THE IMMUNE SYSTEM

We all get sick sometimes...but then we get better.

What happens when we get sick?

Why do we get better?

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• Let's start at the beginning. What does it mean when someone says "I feel sick today?" What is a disease? By understanding the different kinds of diseases it is possible to see what types of disease the immune system helps you handle.

• When you "get sick", your body is not able to work properly or at its full potential. There are many different ways for you to get sick - here are some of them: Mechanical damage. If you break a bone or tear

a ligament you will be "sick" (your body will not be able to perform at its full potential). The cause of the problem is something that is easy to understand and visible.

• Organ degradation - In some cases an organ is damaged or weakened. For example, one form of "heart disease" is caused by obstructions in the blood vessels leading to the heart muscle, so that the heart does not get enough blood.

• Genetic disease - A genetic disease is caused by a coding error in the DNA. The coding error causes too much or too little of certain proteins to be made, and that causes problems at the cellular level. For example, albinism is caused by a lack of an enzyme called Tyrosinase. That missing enzyme means that the body cannot manufacture melanin, the natural pigment that causes hair color, eye color and tanning.

• Cancer - Occasionally a cell will change in a way that causes it to reproduce uncontrollably. For example, when cells in the skin called melanocytes are damaged by ultraviolet radiation in sunlight they change in a characteristic way into a cancerous form of cell. The visible cancer that appears as a tumor on the skin is called melanoma.

• Viral or bacterial infection - When a virus or bacteria (also known generically as a germ) invades your body and reproduces, it normally causes problems. Generally the germ's presence produces some side effect that makes you sick. – The polio virus releases toxins that destroy

nerve cells (often leading to paralysis)

• Your body is a multi-cellular organism made up of perhaps 100 trillion cells.

• The cells in your body are fairly complicated machines. Each one has a nucleus, energy production equipment, etc.

• Bacteria are single-celled organisms that are much simpler. For example, they have no nucleus. They are perhaps 1/100th the size of a human cell and might measure 1 micrometer long.

• Bacteria are completely independent organisms able to eat and reproduce - they are sort of like fish swimming in the ocean of your body.

• Under the right conditions bacteria reproduce very quickly: One bacteria divides into two separate bacteria perhaps once every 20 or 30 minutes.

• At that rate, one bacteria can become millions in just a few hours.

• A virus is a different breed altogether.

• A virus is not really alive.

• A virus particle is nothing but a fragment of DNA in a protective coat.

• The virus comes in contact with a cell, attaches itself to the cell wall and injects its DNA (and perhaps a few enzymes) into the cell.

• The DNA uses the machinery inside the living cell to reproduce new virus particles. Eventually the hijacked cell dies and bursts, freeing the new virus particles; or the viral particles may bud off of the cell so it remains alive. In either case, the cell is a factory for the virus.

The Lytic Cycle

• Viral and bacterial infections are by far the most common causes of illness for most people. They cause things like colds, influenza, measles, mumps, malaria, AIDS and so on. The job of your immune system is to protect your body from these infections. The immune system protects you in three different ways:

1. It creates a barrier that prevents bacteria and viruses from entering your body.

2. If a bacteria or virus does get into the body, the immune system tries to detect and eliminate it before it can make itself at home and reproduce.

3. If the virus or bacteria is able to reproduce and start causing problems, your immune system is in charge of eliminating it.

ANATOMY OF THE IMMUNE SYSTEM

• The immune system is localized in several parts of the body– immune cells

develop in the primary organs - bone marrow and thymus (yellow)

– immune responses occur in the secondary organs (blue)

ANATOMY OF THE IMMUNE SYSTEM• Thymus – glandular organ near the heart – where T cells learn

their jobs

• Bone marrow – blood-producing tissue located inside certain bones– blood stem cells give rise to all of the different types of blood cells

• Spleen – serves as a filter for the blood– removes old and damaged red blood cells – removes infectious agents and uses them to activate cells called

lymphocytes

• Lymph nodes – small organs that filter out dead cells, antigens, and other “stuff” to present to lymphocytes

• Lymphatic vessels – collect fluid (lymph) that has “leaked” out from the blood into the tissues and returns it to circulation

• All white blood cells are known officially as Leukocytes.

• White blood cells are not like normal cells in the body - they actually act like independent, living single-cell organisms able to move and capture things on their own.

•White blood cells behave very much like amoeba in their movements and are able to engulf other cells and bacteria.

• Many white blood cells cannot divide and reproduce on their own, but instead have a factory somewhere in the body that produces them. That factory is the bone marrow.

• Antibodies are produced by white blood cells.

• They are Y-shaped proteins that each respond to a specific antigen (bacteria, virus or toxin).

• Each antibody has a special section (at the tips of the two branches of the Y) that is sensitive to a specific antigen and binds to it in some way.

• When an antibody binds to the outer coat of a virus particle or the cell wall of a bacterium it can stop their movement through cell walls. Or a large number of antibodies can bind to an invader and signal to the complement system that the invader needs to be removed.

• The complement system, like antibodies, is a series of proteins. There are only a handful of proteins in the complement system, and they are floating freely in your blood.

• Complements are manufactured in the liver.• The complement proteins are activated by and

work with (complement) the antibodies, hence the name.

• They cause lysing (bursting) of cells and signal to phagocytes that a cell needs to be removed

PASSIVE IMMUNITY

Antibodies (Y) are also found in breast milk.

The antibodies received through passive immunity last only several weeks.

While your immune system was developing, you were protected by immune defenses called antibodies. These antibodies traveled across the placenta from the maternal blood to the fetal blood.

YOUR ACTIVE IMMUNE DEFENSES

Innate Immunity- invariant (generalized)- early, limited specificity- the first line of defense

Adaptive Immunity- variable (custom)- later, highly specific- ‘‘remembers’’ infection

INNATE IMMUNITY

Innate immunity consists of:

• Barriers

• Cellular response– phagocytosis– inflammatory reaction– NK (natural killer) and mast cells

• Soluble factors

When you were born, you brought with you several mechanisms to prevent illness. This type of immunity is also called nonspecific immunity.

INNATE IMMUNITY Barriers

• Physical

– skin– hair– mucous

• Chemical

– sweat– tears– saliva– stomach acid– urine

INNATE IMMUNITY Cellular response

• nonspecific - the same response works against many pathogens

• this type of response is the same no matter how often it is triggered

• the types of cells involved are macrophages, neutrophils, natural killer cells, and mast cells

• a soluble factor, complement, is also involved

Cell Types

1. Lymphocytes: derived in bone marrow from stem cells 10^12

A) T cells: stored & mature in thymus-migrate throughout the body

-Killer Cells Perform lysis (infected cells)Cell mediated immune response

-Helper CellsEnhance T killer or B cell

activity -Supressor CellsReduce/suppress immune

activityMay help prevent auto immune

disease

B)B-Cells: stored and mature in spleen

• secrete highly specific Ab to bind foreign substance (antigen: Ag), form Ab-Ag complex

• responsible for humoral response• perform antigen processing and presentation

• differentiate into plasma cells (large Ab secretion)

Lymphocytes (cont.)

2.Neutrophils- found throughout body, in blood-phagocytosis of Ab-Ag CX

3.Macrophages- throughout body, blood, lymphatics-phagocytose non-specifically (non Ab coated Ag)-phagocytose specifically Ab-Ag CX-have large number of lysosomes (degradative enzyme)-perform Ag processing and presentation-present Ag to T helper cell-secrete lymphokines/ cytokines to stimulate T helper

cells and immune activity

4. Natural Killer Cells-in blood throughout body-destroy cancer cells-stimulated by interferons

Macrophages engulf pathogens and dead cell remains

Neutrophils release chemicals that kill nearby bacteria

• pus = neutrophils, tissue cells and dead pathogens

Phagocytic cells include:

Phagocyte migration

Neutrophils and macrophages recognize chemicals produced by bacteria in a cut or scratch and migrate "toward the smell". Here, neutrophils were placed in a gradient of a chemical that is produced by some bacteria. The cells charge out like a "posse" after the bad guys.

CELLS alive!

Macrophages

• WBCs that ingest bacteria, viruses, dead cells, dust

• most circulate in the blood, lymph and extracellular fluid

• they are attracted to the site of infection by chemicals given off by dying cells

• after ingesting a foreign invader, they “wear” pieces of it called antigens on their cell membrane receptors – this tells other types of immune system cells what to look for

Macrophage and E. coli

©Dennis Kunkel Microscopy, Inc., www.DennisKunkel.com

Macrophage ingesting yeast

This human macrophage, like the neutrophil, is a professional "phagocyte" or eating cell (phago = "eating", cyte = "cell"). Here, it envelops cells of a yeast, Candida albicans. After ingestion, the white cell must kill the organisms by some means, such as the oxidative burst.

CELLS alive!

Neutrophils

• WBCs – are phagocytic, like macrophages

• neutrophils also release toxic chemicals that destroy everything in the area, including the neutrophils themselves

Neutrophil phagocytosing S. pyogenes, the cause of strep throat

Human neutrophils are WBCs that arrive quickly at the site of a bacterial infection and whose primary function is to eat and kill bacteria. This neutrophil ingesting Streptococcus pyogenes was imaged in gray scale with phase contrast optics and colorized.

CELLS alive!

Neutrophil killing yeast

One way that neutrophils kill is by producing an anti-bacterial compound called “superoxide anion“, a process called oxidative burst. Here, an amoeboid human neutrophil senses, moves toward and ingests an ovoid yeast. In the next two panels, oxidation can be seen by using a dye, and is colorized here.

YEAST

NEUTROPHIL

CELLS alive!

Complement• complement is not a cell but a group of proteins

• these proteins circulate in the blood

• complement plays a role in inflammatory responses of both the innate and adaptive immune responses

INNATE IMMUNITY Cellular response

Complement

• complement is not a cell but a group of proteins

• these proteins circulate in the blood– help to recruit phagocytes to site of inflammation and

activate them– bind to receptors on phagocytes, helping to remove agent of

infection– form pores in the invader or infected cell’s membrane (like

the NKs do) – activate mast cells to release histamine and other factors

• complement plays a role in inflammatory responses of both the innate and adaptive immune responses

INNATE IMMUNITY Cellular response

ComplementSeries of enzymes which are sequentially

activated and result in lysis of cell membrane of infected cell at bacterium

Permeablizes membrane leaky

Complement binding and activation

~35 enzymes and factors involved in cascade

Natural killer cells (NK cells)

• instead of attacking the invaders, they attack the body’s own cells that have become infected by viruses

• they also attack potential cancer cells, often before they form tumors

• they bind to cells using an antibody “bridge”, then kill it by secreting a chemical (perforin) that makes holes in the cell membrane of the target cell. With enough holes, the cell will die, because water rushing inside the cell will induce osmotic swelling, and an influx of calcium may trigger apoptosis.

Mast cells

• are found in tissues like the skin, near blood vessels.

• are activated after antigen binds to a specific type of antibody called IgE that is attached to receptors on the mast cell.

• activated mast cells release substances that contribute to inflammation, such as histamine.

• mast cells are important in allergic responses but are also part of the innate immune response, helping to protect from infection.

INNATE IMMUNITY – Soluble factors

• Interferon– a chemical (cytokine) produced by virus-infected

cells that contributes to their death by apoptosis

• Acute phase proteins – proteins in the plasma that increase during

infection and inflammation– can be used diagnostically to give an indication of

acute inflammation

Apoptosis or cell death

Human neutrophils released into the blood "commit suicide“ after only 1 day. A neutrophil (left) undergoes apoptosis, a series of changes including violent membrane blebbing and fragmentation of DNA. Apoptotic cells break into smaller pieces called apoptotic bodies that other body cells recognize and eat.

CELLS alive!

• Your mom’s antibodies were effective for just a short time at birth, but your innate immune system can be activated quickly. It is always your first line of defense during an infection, but it can’t always eliminate the germ.

• When this happens, your body initiates a focused attack against the specific pathogen that is causing the infection. This attack may lead to long-term protection against that pathogen.

• This type of immunity is called adaptive immunity, the customized second line of defense.

YOUR ACTIVE IMMUNE DEFENSES

Innate Immunity- invariant (generalized)- early, limited specificity- the first line of defense

Adaptive Immunity- variable (custom)- later, highly specific- ‘‘remembers’’ infection

1. Barriers - skin, tears

2. Phagocytes - neutrophils, macrophages3. NK cells and mast cells4. Complement and other proteins