Introduction

Smallpox Eradication

THE IMMUNE SYSTEMThe Invaders The Defender

Overview of the Immune System

Overview of your immune system• First line of defense: Physical barriers that viruses, bacteria

must cross– skin covers ~2 m2

– Mucous membranes that line digestive, respiratory, reproductive tracts cover ~400 m2

• Second line of defense: Innate immune system (germline-encoded receptors -- no adaptation to specific pathogens)– Macrophages (Greek for “big eater”), neutrophils, natural killer (NK)

cells– Cytokines -- hormone-like proteins that mediate inflammation,

Complement proteins

• Third line of defense (vertebrates only): Adaptive immune system (adapts to defend against specific pathogens using variable receptors)– B cells make antibodies that vary -- can make an antibody specific

for any new antigen– T cells mediate cellular responses using variable receptors (T cell

receptors; TCRs)

Antibodies Cytokines Complement Inflammatory mediators

COMPONENTS OF THE IMMUNE SYSTEM

Cellular components of the immune system

Soluble mediators of the immune system

Lymphocytes Phagocytes Granulocytes

Large granular lymphocyte

T-cell

B-cell Mononuclear phagocyte

Neurtrophil

Eosinophil

Basophil

Mast cell

Platelets

Others

Immune cells and other blood cells made in bone marrow -- all are descendents of self-renewing stem

cells

p. 4 “How the Immune System Works” by Lauren Sompayrac

Make variable antibodies

Membrane-bound variable T cell receptors

Kill cells that are missing self proteins

Phagocyte

Phagocyte

Note these are adult stem cells, NOT embryonic

stem cells.

Innate Immunity• Initial response to microbes• Stimulates adaptive immune

response• Components are directed by

adaptive immune response to remove foreign material

The innate immune system responds more quickly than adaptive immune

system.Why is a quick response important?• Starting with one bacterium that doubles

every thirty minutes --> 100 x 1012 bacteria in one day

• 100 x 1012 bacteria equivalent to ~100 liters of a dense culture

• Total volume of blood in human ~5 liters• VERY important to check a bacterial infection

quickly!

Three components of the innate immune system

• Phagocytes (cells) (e.g., macrophages)• Complement proteins• Natural killer (NK) cells

Innate immune receptors recognize features common to many pathogens. Receptors are employed by all cells of a given cell type. Response does not lead to immunological memory.

Adaptive immune receptors are antigen specific. Antigen receptors of adaptive immune system are clonally distributed on individual lymphocytes. Response can lead to immunological memory.

Macrophages can engulf and digest bacteria

p. 4 “How the Immune System Works” by Lauren Sompayrac

Macrophage about to eat a bacterium

http://www.biochemweb.org/neutrophil.shtml

QuestionWhich component of bacteria serves as a very potent stimulant of the innate immune system?

1) Ribosomes2) Proteins3) Carbohydrates4) DNA5) RNA6) Plasmids

QuestionCarbohydrates on viruses strongly activate the innate immune system.

1) True2) False

Complement system• Ancient system (found in invertebrates such as

sea urchins)• ~20 different proteins that work together to

destroy invaders and recruit immune cells• Activated three different ways

– “Classical” pathway: by antibodies bound to pathogen (vertebrates only)

– “Alternative” pathway: by bacterial surfaces– Lectin activation pathway: by binding of mannose-

binding lectin (MBL) to yeast, bacteria, parasites or viruses (e.g., HIV)

• Activation of complement system is tightly regulated because end results can be dangerous

Figure 2-18The three pathways of complement activation converge

Combination of adaptive and innate immune responses Innate immunity Innate immunity

Figure 2-11Binding of mannose-binding

lectin, a plasma protein, initiates lectin pathway of complement

activation. MBL discriminates self

carbohydrates from non-self carbohydrates by recognition of a particular pattern of sugar residues

Figure 2-35 part 3 of 3One of the end results of complement activation -- the membrane attack complex kills a cell

Electron micrographs of ~100 Å diameter membrane attack complex channels

Laboratory uses of complement:isolate one population of cells by

killing off another populationExample:

Have mixture CD4 T-cells and CD8 T-cells

Want only CD8 T-cells

Add anti-CD4 antibody to mixture of T cells. It binds. Now add complement, and CD4 T-cells will be killed, leaving you with CD8 T-cells only.

QuestionWhich type of pathogen is easier for the innate immune system to deal with: bacteria or viruses?

1) Bacteria

2) Viruses

So far, we’ve talked only about active recognition of features of pathogens…But pathogens have also developed ways to remove some of the cell’s critical proteins, often so that they can escape detection by the immune system.

For example, in the adaptive immune system, T lymphocytes (T cells) recognize viral fragments (peptides) bound to MHC proteins.

It’s hard for a virus to hide out in a cell if the cell surface MHC proteins contain viral fragments that can be recognized by T cells.

What’s a virus to do? Get rid of the host MHC proteins!

For every strategy a virus comes up with, the immune system (usually) has an

answer…Natural killer cells recognize cells

that do not express adequate levels of MHC proteins on their surface.

They respond to “missing self”.

Natural killer (NK) cells• Can kill tumor cells, virus-infected cells, bacteria,

parasites, fungi in tissues

• Identify targets based on “missing self” – Two types of NK receptors: inhibitory and activating– If inhibitory receptor recognizes a self protein (a class I MHC

molecule) on a target cell, the NK cell is turned OFF even if activating receptor binds a ligand on the same target cell

– If activating receptor binds a ligand, but inhibitory receptor does not (target cell has down-regulated class I MHC proteins), NK cells kill

– Many virally-infected cells and tumor cells down-regulate expression of class I MHC molecules (NK cells important for preventing cancers)

The immune cells we’re talking about are called white blood cells.

This means they are in the ____.

How do they get to a site of infection?

Figure 1-7

Figure 1-5

Antibody Secretion

Activation ofT and B cells, Macrophages,Inflammation

Target Cell Lysis

Phases of Adaptive Immune Responses

• Recognition• Activation• Effector• Homeostasis

Figure 1-10

Activation

Figure 2-13

Figure 2-14

Figure 2-16

Figure 2-18

Figure 2-19

Figure 2-20

Antigens

Figure 3-4

Figure 3-8