cholesterol is damaged in the process, and oxidized cholesterol is bad for the body.[29]
That's why getting antioxidants in a steady supply throughout the day is important. Let your vitamins and minerals protect you from free radicals so they can allow your cholesterol to play all of its other life-saving roles.
Video 1. Oxidized Cholesterol as a Cause of Alzheimer's Disease (YouTube link)
What is Inflammation?
By itself, cholesterol does not cause heart disease and stroke. Atherosclerosis is an inflammatory disease. It's what inflammation does to cholesterol that causes arterial plaques.[11]
Inflammation is simply our body’s natural defense to a foreign intruder (i.e., bacteria, toxin or virus).[1] The cycle of inflammation is perfect in how it protects our body from these bacterial and viral intruders. However, if we chronically expose the body to injury by toxins or western diets the human body was never designed to process, a condition occurs called chronic inflammation.
Connection between Inflammation and Plasma Fibrinogen Level
There's a strong and well-established connection between inflammation and plasma fibrinogen level.
Here's a breakdown of their relationship:[35-39]
Inflammation: When your body encounters a threat, like an infection or injury, the immune system triggers inflammation. This process involves releasing various chemicals, including cytokines, that signal the body to heal and defend itself. Fibrinogen: This is a plasma protein essential for blood clotting. It helps form a fibrin mesh that traps blood cells and platelets, stopping bleeding. The Link: During inflammation, cytokines also stimulate the liver to produce more fibrinogen. This increased production elevates plasma fibrinogen levels, contributing to several outcomes:
Acute Phase Response: This refers to the body's overall response to inflammation, and elevated fibrinogen is a hallmark feature.
Blood Clotting: Higher fibrinogen levels increase the blood's clotting potential, potentially leading to risks like thrombosis (blood clot formation) if not regulated properly.
Chronic Inflammation: In conditions with long-term inflammation, like autoimmune diseases or rheumatoid arthritis, chronically elevated fibrinogen levels are often observed. This might contribute to tissue damage and disease progression.
Important Points:
Not everyone with elevated fibrinogen levels will experience complications. Other factors like genetics, lifestyle, and underlying health conditions play a role.
Treatment for high fibrinogen typically focuses on addressing the underlying inflammatory cause, not directly lowering fibrinogen itself.
Consulting a healthcare professional is crucial if you have concerns about your fibrinogen levels or inflammatory status.
Video 2. High Cholesterol is Healthy! [with David Diamond, PhD] (YouTube link)
Causal Effect of Blood Clotting on Heart Attack and Stroke
Blood clotting plays a crucial role in both heart attacks and strokes, but the specific causal links differ slightly.
Key Points:
Blood clots themselves don't directly cause heart attacks or strokes. However, they worsen pre-existing conditions and trigger the events.
Different types of arteries and specific causes of clot formation contribute to each scenario.
Prevention focuses on managing risk factors for plaque buildup, blood clotting, and heart/brain health.
Summary
In this article, we have shown you that cholesterol is an essential nutrient. Driving your cholesterol levels down too far can cause serious health problems.
In a first study that explores the independent risk factors of long-term all-cause mortality in coronary artery disease patients with well-controlled LDL-C levels, authors have found that:[32]
The relative risk was highest for severe malnutrition. Considering the prevalence of identified risk factors, the highest population attributable risk was found for mild malnutrition, followed by chronic kidney disease, moderate malnutrition, age ≥75 years, congestive heart failure, severe malnutrition and atrial fibrillation.
To recap, atherosclerosis is an inflammatory disease. Inflammation in general are almost never the presence of too much cholesterol alone—rather they are too little of many other compounds: antioxidants, vitamins, minerals, omega-3 fatty acids, etc.
Without inflammation, cholesterol would move freely throughout the body as nature intended. It is inflammation that causes cholesterol to become trapped. As noted in previous section, chronic inflammation is harmful while acute inflammation is beneficial. To become healthy is to avoid chronic inflammation. As Dr. Dwight Lundell pointed out, the culprits of chronic inflammation is our western diets:[1,8]
What are the biggest culprits of chronic inflammation? Quite simply, they are the overload of simple, highly processed carbohydrates (sugar, flour and all the products made from them) and the excess consumption of omega-6 vegetable oils like soybean, corn and sunflower that are found in many processed foods.
Without much ado, I would refer you to watch [1] for the causation of heart diseases:
Western diets -> High blood sugar -> Glycation -> Chronic inflammation -> Heart diseases
Remember this: Avoiding heart disease begins and ends with following a healthy lifestyle, not with pharmaceuticals. Poisoning your cells' ability to make cholesterol isn't the best way to avoid heart disease.
Warning: If you have concerns about your cholesterol levels, always consult a qualified healthcare professional for personalized advice based on your individual risk factors and medical history.
Every patient is different, and every case of heart disease involves a multitude of factors, from diet to activity level to lifestyle, as well as the genetic diversity of the human race.
U. Erasmus, Fats That Heal, Fats That Kill (Burnaby BC, Canada: Alive Books, 1993).
Hanukoglu I (Dec 1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis.". J Steroid Biochem Mol Biol 43 (8): 779–804.
U. Ravnskov, "High Cholesterol May Protect Against Infections and Atherosclerosis," QJM Internaltional Journal of Medicine 96 (2003): 927-34.
