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Immune System


Contents

Heterotrophs
First Line of Defence
Second Line of Defence (Innate Immune System)
Third Line of Defence (Adaptive Immune System)
Virus
Immune System Disorders

Heterotrophs

Heterotrophs Attack and Defence There are two types of living organisms in this world. The autotrophs (self-nourishment) live on inorganic materials, while the heterotrophs (different-nourishment) must make use of resource that comes from other organisms in the form of fats, carbohydrates and proteins (Figure 01). Thus, there is always an arm race going on for the latter type - it's a race between attack and defence (Figure 02). Such acts are all too obvious in the macroscopic setting, actually the same kind of struggle is on going all the time in the microscopic environment. The lower frame of Figure 02 shows a swarm of viruses (in blue) attacking an E. coli bacterium with the contractile sheath, which acts like a syringe to squirt the genetic material (DNA) into the host cell.

Figure 01 Heterotrophs
[view large image]

Figure 02 Attack and Defence [view large image]

It responds by secreting enzyme to cleave or disable the foreign DNA or commits suicide to protect the rest of the population if worse comes to worst.

Immune System The subject on immune system in the followings is about the defence of an macroscopic being against the invasion of pathogenic microbes including bacteria, viruses, parasitic worms and fungi. Micro-organisms outnumber the human cells of our bodies by ten to one. Some of them are friendly (up to a point), doing us neither good nor harm, many are important to the functioning of the body, but there are nasty varieties that can cause all kinds of illness. The defence has to be able to tell friends from foes and also doesn't kill itself. The main lines of defence are the innate and adaptive immune systems (Figure 03) when the first line of defence crumbles under the assault.

Figure 03 Immune Systems [view large image]

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First Line of Defence

First Line Defence The first line of defence recruits helps with physical, chemical, and biological components. The methods are rather primitive, but all animals use them in one form or the others. A few of these are illustrated in Figure 04 (left frame). In addition to the three levels of defence as shown in the right frame, human culture/science has added a top layer by sanitating the environment, and by regulating the foods and drinks.

Figure 04 First Line Defence

The three components of the first line defence :
  1. Physical Component - It is the physical barrier that blocks the entry point for pathogenic invasion. It consists of dead skin cells on the external surface, and mucus on the cell wall within.
  2. Physical Component
    • Skin - It is actually the tough layers of dead cells on the outside of the skin, which are frequently replaced. Figure 05 (left frame) displays the seemingly impenetrable scale in Iguana's tail spine. However, the weak spots are in between especially in falling external temperature when they would open up slightly for easier entry.

    Figure 05 Physical Component

    • Mucus - It snares foreign material and carries off dead cells from the mucous membrane. It also secrets chemicals and harbors friendly flora to ward off the invaders.

  3. Chemical Component - It consists of a variety of proteins that bind to and damage the cell walls of bacteria. These wall structures are unique to bacteria, so they present a useful target that can be attacked without risking the health of tissue cells. There are essentially three kinds as shown in Figure 04 and explained briefly below.
    Antibacterial Emzyme
    • Antibacterial Emzyme - Human saliva and tears contain antibacterial compounds such as secretory IgA and lysozyme (see Figure 06 for the secretory glands). These enzymes function by attacking peptidoglycans (found in the cell walls of bacteria). Beside saliva and tears lysozyme is abundant in a number of secretions, such as human milk, mucus, and egg

    Figure 06 Antibacterial Emzyme [view large image]

      white. IgA (Immunoglobulin A) plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined.


    Pore-forming Peptide
    • Pore-forming Peptide - Antimicrobial peptides are an abundant and diverse group of molecules that are produced by many tissues and cell types in a variety of invertebrate, plant and animal species. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores. Figure 07 illustrates the process of positively charged peptide poring hole into the negatively charged cell membrane (via the electrostatic force).

    Figure 07 Pore-forming Peptide [view large image]

    Gastric Acid
    • Gastric Acid - pH of less than 2.0 generally kills all bacteria, but this pH value is rarely maintained for any length of time, especially during food intake, which is when most bacteria enter the stomach. Experiment shows that many micro-organisms do not survive in an environment at pH 1.0 or 2.0, whereas all bacteria tested survived at pH 4.0 - a pH level inside the mucus layer (Figure 08). In the acidic conditions of the stomach bacteria can escape the assault by binding to the food, neutralizing the acid, or preventing the secretion of more acid by the stomach. The H. pylori bacteria (the little bugs in

    Figure 08 Gastric Acid

      Figure 08) create diseases such as gastritis and ulcers by moving in a screw-like motion with the unique flagella and changing to a nonadherent state to avoid the adherence in the mucous layer.

  4. Biological Component - Each part of the gut creates a nurturing environment for precisely the type of bacteria that it needs. For example, the intestine cells would provide a special kind of sugar for a particular bacteria when a signal is received from them. In turn, the bacteria would break down hard-to-digest food, add capillary branches, secrete antibacterial molecules (with exemption for themselves), occupy the space to block out unwanted bacteria, make vitamin K and other goodies for the intestine cells. Figure 09a lists further detail of this symbiotic relationship. Figure 09b shows the presence and abundance of bacterial species in various
    Good Bugs Microbiome anatomical sites on and in the human body and a short description of their functions. The bacteria in each site compile a micro-ecosystem (called microbiome) with the members link together and interact with the environment on or in the host. The microbiome behaves very similar to the macroscopic ecosystem, which exists in equilibrium even under small

    Figure 09a Good Bugs [view large image]

    Figure 09b Microbiome
    [view large image]

    perturbation, except that it can respond quickly to change and different composition could perform the same funtion (to the host).

The Nature magazine has kindly provided "free full access" to a collection of Insight articles about "Intestinal Microbiota in Health and Disease" published on July 7, 2016.

Artificial Defence - Penicillin is a group of antibiotics molecules derived from Penicillium fungi discovered in 1928 by A. Fleming (Figure 09c). They were among the first drugs to be effective against many previously serious diseases, such as bacterial infections caused by staphylococci and streptococci. Penicillins are still widely used today, though misuse has now made many types of bacteria
Penicillin resistant. Common side effects include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection. Other antibiotics include Cephalosporins, Aminoglycosides, Tetracyclines, ... With advances in medicinal chemistry, most modern antibacterials are semisynthetic modifications of various natural compounds. These germ killing products, which are not produced by micro-organisms, such as proflavine, sulfonamide, ... are referred to as antibacterial drugs.

Figure 09c Penicillin [view large image]

It is found that antibiotic use (or mis-use) severely disrupts the microbiome (the micro-ecosystems on and in our body), causing extensive collateral damage. The indiscriminate killing of nonpathogenic members makes it easier for pathogens to invade otherwise stable, occupied environments.

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Second Line of Defence (Innate Immune System)

Phagocytes 2nd Line of Defence The white blood cells (leukocyte) are either amoeba-like single cells for devouring foreign substances or protista with granular chemicals on the surface for combating intruders (by releasing the chemicals). Figure 10 shows some of the different varieties. The upper frame in the image shows a macrophage in the process of devouring some E.coli bacteria, while the lower frame lists some of the various kinds of white blood cells. Essentially, there are two main types - phagocytes for the 2nd line of defence and lymphocytes for the 3rd line of defence. Both of them originate in the bone marrow.

Figure 10 Phagocytes [view large image]

Figure 11 2nd Line of Defence [view large image]



    Action in 2nd Line of Defence (Figure 11) :

  1. The phagocytes normally spread through the body in blood. They can choose to leave the blood vessels by squeezing through the gaps between the capillary cells. Once there, they can settle down or actively go on to patrol the tissue spaces.
  2. The phagocytes' receptors can detect bacterial cell walls and waste products or molecules from stressed and dying human cells.
  3. Once the signals for bacterial invasion are detected, the phagocytes would crawl to the source (much in common with the embryonic cell migration). Upon reaching the trouble spot, they would secrete more signalling molecules for reinforcements, release a cocktail of highly toxic chemicals, and endeavor to engulf and destroy the bacteria.
  4. The chemicals are so lethal that considerable damage is also inflicted to the ordinary human tissue. The result is a local build-up of redness and heat, from the increased blood flow, swelling from the fluid and accumulating cells, and pain from injured nerve endings. In the middle of the inflammation is an area of whitish pus - essentially phagocytes, dead bacteria, and dead human tissue.
  5. When the receptors detect signals from stressed and dead human tissue, e.g., from an injury, excessive violence is triggered. Every living thing in the general area is killed to make sure any disease is stopped in its tracks.

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Third Line of Defence (Adaptive Immune System)

T and B Cells Since small unicellular organisms such as the viruses can alter their genes and appearance rapidly, no macroscopic animals can keep up with the pace correspondingly. Together with the innate immunity, the adaptive immune system has been evolved in vertebrates to deal with this problem. It is based on the "lock and key" mechanism that allows the generation of receptor that fit into the special feature on the pathogenic surface as illustrated in the left frame in Figure 13. Fragments can also be manufactured by macrophage (and dendritic cell, ...) and presented to the B and T-helper cells (Figure 13, right frame) for recognition. The helper (CD4+) T cells summon macrophages and neutrophils to the site of infection, while the cytotoxic (CD8+) T cells kill the pathogens directly.

Figure 12 T and B Cells

Vaccination is the administration of antigenic material (such as fragments of pathogenic protein, or a harmless or weakened strain - the vaccine) to stimulate the immune system for developing adaptive immunity with a pathogen.
See lot more details in "Antibody".

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Virus

Most of the time the virus would just lay dormant as an inert crystal, lifeless as a rock and perhaps staying that way for centuries or millenniums. Yet, unlike a rock, it may wake up at any moment, when there is the warmth and moisture of some vulnerable cell that it can swiftly enter and infect. The structure of viruses consists of a protein capsule containing DNA or RNA with 1000 - 200000 base pairs. Figure 14a shows the virus known as T4 bacteriophage that preys exclusively on bacteria. The lower 69000X image reveals a swarm of viruses attacking an E. coli bacterium with the contractile sheath, which acts like a syringe to squirt the genetic material (DNA) into the host cell. In the spring of 2003 a new strain of coronavirus (Figure 15) causes the "Severe Acute Respiratory Syndrome" (SARS), which is much harder to control than influenza (Orthomyxovirus infection of the upper respiratory tract and lungs) or common cold (Rhinovirus infection of the upper respiratory tract). Viruses survive and reproduce by infecting a cell and commandeering the cellular synthetic machinery to make more viruses. Then the viruses lyse (destroy) the cell and start the cycle over again. DNA virus replication starts from
DNA Virus entering the host cell by endocytosis. The DNA then replicates more of its kind and simultaneously making new coating proteins. These parts assemble to form more viruses, which exit from the host to infect more cells (Figure 14b). The RNA retrovirus (such as the coronavirus) does it somewhat differently because the genetic material is in the form of RNA. It has to undergo a reverse transcription to form cDNA (DNA copied off from the RNA), which is then integrated into the host DNA. It commandeers the host's replication mechanism to make more RNAs, which in turn make more coating proteins for the final assembly of new viruses. The followings provides further details on RNA virus replication in

Figure 14 DNA Virus
[view large image]

7 steps. There are numerous kinds of viruses, this summary only considers the single-stranded, positive-sense (its RNA is the same as mRNA) RNA virus (such as the Coronaviridae), which replicates solely in cytoplasm of the host cell (Figure 15).
There is a progressively deadly strain called coronavirus because it looks like the solar corona under magnification of electron microscope (see insert at lower right corner of Figure 16a). Its date of origin is estimated from 10000 to 3000 million years ago. It caught attention only in 1912 by the strange symptom of an infected cat. Since then the same kind of virus has killed different kind of animals without being identified until the 1960s when it is put under the electron microscope. The lethal effect on human started with the SARS in 2003 for a total of about 8000 cases, and now the SARS2 has progressed to a pandemic from December 2019 with no end in sight as of June 2020 with more than 7 million cases and counting. Here's some unusual properties for this particular strain of SARS-COV2.

According to "Scientists are divided over dosing strategies" published by Nature, 14 January 2021:

...

Many vaccines consist of multiple jabs — the first to trigger an initial immune response to certain proteins produced by a virus or bacterium, and later booster shots calling the immune system’s memory cells into action. It usually takes weeks for these memory cells to be generated. Over time, the immune system also broadens its response, developing memory cells capable of responding not only to specific proteins, but also to some variants of them. This means that a later booster shot is sometimes more effective, says immunologist Akiko Iwasaki at Yale University in New Haven, Connecticut: “Immunologically speaking, it may even help to delay a little.”

This might be especially true for vaccines that use harmless viruses to shuttle the genetic code for coronavirus proteins into cells (e.g., mRNA), says Hildegund Ertl, an immunologist at the Wistar institute in Philadelphia, Pennsylvania. Cells read the code and make the coronavirus protein, triggering immune responses against it. But the immune system might also generate antibodies against the harmless vector virus. If the booster is administered while levels of those antibodies remain high, the vector could be neutralized before it has a chance to deliver its cargo.

This kind of vaccine can also cause cells to express the coronavirus protein for weeks after vaccination. A booster given too soon could arrive while the immune system’s initial response is still raging and memory cells are not yet established. “Until you have memory, your booster immunization is not doing you any good,” says Ertl.

...

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Immune System Disorders

Auto-immune Diseases Immunodeficiency Immune system disorders are the abnormally over-activity or low activity of the immune system. In case of over-activity, the defence attacks and damages its own tissues. It is also known as auto-immune diseases (see Figure 15 for some examples). The treatment generally focuses on reducing immune system activity. Immune deficiency diseases decreases the body's ability to protect itself. Primary immuno-deficiency is cause by inherited genetic mutations (see Figure 16a for an example of mutation in the T and B cells), while secondary immuno-deficiency is the result of pathogenic intrusion. Table 01 lists some specific examples of the various disorders.

Figure 17 Auto-immune Diseases

Figure 18 Immunodeficiency, SCID [view large image]

The "~ genetic" in the table signifies possible genetic mutation causing the failure.


Disease Symptoms Affected Body Parts Failing Immune Components Cure
Allergy Runny nose, itchy eyes, and sneezing Nose, lungs, eyes, and skin Excessive activation of the mast cells and basophils by antibody (~ genetic) Avoid the environmental or dietary allergens, take steroids to reduce immunity
Asthma Wheezing, coughing, chest tightness, shortness of breath Airways Increase in eosinophils, macrophages, neutrophils, or T cells (~ genetic) Avoid smoke, dust, fumes, take corticosteroids
Rheumatoid Arthritis Inflammation, swelling and pain at the joints Joints Antibodies attach to the joints (~ genetic) Antirheumatic drugs, exercise, surgery
Multiple Sclerosis (MS) Pain, blindness, weakness, poor coordination, muscle spasms Insulating covers of nerve cells in the brain and spinal cord Destruction by the immune system (~ genetic) No known cure
Type 1 Diabetes Frequent urination, increased thirst, increased hunger, and weight loss Pancreas Antibodies attack and destroy insulin producing cells (genetic) Immunosuppressive drugs, injections of insulin, pancreas transplantation
Inflammatory Bowel Disease (IBD) Diarrhea, rectal bleeding, urgent bowel movements, abdominal pain, fever Lining of the colon and small intestine Immune system attacks elements of the digestive system (genetic) Anti-inflammatory steroids, surgery
Severe Combined Immunodeficiency (SCID) Vulnerable to infectious diseases Defect in one of at least 9 possible genes Absence of functional T cells leading to improper B cells activation (genetic) Bone marrow transplantation.
Acquired Immune Deficiency Syndrome (AIDS) Opportunistic infections and tumors The whole body Human immunodeficiency viruses (HIV) destroy T-helper (CD4) cells No cure or vaccine, avoid unprotected sex and contaminated blood transfusions

Table 01 Some Immune Disorder Diseases

Immune disorders are not the only diseases suffered by humans. There is a list of "medical conditions" to cover all kinds of illness by courtesy of Wikipedia.