The Immune System

The immune system is one portion of the body’s defense against infection.

There are first line defenses before the immune system comes into play:

1.The skin acts as a barrier. The outer layer is dead cells that do not provide a ‘home’ for foreign

invaders.

2. At points where the body is open (digestive and respiratory systems), there are mucus membranes secreting to trap invaders. The mucus is swept ‘up and out’ by cilia.

3. Mucus, tears and saliva include a potent enzyme called lysozyme that attacks bacterial cell walls.

4. Any invader that gets far enough down the digestive tract to reach the stomach finds a very acid environment that kills most bacteria.

5. Anything that does penetrate the skin encounters non-specific defenses in the form of two of the types of leukocytes (white blood cells). These are the neutrophils (the more abundant type) and monocytes. Monocytes mature into macrophages that are phagocytic (they ‘eat’ foreign cells by endocytosis).

6. There are also leukocytes that are called natural killer cells. They are smaller. They attack and kill cells that have become cancerous, as well as cells infected by viruses.7. There are also chemical defenses in the blood. One type is the complement proteins. These proteins act in 4 ways:

a. They attach to foreign cells and make them easier for phagocytes to recognize and consume.b. They attract phagocytes to sites of infection.c. They bind to foreign cells and cause them to lyse (burst).

d. Finally, they amplify the inflammatory response.

The other component of chemical response is the production of interferons. These are proteins produced by virus-infected cells. In other, non- infected cells, they activate genes that produce anti- viral proteins that protect those cells.

Interferons have been used in the treatment of various viral diseases and some forms of cancer with variable results.

The Inflammatory Response

There is a sequence of steps in the inflammatory response. First, here’s a diagram. Following slides give a more detailed text.

1. Cells adhering to the skin and linings of organs, called mast cells, release histamine when damaged. The leukocytes called basophils also release histamine.

2. Histamine causes local capillaries to become leaky. Blood plasma and phagocytes escape into the tissue fluid. That causes swelling in the area.

3. Enzymes moving into the tissue fluid that attack foreign cells and debris are part of the reason the area becomes hot (and possible painful).

4. Complement proteins attract phagocytes to the site of injury. They (neutrophils first, then monocytes) become macrophages. The macrophages engulf foreign material by endocytosis. Breakdown of engulfed material within the macrophages also produces a part of the heat.

5. Healing ensues. Histamine and complement protein signaling ends. Capillaries return to normal.

We now know a lot about the molecular process that initiates cellular defenses. The cell surface receptor is called “toll”.

When a foreign substance/cell fragment is bound to it, a cascade of reactions is initiated that results in the transcription of at least 40 genes involved in both the non-specific defenses already discussed and the specific defenses we’ll consider now.

Specific Defenses

This is the part of the response we usually think of when talking about an immune response.

There are two terms you need to understand to begin:

antigen – is a foreign molecule, whether free or part of a foreign cell, that elicits and immune response.

antibody – is a protein found in the blood plasma that attaches to a particular antigen, identifying it and helping to counter its effects.

The immune system is very specific.

Each antigen (the term actually comes from “antibody generating”) is ‘recognized’ by a specific antibody, and the system ‘remembers’ antigens to which it’s been exposed for extended periods.

Immunity means resistance to specific invaders.

We become immune either by exposure to the antigen (active immunity) or by being given (injected) the antibodies produced in another organism (passive immunity).

Vaccination is one way to achieve active immunity.

Vaccines are generally inactivated forms of disease organisms, but with their antigenic determinants (surface proteins, for example) still present.

We have all been vaccinated for smallpox, polio, mumps and measles. Once vaccinated, we are almost perfectly immune to those diseases for life.

How does the system work?

It is based in the activities of lymphocytes – white blood cells that reside mostly in the lymphatic system.

There are two key types of lymphocytes. Both originate in bone marrow.

One kind develops and specializes there – the B cells. They are responsible for humoral immunity

The other kind migrates from the marrow to the thymus, and develops there into T cells. They are responsible for cell-mediated immunity.

Humoral immunity

When ‘stimulated’ by recognizing a specific antigen, B cells secrete antibodies into the lymph and blood plasma. By means of the circulation, those antibodies are carried to the site of infection.

Note that a single foreign organism may have many surface proteins that bind different antibodies.

Each B cell produces one specific antibody.

How do B cells recognize an invader?

It builds the antibody molecule into its cell membrane, as antigen receptors. When the antigen binds to the receptor, the B cell multiplies. Some B cells secrete antibody (now called plasma cells). Others are ‘memory’ cells, used if the antigen again appears. This B cell produces type A antibody from the previous slide.

Cell-mediated immunity

T cells from the thymus that finished development in the lymphatic system then circulate there and in the blood.

T cells, too, have specific receptors (here called T cell receptors) built into their cell membranes. They recognize virus-infected cells and even tumor cells. But they are also the cells responsible for transplant rejection.

There are two kinds of T cells:Helper T cellsCytotoxic T cells

Cytotoxic T cells (or ‘killer’ cells) cause other cells (e.g. virus-infected cells) to lyse and die.

Helper T cells assist other lymphocytes in both humoral and cell-mediated responses. How? They activate both B and cytotoxic T cells.

The humoral immune response is a series of steps. 1. a foreign cell is broken up by a phagocytic cell.

2. broken pieces have antigenic determinants. They are bound to proteins of the MHC (major histocompatibility complex), transported to the cell membrane of the phagocyte (now an antigen-presenting cell), and attached there, ‘presented’ to helper T cells.

3. If a helper t cell has a T-cell receptor that ‘fits’ the presented antigen, and it is bound to an MHC (self) protein, it begins dividing (stimulated by interleukin2), forming a clone of identical cells. Up to this step we are in the activation phase.

4. We now enter the effector phase. B cells also ‘present’ antigens they have bound, and also attached to an MHC glycoprotein. A helper T cell only binds to a B cell presenting the same antigen it has reacted to. If a ‘match’ is made, the T cell stimulates the B cell into the clonal division (multiplication) already described. Some become plasma cells.

The cell-mediated immune response is similarly a series of steps: 1. Virus-infected and mutated cells also present antigens. The altered DNA produces ‘foreign’ proteins or fragments that are attached to a different class of MHC glycoproteins and presented on the cell surface.

2. A cytotoxic T cell with a ‘fit’ to the presented complex binds to it and is activated to proliferate and differentiate.

3. Cytotoxic T cells then produce molecules that insert themselves into the cell membrane of the infected or altered cell, causing it to lyse.

It doesn’t matter why the foreign protein is displayed on the surface of a cell. It can occur due to virus or bacterial attack, but also because of genetic alterations (mutations) associated with a cell becoming cancerous.

This defense mechanism is probably why cancer is as rare as it is. Surveillance destroys many cancerous cells before they can multiply to the point of forming a tumor.

The first time exposure to an antigen occurs, the response that occurs is called a primary immune response. It is slower, because all those steps must occur.

A second exposure elicits a much faster response, a secondary immune response. The B cells have already been produced, and are ‘memory’ cells.

For this whole lecture, antibodies have been key. What are they?

Antibodies are proteins made up of 4 joined polypeptide chains. Two of the chains are called ‘heavy’ chains, and two are ‘light’.

C means constant regionV means variable region

The diagram is a simple model. Reality, in the form of a computer model of the molecule, is a little more complex:

The different C regions represent different classes of antibodies (immunoglobins). There are 5 classes:

IgM, IgA, IgD, IgE, and IgG

Variability comes from differences in the variable regions. The DNA that codes for the variable regions is hypervariable and mutable. Even without mutation, humans can produce ~20,000,000 different antibodies.

There are a number of ways that antibodies (humoral immunity) mark invaders for disposal.

Malfunction or failure of the immune system underlies many serious diseases other than cancer.

One class of diseases are autoimmune diseases. In these diseases the immune system inappropriately reacts against the body’s own tissues. Among them:

systemic lupus erythematosus – B cells make antibodies against your own cellular breakdown products

Rheumatoid arthritis – antibodies attack joint cartilage and bone

Type I (insulin-dependent) diabetes – attack on the insulin producing cells of the pancreas

multiple sclerosis – T cells attack the myelin sheath that surrounds and speeds conduction down neural axons

Hashimoto’s disease – attack on the thyroxin producing cells of the thyroid gland

Another group are called immunodeficiency diseases:

SCID (severe combined immunodeficiency) – neither T nor B cells are active; severe sensitivity results.

AIDS – the HIV virus infects and inactivates helper T cells. Without them both humoral and cell- mediated immunity are severe ly compromised.

HIV (human immunodeficiency virus) infection is incurable. Attempts to develop a vaccine have been (and are probably likely to remain) unsuccessful.

The reason is the mutability of the virus. I’ve been told that between infection by one strain of the virus and the onset of AIDS (acquired immune deficiency syndrome), enough mutations have occurred that there are ~70 different strains in a person’s system. The lag time between infection and disease state is typically very long. Here’s an approximate time course:

The syndrome of effects, however, is being treated successfully by a ‘cocktail’ of drugs. This life cycle of the virus shows you where the drugs act: