Immune Response

Cell Biology and Its Application BI-1202

MIT, EGR, RRE & AB, SITH ITB

Why an immune system?

Attack from outside
Everybody must defend himself from many dangerous pathogens viruses
HIV, flu, cold, measles, chicken pox

bacteria
pneumonia, meningitis, tuberculosis Lyme disease

fungi
yeast (Athletes foot)

protists
amoeba, malaria

Attack from inside

cancers = abnormal body cells
Mmmmm, Whats in your lunchbox?

Two major kinds of defense have evolved that counter these threats Innate immunity and acquired immunity Innate immunity Is present before any exposure to pathogens and is effective from the time of birth Involves nonspecific responses to pathogens Acquired immunity/adaptive immunity Develops only after exposure to inducing agents such as microbes, 3m toxins, or other foreign substances Involves a very specific response to pathogens

A summary of innate and acquired immunity

INNATE IMMUNITY Rapid responses to a broad range of microbes External defenses Skin Mucous membranes Secretions Internal defenses Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Humoral response (antibodies) Cell-mediated response (cytotoxic lymphocytes) ACQUIRED IMMUNITY Slower responses to specific microbes

Invading microbes (pathogens)

1st line: Non-specific External defense

Barrier
skin
Lining of trachea:
ciliated cells & mucus secreting cells

Traps
mucous membranes, cilia, hair, earwax

Elimination
coughing, sneezing, urination, diarrhea

Unfavorable pH
stomach acid, sweat, saliva, urine

Lysozyme enzyme
digests bacterial cell walls tears, sweat

2nd line: Non-specific internal defenses

Patrolling cells & proteins
attack pathogens, but dont remember for next time
leukocytes
phagocytic white blood cells macrophages, neutrophils, natural killer cells

bacteria

complement system
proteins that destroy cells

macrophage

inflammatory response
increase in body temp. increase capillary permeability attract macrophages

yeast

Lymph system

Production & transport of leukocytes Traps foreign invaders

lymph vessels
(intertwined amongst blood vessels)

lymph node

Development of Red & White blood cells

Red blood cells

inflammatory response

fight parasites

Leukocytes Lymphocytes
develop into macrophages short-lived phagocytes 60-70% WBC

Leukocytes: Phagocytic WBCs

Attracted by chemical signals released by damaged cells
ingest pathogens digest in lysosomes

Neutrophils
most abundant WBC (~70%) ~ 3 day lifespan

Macrophages
big eater, long-lived

Natural Killer Cells

destroy virus-infected cells & cancer cells

Destroying cells gone bad!

Natural Killer Cells perforate cells
release perforin protein insert into membrane of target cell forms pore allowing fluid to flow in & out of cell natural killer cell cell ruptures (lysis)
apoptosis
perforin
cell membrane

vesicle

perforin punctures cell membrane

cell membrane

virus-infected cell

Anti-microbial proteins
Complement system
~20 proteins circulating in blood plasma attack bacterial & fungal cells
form a membrane attack complex perforate target cell apoptosis
cell lysis
complement proteins form cellular lesion

extracellular fluid

plasma membrane of invading microbe

complement proteins

bacterial cell

Anti-microbial proteins
Complement system

Inflammatory response
Damage to tissue triggers local non-specific inflammatory response
release chemical signals
histamines & prostaglandins

capillaries dilate, become more permeable (leaky)

delivers macrophages, RBCs, platelets, clotting factors
fight pathogens clot formation

increases temperature
decrease bacterial growth stimulates phagocytosis speeds up repair of tissues

Fever
When a local response is not enough
system-wide response to infection

activated macrophages release interleukin-1

triggers hypothalamus in brain to readjust body thermostat to raise body temperature

higher temperature helps defense

inhibits bacterial growth stimulates phagocytosis speeds up repair of tissues

causes liver & spleen to store iron, reducing blood iron levels
bacteria need large amounts of iron to grow

Fever

3rd line: Acquired (active) Immunity

Specific defense with memory
lymphocytes
B cells T cells
B cell

antibodies
immunoglobulins

Responds to
antigens
cellular name tags
specific pathogens specific toxins abnormal body cells (cancer)

How are invaders recognized?

Antigens
cellular name tag proteins
self antigens
no response from WBCs

foreign antigens
response from WBCs pathogens: viruses, bacteria, protozoa, parasitic worms, fungi, toxins non-pathogens: cancer cells, transplanted tissue, pollen

self

foreign

Lymphocytes
B cells
mature in bone marrow humoral response system
humors = body fluids attack pathogens still circulating in blood & lymph

bone marrow

produce antibodies

T cells
mature in thymus cellular response system
attack invaded cells

Maturation
learn to distinguish self from non-self antigens
if react to self antigens, cells are destroyed during maturation

 The roles of the major participants in the acquired immune response

Humoral immune response Cell-mediated immune response First exposure to antigen

Intact antigens

Antigens engulfed and displayed by dendritic cells Activate Secreted cytokines activate

Antigens displayed by infected cells Activate

Activate

B cell

Helper T cell

Cytotoxic T cell

Gives rise to

Gives rise to

Gives rise to

Plasma cells

Memory B cells

Active and memory helper T cells

Memory cytotoxic T cells

Active cytotoxic T cells

Secrete antibodies that defend against pathogens and toxins in extracellular fluid

Defend against infected cells, cancer cells, and transplanted tissues

Figure 43.14

The role of helper T cells in acquired immunity

1 After a dendritic cell engulfs and degrades a bacterium, it displays bacterial antigen fragments (peptides) complexed with a class II MHC molecule on the cell surface. A specific helper T cell binds to the displayed complex via its TCR with the aid of CD4. This interaction promotes secretion of cytokines by the dendritic cell. Cytotoxic T cell Dendritic cell Bacterium Peptide antigen Class II MHC molecule TCR 2 1 CD4 Dendritic cell Cytokines 2 Proliferation of the T cell, stimulated by cytokines from both the dendritic cell and the T cell itself, gives rise to a clone of activated helper T cells (not shown), all with receptors for the same MHCantigen complex. 3 Helper T cell Cell-mediated immunity (attack on infected cells) Humoral immunity (secretion of antibodies by plasma cells)

B cell
3 The cells in this clone secrete other cytokines that help activate B cells and cytotoxic T cells.

Figure 43.15

B cells
Attack, learn & remember pathogens circulating in blood & lymph Produce specific antibodies against specific antigen Types of B cells plasma cells
immediate production of antibodies rapid response, short term release

memory cells
continued circulation in body long term immunity

1 After a macrophage engulfs and degrades

a bacterium, it displays a peptide antigen complexed with a class II MHC molecule. A helper T cell that recognizes the displayed complex is activated with the aid of cytokines secreted from the macrophage, forming a clone of activated helper T cells (not shown).

A B cell that has taken up and degraded the same bacterium displays class II MHCpeptide antigen complexes. An activated helper T cell bearing receptors specific for the displayed antigen binds to the B cell. This interaction, with the aid of cytokines from the T cell, activates the B cell.

3 The activated B cell proliferates

and differentiates into memory B cells and antibody-secreting plasma cells. The secreted antibodies are specific for the same bacterial antigen that initiated the response.

Bacterium Macrophage Peptide antigen

Class II MHC molecule

1

B cell
2

Clone of plasma cells

Secreted antibody molecules

TCR

CD4 Cytokines

Endoplasmic reticulum of plasma cell

Helper T cell

Activated helper T cell

Clone of memory B cells

Figure 43.17

Exposure to antigen

Antibody levels

IgM

IgG

each B cell ~50,000 antibodies

Weeks

Y
6

millions of antibodies respond to millions of foreign antigens

Classes of Immunoglobulin: IgM, IgG, IgA, IgE, IgD binding region matches molecular shape of antigens each antibody is unique & specific

Proteins that bind to a specific antigen

Y Y Y Y Y Y Y

Antibodies

Y Y

Y Y

Y Y

Y Y Y

Y Y Y Y Y Y

Antibodiy Isotypes

Y Y Y

Y Y

 Infected cells digest some pathogens

Major histocompatibility (MHC) proteins

How do T cells know a cell is infected?

proteins which constantly carry bits of cellular material from the cytosol to the cell surface snapshot of what is going on inside cell give the surface of cells a unique label or fingerprint

MHC proteins carry pieces to cell surface

foreign antigens now on cell membrane called Antigen Presenting Cell (APC)
macrophages can also serve as APC

tested by Helper T cells infected cell MHC proteins displaying foreign antigens

TH cell
T cell with antigen receptors

 Attack, learn & remember pathogens hiding in infected cells

recognize antigen fragments also defend against non-self body cells
cancer & transplant cells

T cells

Types of T cells
helper T cells
alerts rest of immune system

killer (cytotoxic) T cells

attack infected body cells

memory T cells
long term immunity

T cell attacking cancer cell

T cell response
APC: infected cell
recognition

killer T cell
helper T cell helper T cell helper T cell
clones

helper T cell
interleukin 1

activate killer T cells stimulate B cells & antibodies

Y Y

or

APC: activated macrophage

helper T cell
recognition

Y
Y Y Y Y Y Y Y

Y Y Y Y Y

Y Y Y

 The activated cytotoxic T cell

Secretes proteins that destroy the infected target cell
2 The activated T cell releases perforin 1 A specific cytotoxic T cell binds to a molecules, which form pores in the class I MHCantigen complex on a target cell membrane, and proteolytic target cell via its TCR with the aid of enzymes (granzymes), which enter the CD8. This interaction, along with target cell by endocytosis. cytokines from helper T cells, leads to the activation of the cytotoxic cell. 3 The granzymes initiate apoptosis within the target cells, leading to fragmentation of the nucleus, release of small apoptotic bodies, and eventual cell death. The released cytotoxic T cell can attack other target cells.

Cytotoxic T cell Perforin

Released cytotoxic T cell Cancer cell

Granzymes 1 TCR Class I MHC molecule CD8 2 Pore 3

Apoptotic target cell

Target cell

Peptide antigen

Figure 43.16

Cytotoxic T cell

Summary of specific immune response

Susumu Tonegawa won the 1987 Nobel Prize in Physiology or Medicine for demonstrating how B cells create the enormous diversity of antibodies from only a few genes
RRE & AB, SITH ITB

Acquired immunity

Active natural (contact with infection): develops slowly, is long term, and antigen specific.

Active artificial Passive natural (immunization): develops (transplacental= slowly, lasts for several mother to child): years, and is specific to the develops immediately, antigen for which the is temporary, and immunization was given. A affects all antigens to vaccine can be a weakened which the mother has (non-lethal) form of invader immunity. or a toxic by-product of an invader.

Passive artificial (injection of gamma globulin): develops immediately, is temporary, and affects all antigens to which the donor has immunity.

HIV & AIDS

Human Immunodeficiency Virus
virus infects helper T cells
helper T cells dont activate rest of immune system: killer T cells & B cells also destroys helper T cells

AIDS: Acquired ImmunoDeficiency Syndrome

infections by opportunistic diseases death usually from opportunistic infections
pneumonia, cancers
HIV infected T cell

Immune system malfunctions

Auto-immune diseases
immune system attacks own molecules & cells
lupus
antibodies against many molecules released by normal breakdown of cells

rheumatoid arthritis
antibodies causing damage to cartilage & bone

diabetes
beta-islet cells of pancreas attacked & destroyed

multiple sclerosis
T cells attack myelin sheath of brain & spinal cord nerves

Allergies
over-reaction to environmental antigens
allergens = proteins on pollen, dust mites, in animal saliva stimulates release of histamine

Rheumatoid arthritis
Is an autoimmune disease that leads to damage and painful inflammation of the cartilage and bone of joints

Figure 43.21

Allergies
Stage 1 Stage 2

Pollen is a harmless protein, yet we can become allergic to it. Most of the symptoms are caused by histamines released by mast cells. That is why antihistamines are used to treat allergies. Allergies are an immune system reaction to harmless antigens.