1 the immune system we all get sick sometimes...but then we get better. what happens when we get...

1

THE IMMUNE SYSTEM

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

What happens when we get sick?

Why do we get better?

2ANATOMY 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)

Lymphatic System

• Like another circulatory system• Group of tissues and organs that

collects excess fluid and returns it to your blood

• Helps fight pathogens

ThymusLymph nodesLymphatic vesselsSpleenTonsil

• Lymph capillaries – absorb fluid and small particles (dead cells/pathogens) near cells

• Lymphatic vessels carry this lymph back towards your neck where it drains into veins of the cardiovascular system

• Lymph nodes – small bean shaped masses of tissue that remove pathogens and dead cells from the lymph– Lymphocytes are types of WBC’s that fill

lymph nodes and attack pathogens

• Lymph nodes get swollen when you have an infection. Why???

• Thymus – gland that makes T cells ready to fight

• Spleen – soft and spongy organ that – Serves and a filter for the blood– produces lymphocytes– removes old/damaged RBC’s– Removes infectious agents and uses

them to activate lymphocytes

• Tonsils – tissue that stores WBC’s and fights infections

7

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.

8

YOUR ACTIVE IMMUNE DEFENSESINDUCTION OF AN IMMUNE

RESPONSEForeign invaders - viruses, bacteria, allergens, toxins and parasites- constantly bombard our body.

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

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

9

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.

10

INNATE IMMUNITY Barriers

• Physical

– skin– hair– mucous

• Chemical

– sweat– tears– saliva– stomach acid– urine

11

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

12

Macrophages engulf pathogens and dead cell remains

Neutrophils release chemicals that kill nearby bacteria

• pus = neutrophils, tissue cells and dead pathogens

Phagocytic cells include:

13

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!

14

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

15

Macrophage and E. coli

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

16

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!

17

Neutrophils

• WBCs – are phagocytic, like macrophages

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

18

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!

19

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!

20

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


21

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


22

Inflammatory response

Step 1. Circulation to the site increases tissue warm, red and swollen

Step 2. WBCs leak into tissues phagocytes engulf and destroy bacteria

• chemical and cell response to injury or localized infection

• eliminates the source of infection

• promotes wound healing


23

Inflammatory response (cont’d)

The release of histamine and prostaglandin causes local vessel dilation resulting in:

• more WBCs to site

• increased blood flow redness and warmth

• increased capillary permeability

• phagocytes move out of vessels into intracellular fluid (ICF)

• edema (swelling) due to fluids seeping from capillaries


24

Inflammatory response (cont’d)

POSITIVE

• indicate a reaction to infection

• stimulate phagocytosis

• slow bacterial growth– increases body temperature

beyond the tolerance of some bacteria

– decreases blood iron levels

NEGATIVE

• extreme heat enzyme denaturation and interruption of normal biochemical reactions

> 39° C (103°F) is dangerous

> 41°C (105°F) could be fatal and requires medical attention

Fevers have both positive and negative effects on infection and bodily functions


25

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.

26

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.

27

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

28

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!

29

• 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.

30





1. Barriers - skin, tears

2. Phagocytes - neutrophils, macrophages3. NK cells and mast cells

4. Complement and other proteins

31

This immunology curriculum and integrated laboratory modules were created by teachers and scientists working together through a grant from the National Science Foundation to the Nanobiotechnology Center in collaboration with the Cornell Institute for Biology Teachers, which is funded by the Howard Hughes Medical Institute.

Collaborators for this project:

Harriet Beck, Wellsville Central School

Jim Blankenship, Cornell Institute for Biology Teachers

Rita Calvo, Cornell University

Jerrie Gavalchin, Cornell University

Mary Kay Hickey, Dryden High School

Susan Oliver, Dundee High School

Jeanne Raish, Avoca Central School

Anna Waldron, Nanobiotechnology Center

This material is based upon work supported in part by the STC Program of the National Science Foundation under Agreement No. ECS-9876771. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

32YOUR ACTIVE IMMUNE DEFENSESINDUCTION OF AN IMMUNE







33ADAPTIVE IMMUNE RESPONSE

• a specific response

• results in acquired immunity

• long term immunity - “memory”

• involves two types of lymphocytes:– T cells– B cells

34

ADAPTIVE IMMUNE RESPONSE

• the specific response is customized for each pathogen• responsible for acquired immunity• involves antigen-presenting cells and two types of lymphocytes • turns on when needed - inducible• “remembers” the pathogens it has “seen” and goes into action faster

the second time• may confer lifelong immunity

35

White Blood Cells (WBCs)There are two main types of WBCs involved in the adaptive

immune response:

• antigen-presenting cells (APCs)- not pathogen-specific- ingest foreign substances and break them down- e.g., macrophage

• lymphocytes - pathogen-specific- different types recognize different invaders and lead to their

destruction

36

Human red and white blood cells

Human red blood cells (red), activated platelets (purple) and white blood cells - monocyte (green) and T lymphocyte (orange).

Colorized-SEM (scanning electron micrograph)

Magnification:-1200x--(Based on an image size of 1 inch in the narrow dimension)

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

http://www.denniskunkel.com/

37

Types of lymphocytesThere are two types of lymphocytes. Both form from bone marrow stem cells:

T cells mature in the thymus

B cells mature in the bone marrow

Both cell types enter the lymph nodes and spleen after they are mature. From there they can look for foreign invaders in the bloodstream.

38

T cells

• there are millions of different T cells – the difference is in their receptors (surface markers)

• each T cell has a unique receptor that will recognize a different foreign substance

• mature in the thymus, where they learn to tell the difference between self and “non-self”

- critical, because if they did attack “self”, autoimmune disease could result

39T cell training• T cell precursors arrive in the thymus from the bone marrow

• there, they express specific T cell receptors and meet cells that “wear” bits of self proteins, called MHC (major histocompatibility complex), that are markers for the body’s own cells

• there are two steps- first, T cells must recognize self-MHC, or they are destroyed- in a second step, T cells that bind too tightly to self-MHC are also destroyed

• remaining T cells go to the spleen and lymph nodes, and wait for antigens. If they recognize an antigen, some will “go into battle” and others become memory cells

40

Steps in T cell development

Step 1. Positive selection occurs in the thymic cortex

MHC self-recognition molecules

41

Steps in T cell development (cont’d)

Step 2. Negative selection occurs in the thymic medulla.

42

Types of T cells

Based on function, there are different types including:

• helper T cells – start the immune response

• cytotoxic T cells – kill the body’s abnormal cells, like virus-infected cells and cancer cells

• suppressor T cells – suppress the activities of other T cells, helping to end the immune response

43

A Cytotoxic T Cell Attacking and Killing a Virus-Infected Target Cell

Here, the smaller cytotoxic T cell or Tc (arrow) is attacking and killing a much larger virus-infected cell. The T cell will survive while the infected cell is destroyed.

CELLS alive!

44

B cells

• produced and mature in bone marrow

• each B cell produces and wears a unique antibody on its surface

• clonal selection - when a B cell encounters a matching antigen, it begins to divide rapidly. Some then become plasma cells that all produce the same antibody, and then die. Others become memory cells.

• the specific antibody produced by a plasma cell is also secreted in soluble form and circulates in the blood

45

Different types of B cells have different receptor molecules.

When a pathogen (germ) “locks on” to a receptor, that type of B cell is selected.

The selected B cell divides rapidly to make lots of copies of itself. The copies make lots of antibodies against the pathogen.

Selection of B cells by antigen (clonal selection)

46

Antibodies

• specific – react with only one antigen

• Are Y-shaped proteins called immunoglobulins (Ig)

• each is made of two heavy and two light chains of amino acids, held together by disulfide bonds

47Antibody structure

- parts of the antibody (Ab) are constant, i.e., the same for every antibody

- parts are variable - the arms of the “Y” have different amino acid sequences that cause specific binding to antigen

Each is made of two identical heavy and two identical light amino acid chains, held together by disulfide bonds

• the fact that there are many different variable regions results in antibodies that react with almost any antigen you could possibly encounter!

48

Antibody – another view

- variable regions of the light chain (grey) and the heavy chain (yellow) form the antigen binding site

- light chain constant region is blue while heavy chain constant region is red. The two chains are joined by carbohydrate (purple).

©Mike Clark, www.path.cam.ac.uk/~mrc7/

http://www.path.cam.ac.uk/~mrc7/

49

Four classes of secreted antibodies• IgM – a pentamer – five Y-shaped immunoglobulins joined together – the

“early” Ab, it is produced before any of the other types – it activates complement

• IgG – the most common form, and the major one for secondary responses

• IgA – mostly a dimer – two Y-shaped immunoglobulins secreted in saliva, colostrum, milk, semen, mucus

• IgE – binds to receptors found on mast cells – involved in allergy and parasitic infections

50

AntigensAntigen (Ag) – the molecule an antibody (Ab) binds to

• usually a foreign substance• each antigen has different sites that antibodies can bind to, so that

one antigen can be bound by several different antibodies

• examples in the case of allergy could be pollen, cat dander, or a chemical in soap

51

How Antibody Binds to Antigen

The top part of this figure shows how different shaped antigens can fit into the binding site of antibodies: left, pocket; center, groove; right, extended surface. The panels below show space-filling or computer-generated models indicating where contact between the peptide antigen and antibody occurs.

52

How an Antibody WorksWhen an Ab finds its Ag on an invader, it will bind there and act as a

“trash tag”, marking it for destruction by “killer” cells, macrophages or complement

Antibody binds to target antigen

Receptor for constant region of antibody on NK cell recognizes a bound antibody

After binding, the NK cell is signaled to kill the target cell

The target cell dies by apoptosis and/or membrane damage

53

• You have about a trillion different antibodies able to react with millions of different types of Ag

• but you only have about 30,000-60,000 genes which code for all the proteins you need in your entire body, most of which are not Ab

• so there cannot be one gene for one antibody to code for these – we wouldn’t have enough antibodies!

So how can your body produce Ab to so many antigens, even those it’s never seen?

The Number Dilemma

54

Antibody Variability

There are several reasons why there are an enormous number of different antibodies:

• different combinations of heavy and light chains which are encoded by different genes

• recombination

• others

55

Antibody Genes

Genes for antibodies aren’t like most other genes - they come in pieces (“gene-lets”):

• variable segments (V) – many different versions• diversity segments (D) – several different versions• joining segments (J) – a few different versions• constant segments (C) – a few different versions that are nearly

identical

56

A unique recombination occurs in each B cell

• each B cell combines these gene segments to make an Ab chain like shuffling a deck of cards

- V, D, and J for the heavy chain, V and J for the light chain

• since there are multiple types of each gene segment, there are many thousands of possible V-D-J combinations so that each B cell gets a unique combination of segments!

Unique combination of segments becomes joined by somatic gene rearrangement

57A unique recombination occurs in each B cell

• each B cell combines these gene segments to make an Ab chain like shuffling a deck of cards

- V, D, and J are joined to C for the heavy chain, V and J are joined to C for the light chain

58Since there are multiple types of each gene segment, there are many thousands of possible V-D-J combinations so that each B cell gets a unique combination of segments! Additional diversity occurs because there are two types of light chains.

59

Other sources of variability

• when V, D, and J pieces are joined, they may not always be joined perfectly – if some base-pairs are lost or added, the Ab will end up with a different amino acid sequence

• variable region genes mutate at a higher rate than other genes in your body

60








1. APCs present Ag to T cells

2. Activated T cells provide help to B cells and kill abnormal and infected cells

3. B cells - produce antibody specific for antigen

61

This immunology curriculum and integrated laboratory modules were created by teachers and scientists working together through a grant from the National Science Foundation to the Nanobiotechnology Center in collaboration with the Cornell Institute for Biology Teachers, which is funded by the Howard Hughes Medical Institute.

Collaborators for this project:

Harriet Beck, Wellsville Central School

Jim Blankenship, Cornell Institute for Biology Teachers

Rita Calvo, Cornell University

Jerrie Gavalchin, Cornell University

Mary Kay Hickey, Dryden High School

Susan Oliver, Dundee High School

Jeanne Raish, Avoca Central School

Anna Waldron, Nanobiotechnology Center


62

Permission to use images were secured by the NBTC from various sources:

KUBY IMMUNOLOGY by Richard A. Golsby and Thomas J. Kindt and Barbara A. Osborne. © 1992, 1994, 1997, 2000 by W.H. Freeman and Company. Used with permission.

© 2001 From Immunobiology: The Immune System in Health and Disease, Fifth edition by Charles A. Janeway, Paul Travers, Mark Walport and Mark Shlomchik. Reproduced by permission of Routledge, Inc., part of The Taylor & Francis Group.

© 2000 From The Immune System by Peter Parham. Reproduced by permission of Routledge, Inc., part of The Taylor & Francis Group.

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

CELLS alive! www.cellsalive.com

Mike Clark, www.path.cam.ac.uk/~mrc7/



http://www.cellsalive.com/


63

Permission to use images were secured by the NBTC from various sources:

KUBY IMMUNOLOGY by Richard A. Golsby and Thomas J. Kindt and Barbara A. Osborne. © 1992, 1994, 1997, 2000 by W.H. Freeman and Company. Used with permission.

© 2001 From Immunobiology: The Immune System in Health and Disease, Fifth edition by Charles A. Janeway, Paul Travers, Mark Walport and Mark Shlomchik. Reproduced by permission of Routledge, Inc., part of The Taylor & Francis Group.

© 2000 From The Immune System by Peter Parham. Reproduced by permission of Routledge, Inc., part of The Taylor & Francis Group.

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

CELLS alive! www.cellsalive.com

Mike Clark, www.path.cam.ac.uk/~mrc7/



http://www.cellsalive.com/


1 the immune system we all get sick sometimes...but then we get better. what happens when we get...

Documents

dead cells

infection slide

tissue cells

immune system

cardiovascular system

types of cells

body immune cells

cells alive