Unit 21: Immunity — Long Questions

Macrophages and neutrophils are germ-killer cells of blood forming part of the second line of (non-specific) defence.

Macrophages develop from monocytes, a type of white blood cell. A macrophage ingests a bacterium by endocytosis and kills it using its lysozyme enzymes. Some macrophages are fixed within organs such as the lungs, liver, spleen and brain, while most patrol the blood, lymph and interstitial fluid looking for invaders.

Neutrophils are also white blood cells and use three methods to kill pathogens: (1) phagocytosis — engulfing and digesting the pathogen; (2) releasing soluble antimicrobial chemicals onto pathogens; (3) generating and releasing a network of DNA fibres that bind to pathogenic bacteria and kill them.

Both cell types patrol the bloodstream, recognize microbes lacking self-proteins, and attack only such foreign cells, leaving the body's own self-protein-bearing cells unharmed.

The complement system consists of more than a dozen different proteins, produced in the liver, that circulate in blood in an inactive state. When they encounter a microbe they activate in a sequence — the first protein activates the second, and so on. The final five proteins assemble into a membrane-attack complex (MAC), which inserts into the plasma membrane of the microbe and punctures it. This allows fluids and salts to move into the microbe, causing it to swell and burst.

Interferons are protective proteins belonging to the cytokine class, released by virus-infected cells. They diffuse to nearby, uninfected cells and cause them to enhance their anti-viral defences, making it harder for viruses to infect them. Interferons also act as communication signals between cells, triggering the immune system's protective defences and activating other immune cells such as natural killer cells and macrophages.

Inflammation is triggered when infected or injured cells release chemical signals such as histamines and prostaglandins. These chemicals cause local expansion (dilation) of blood vessels, increasing capillary blood flow at the site of injury or infection, and make capillaries more permeable, allowing fluid to leak out. This produces the classic signs of inflammation: redness, swelling and warmth at the affected spot.

The heat generated makes the site unfavourable for microbial growth, promotes healing, and raises the mobility of white blood cells. More phagocytes (macrophages and neutrophils) migrate from the blood into the inflamed tissue, where they engulf microbes; monocytes arrive and release chemicals to kill microbes, after which macrophages clean up dead microbes, cells and debris (forming pus in some infections). Because it acts the same way against any invading microbe rather than against a specific one, and is often strong enough on its own to stop the spread of microbes, it is considered one of the most generalized non-specific defences.

The immune system (third line of defence) is not localized to one place; rather it is made up of white blood cells that arise in bone marrow and circulate in blood and lymph, and are also found in lymph nodes, spleen, liver, thymus and bone marrow. The three main kinds of white blood cells forming the immune system are monocytes, T cells, and B cells.

Monocytes circulate in blood and enter interstitial fluid, where they mature into macrophages that phagocytose and destroy microbes and produce proteins that activate helper T cells; other monocytes mature into phagocytes residing in the liver, spleen, lymph nodes and other tissues, clearing cellular debris and assisting tissue repair.

T cells develop from bone-marrow stem cells, migrate to the thymus to mature, and develop the ability to recognize specific antigens on invading microbes. There are four kinds — helper, cytotoxic, inducer, and suppressor T cells — which together carry out cell-mediated immunity.

B cells also develop in the bone marrow but mature there itself, then circulate in blood and lymph. Each B cell is specialized to recognize a particular antigen; on encountering it, the B cell divides into plasma cells that produce antibodies, carrying out antibody-mediated immunity.

Acquired immunity is the specific, third line of defence developed during growth, and is of two types: active and passive.

In active immunity, the body itself prepares antibodies against the antigens of a microbe. It gives long-lasting protection because memory cells are formed. Active immunity may be natural or artificial: in natural active immunity, the body produces antibodies naturally after exposure to antigens during an actual infection, making it the most effective form of immunity; in artificial active immunity, weakened antigens are deliberately introduced into the body (vaccination), stimulating antibody production against the real antigen.

In passive immunity, the individual is given ready-made antibodies to combat specific microbes rather than making them. Since no memory cells are produced, passive immunity acts quickly but is short-lived compared to active immunity.

Cell-mediated immunity, carried out by T cells, protects the body from virus infections and cancer by killing abnormal or virus-infected cells, using the same membrane-puncturing mechanism as natural killer cells. Its key events are:

1. Proliferation: An activated helper T cell produces T cell growth factor, which causes proliferation of all types of T cells, forming large clones capable of recognizing the antigen.
2. Activation: The activated helper T cell secretes a second factor that attracts macrophages to the infection site.
3. Induction: Helper T cells activate inducer T cells in the thymus, which trigger maturation of lymphocytes into T cells.
4. Attack: Receptors on cytotoxic T cells recognize infected body cells, bind to them, and disrupt their membranes, causing the infected cells to burst.
5. Suppression: Suppressor T cells, whose numbers rise slowly, eventually (after 1–2 weeks) become numerous enough to shut down the cytotoxic T cell response.
6. Memory: A population of helper and cytotoxic T cells persists as memory cells, probably for the life of the individual, providing a rapid response if the same microbe is encountered again.

Antibody-mediated (humoral) immunity, triggered alongside cell-mediated immunity when a helper T cell is stimulated, is carried out by B cells, which mark antigens for destruction rather than attacking them directly. Its key events are:

1. Proliferation: Each B cell binds antigen through B receptor proteins on its surface; helper T cells recognize these antigen-bound B cells, bind to them, and release proteins that stimulate the B cell to proliferate into many plasma cells.
2. Differentiation and Secretion: Most plasma cells stop reproducing and instead produce large amounts of B receptor protein, which is secreted as antibodies.
3. Attack: Antibodies mark the antigen for destruction by one of three mechanisms — activating complement proteins that puncture the antigen-coated cell's membrane causing it to swell and burst; being recognized by macrophages, which ingest and break down the antigen; or being recognized by killer cells, which bind to and kill antibody-coated antigens.
4. Suppression: After several weeks, suppressor T cells shut down the antibody response.
5. Memory: Some plasma cell clone members persist as memory B cells instead of producing antibodies, providing a rapid secondary response if the same antigen is encountered again.

Allergies result from the hypersensitivity of the immune system to weak antigens (allergens) — such as dust, moulds, pollen, cat dander, certain foods, and some medicines like penicillin — that do not normally cause an immune response in most people.

After exposure to an allergen, some people produce E-antibodies, which bind to mast cells present in connective tissues around blood vessels. These mast cells then release histamines, which start an inflammatory response: dilation of blood vessels, leakage of fluid, sneezing, runny nose, and itching. In some individuals, the histamine release can be severe enough to cause life-threatening anaphylactic shock, in which swelling makes breathing difficult.

Treatment includes antihistamine drugs that block the action of histamines for temporary relief, or desensitization, in which repeated injection of allergen extracts induces production of G-antibodies that neutralize the allergen before it can trigger the E-antibody/mast cell response.

Normally, T and B cells of the immune system attack and kill only foreign molecules and cells because every person's own cells carry self-proteins — molecular 'fingerprints' recognized by that person's own T and B cells. When a person receives an organ transplant, the self-proteins on the donated organ may not match the recipient's own self-proteins. As a result, the recipient's T cells may attack the cells of the transplanted organ, and B cells may produce antibodies against its proteins, a problem called transplant rejection.

To minimize rejection, doctors look for a donor whose self-proteins closely match the recipient's (the preference order being identical twin > sibling > parent > unrelated donor), and use immunosuppressant drugs to suppress the recipient's immune response against the transplant, though this also reduces the ability to fight infections. Two further approaches exist: using monoclonal antibodies to destroy the T cells attacking the transplant, or using stem cells to build a new immune system that recognizes the transplant as self.

Normally, inflammation is triggered when infected or injured cells release histamines and prostaglandins, producing redness, swelling and warmth that help fight infection and promote healing. In arthritis, however, inflammation occurs in joints in the absence of any actual infection or injury — in rheumatoid arthritis, specifically, the immune system mistakenly produces antibodies against the body's own cartilaginous joint tissue, damaging it as though it were foreign. Since the inflammatory machinery is activated without a genuine external threat, and is instead directed against the body's own tissue, it is a misdirected immune response rather than a protective one.

Fever is a useful non-specific defence at moderate levels — it hinders the reproduction of bacteria and viruses, directly kills temperature-sensitive microbes, and speeds up the action of neutrophils and macrophages. However, body temperature rising too high becomes dangerous to the patient rather than only to the microbe: temperatures above 103°F (39.4°C) are considered dangerous and those above 105°F (40.5°C) are often fatal, since excessive heat can damage the body's own proteins and tissues. Physicians therefore prescribe antipyretic drugs to bring a dangerously high fever back down to a safer range, while the rest of the immune system (phagocytes, antibodies, memory cells) continues to clear the infection — protecting the patient from the harm of extreme fever without removing the other defences against the microbe.

Runny nose and skin rashes in allergic patients are caused by histamines released from mast cells after E-antibodies bind an allergen; histamines dilate blood vessels and cause fluid leakage, producing sneezing, runny nose, itching, and rashes. Since these symptoms are a direct effect of histamine action rather than of the allergen itself, antihistamine drugs, which block the action of histamines, relieve these symptoms by counteracting their underlying cause, giving the patient temporary relief.

Monoclonal antibodies are antibodies that attach to only one determinant (a specific small portion) of an antigen, unlike polyclonal antibodies, which attach to many different portions of the same antigen's surface. In 1984, Cesar Milstein and George Köhler were awarded the Nobel Prize for discovering how to produce monoclonal antibodies: they fused antibody-producing plasma cells with myeloma (cancer) cells to form hybrid cells called hybridomas. These hybridoma cells used the genes of the plasma cell to make a specific antibody while using the myeloma genes to grow and divide rapidly and indefinitely, yielding a continuous supply of a single, specific antibody.

This accomplishment revolutionized biological research and medicine because monoclonal antibodies can be used to purify specific molecules from complex mixtures (interferon, for example, was purified this way), and in medicine they serve as vehicles for delivering specific therapies, including ongoing research into radioactive monoclonal antibodies targeted against antigens found only on cancer cells, to selectively destroy tumours.