BIOE 301 Lecture Eight

Amit MistryFeb 6, 2007

BIOE 301 – Lecture 8

WARM-UP

Observation: Global average near-surface atmospheric temperature rose 1.1 ± 0.4 °Fahrenheit in the 20th century. What is the scientific approach to

this? What is the engineering approach

to it?

Review of Lecture 7

Science “Science is the human activity of

seeking natural explanations for what we observe in the world around us.”

Five steps of the scientific method

Engineering Systematic design, production and operation

of technical systems to meet practical human needs under specified constraints

Six steps of the engineering design method

Q3: How can technology solve health care

problems? CS1: Prevention

of infectious disease

Roadmap of CS 1 Science

Organisms that cause infectious disease Immunity

Engineering How to make a vaccine

Vaccines: From idea to product Societal Impact

Health and economics Ethics of clinical trials Developed world/Developing world

Connections – First day of class

What caused the first bone marrow transplants to be rejected by recipients?

Bone Marrow - Pluripotent Stem Cells

Hematopoietic stem cells differentiate into: White blood cells Red blood cells Platelets

Mesenchymal stem cells differentiate into: Bone, cartilage, muscle

White Blood Cells

Neutrophil Lymphocyte Macrophage

“The Defense”“The Good Guys”

Pathogens

How They Cause Disease

“The Offense”“The Bad

Guys”

Types of Pathogens Bacteria

Cells with membrane and cell wall (usually) Can survive outside host; reproduce without

host Can be killed or inhibited by antibiotics

Viruses Nucleic acid core with protein envelope Use host intracellular machinery to

reproduce Cannot be killed with antibiotics >50 different viruses that can infect humans

Question:

Based on your understanding of the characteristics of bacteria, viruses, and blood cells, identify which item best represents each and be able to explain why you chose each. Bacterium Virus Blood cell

Pathogens

Human hair – 100,000,000 nm

Red blood cell – 7,000 nm

E. coli bacteria – 800 nm

Virus – 100 nm

www.awcommunity.orgwww.its.caltech.edu/~boozer

Bacteria

How do Bacteria Cause Disease?

Invade host Reproduce Produce toxins disturb cell

function Examples

Escherichia Coli Bacillus Anthracis Microbacterium tuberculosis Streptococcus pneumoniae

http://www.cubanology.com/Articles/Virus_vs_Bacteria.htm

Virus

How do Viruses Cause Disease?

Virus invades host cell Binds to cell membrane receptors Endocytosis brings virus into cell

Virus takes over cell Use viral nucleic acid and host cell

resources to make new viral nucleic acid and proteins

More virus is released from host cell Virus causes host cell to lyse OR Viral particles bud from host cell surface

Virus examples: Influenza, HIV, West Nile, HepatitisHuman Papillomavirus, Viriola Major

Using Viruses for Good, not Evil

Gene Therapy: infect cells with beneficial DNA

Diabetes SCID Cancer Sickle cell anemia MS Cystic fibrosis

www.nih.gov

Pathophysiology of HIV/AIDS

Pathophysiology of HIV/AIDS

The Immune System

How Are We Protected Against

Pathogens?

Types of Immunity

Three layers of immunity: Physical Barriers Innate Immune System

All animals possess Adaptive Immune

System Vertebrates possess

Keep pathogens out Kill them if they get in

Types of Immunity - Defense

Line of scrimmage

Physical Barriers = Defensive Line

Innate = Secondary Defense

Adaptive = Coach

Types of Immunity Physical Barriers

Skin (2 square meters) Mucous Membranes (400 square meters)

Innate Immune System Produces general inflammatory response

when pathogens penetrate physical barriers

Adaptive Immune System Can adapt to defend against any invader Important when innate immune system

cannot defend against attack Provides immune system with “memory”

Physical Barriers

What happens when you get a splinter?

What happens when you get a splinter?

Pathogens gets past physical barrier1. Macrophages eat bacteria on splinter

Phagocytosis

2. Activated macrophages produce chemicals which: Increase local blood flow Increase permeability of

blood vessels Recruit other phagocytes to site

RednessHeat

Swelling

Pus

What happens when you get a splinter?

Phagocytosishttp://jcs.biologists.org/cgi/content/full/119/9/1903/DC1

Innate Immune System

Primarily effective against pathogens outside of cells

Two main weapons: 1) Professional phagocytes

Cells that eat stuff 2) The complement system

Proteins that tag stuff for destruction

Components of Innate Immune System

1) Macrophages: Sentinels that patrol periphery If they find an invader, they

become “activated” If activated, they:

Send signals to recruit other immune system cells (Neutrophils)

Become vicious killers Present antigen to adaptive immune system

(more on this later)

Components of Innate Immune System

2) Complement proteins Present in tissues &

blood Attach to surfaces of

bacteria and viruses Target them for

destruction by phagocytes

Form Membrane Attack Complexes

Recruit other immune cells from blood

Adaptive Immune System

Antibody-mediated: Fight pathogens

outside of cells Cell-mediated:

Fight pathogens inside of cells

What is an antibody? Bridge between:

Pathogen Tool to kill it

Antibodies have two important regions: Fab region:

Binds antigen Binds surface of virus-

infected cell Fc region:

Binds macrophages and neutrophils, induces phagocytosis

Binds natural killer cell, induces killing

Question:

Which components of your kit are most like antibodies?

Arrange the components of the kit to demonstrate how these antibodies “bridge” a pathogen and the tool to kill it?

Antibodies How are antibodies made?

B cells Lymphocytes that make antibodies Have B cell receptors on surface 100 million different types of B cells, each

with different surface receptors B cell receptors are so diverse they can

recognize every organic molecule When a B cell binds antigen:

Proliferates - In one week, clone of 20,000 identical B cells

Secretes antibody

Adaptive Immune System How do we kill virus once inside the cell?

Antibodies cannot get to it Need T cells

T Cells Recognize protein antigens When bind antigen, undergo clonal selection Three types of T Cells:

Killer T Cells (Cytotoxic T Lymphocytes – CTLs) Helper T Cells (targeted by HIV) Regulatory T Cells

How do T Cells ID Virus Infected Cells?

Antigen Presentation All cells have MHC molecules on surface When virus invades cell, fragments of viral

protein are loaded onto MHC proteins T Cells inspect MHC proteins and use this

as a signal to identify infected cells

Question:

Using the components of the kit, demonstrate the two steps required for viral antigens to be presented on the MHC complexes on the surface of the blood cell.

Question:

Demonstrate how the T cell can identify a virus infected cell.

Why is this component of the adaptive immune system a significant advance over the innate immune system?

Immunologic Memory

First time adaptive immune system is activated by an antigen: Build up a clone of B cells and T cells Takes about a week After infection is over, most die off Some remain – memory cells

Second time adaptive immune system is activated by that antigen: Memory cells are easier to activate Response is much faster – no symptoms

Putting it all together

Putting it all togetherVirus invades Antibodies bind Prevent virus function

Signal phagocytosis

Present antigen

Activates Killer T cells

Activates B cells

Make more antibodies

Infects cells

Antigen presentation

Kill infected cells!

Virus invades Antibodies bind Prevent virus function

Signal phagocytosis

Present antigen

Activates Killer T cells

Activates B cells

Make more antibodies

Infects cells

Antigen presentation

Kill infected cells!

Cell-mediated

Antibody-mediated

Summary of Lecture 8

Pathogens: Bacteria and Virus Levels of Immunity:

Barriers First line of defense Innate Inflammation

Phagocytes Complement

Adaptive Immunologic memory Cell mediated immunity Pathogens within

cells Antibody mediated immunity Diversity to recognize 100 million antigens

Turn in HW 4 today

Next Time Project Task 2 due on 2/8/07 Influenza virus Vaccines

The most cost-effective medical intervention known to prevent death or disease

For more info:

National Bone Marrow Program http://www.marrow.org/

Baylor Center for Cell and Gene Therapyhttp://www.bcm.edu/genetherapy/

Immunobiology – BIOS 423 - Dr. Novotny