Overview of Host Defenses

Christopher M. Snyder
christopher.snyder@jefferson.edu
 Overview of Host
1 Defenses

2 Innate Host
Defenses
Immune Effector
3 Adaptive Immune System Adaptive Immune Responses 8 Mechanisms and Memory
– Primary Development
5 6 7 Humoral Effector
Antigen Processing &
9 Mechanisms and
4 Presentation
Immune Deficiencies

10 11 12 13 14 15
Immunology Synthesis: Hypersensitivity
Autoimmunity Immunodeficiency Biologics
Mucosal Immunology Allergy

16 17 18 19
Tumor Non-steroidal anti- Antihistamines &
Vaccinology
Immunology inflammatory drugs Allergy Pharm

20 21 22 23
Drugs & the Pharmacology
Transplantation
Immune System Interactive Review
 What is pus?

Ulcer Infected Ulcer

Why can’t we ever get rid of herpes
infections?
Why does a bone marrow graft lead to
graft vs. host disease?

http://www.cmaj.ca/cgi/content-nw/full/170/10/1569/
How does my immune system know
me from stuff that’s not me?
viruses

bacteria
• Immunity: The ability of an organism to
resist a particular infection or toxin
– From the Latin immunitas/immunis =
“exemption”

• Recognized long ago that people surviving

a particular infection were no longer
susceptible.
Immunity in Practice:
The first vaccination

In 1796: Edward
Jenner inoculated
James Phipps (an 8-
yr old boy!) with
cowpox. 6 weeks
later, Jenner
challenged Phipps
with small pox and
he was immune.
 So What Happens??

Pathogen
enters Immunity!
your body
 Questions to be answered in this
lecture
1. What are the differences between innate and
adaptive immunity?
– What are the players of each and how do they fit into
your layers of immune defense?

1. What are the stages of an immune response?

2. How is the adaptive immune system better than

Norton Antivirus?

3. How do adaptive immune cells recognize foreign

molecules with specificity?
 Layers of Defense:
Innate and Adaptive Immunity
1. Physical Barriers:
– Your skin and epithelial surfaces prevent invasion
– Barriers include microbial communities that also limit
invasion.
2. Innate Immune System:
– Rapid: Responds in hours
– “Profiles” pathogens
3. Adaptive Immune System:
– Delayed: Responds in days
– Specific for each individual pathogen
 Immune Receptors
• Recognition of foreign molecules occurs through
receptors:
– Proteins expressed by immune cells
 Innate Immune Recognition: Profiling
• Innate immune cells express receptors that recognize
molecular patterns associated with pathogens or
stressed/dying cells
– Pattern Recognition Receptors (PRRs)
Krysko et. al., Trends in Immunology 2011

Pathogen Associated Molecular Patterns Damage Associated Molecular Patterns

(PAMPs) (DAMPs)
Immune Receptors
LPS from bacterial
cell walls
 Innate immune cells share identical
receptors
• Pattern recognition
receptors are shared.

• All innate immune cells

of a particular type
express the same set of
receptors with the same
specificities
 Immune response is modulated by the type of
pathogen

• Multiple receptors for

PAMPs and DAMPs
– Innate immune cells respond
respond to different PAMPs or
DAMPs differently
– Different cytokines, or
chemokines are produced

• Intracellular and
Extracellular pathogens
trigger different pathways
 Players of the Innate Immune System
• Granulocytes: Neutrophils, Mast Cells,
Basophils, Eosinophils

• Phagocytes: Macrophages, Dendritic Cells

• Innate Lymphocytes: Natural Killer cells, gd-T

cells, NK-T cells, ILCs
We have lots of these cells at steady
state – waiting for an infection.
Invasion and Infection

Borrelia
bacteria

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream
 Stages of Innate Immune Responses
1. Recognition

2. Activation

3. Expansion

4. Resolution
(1) Recognition of PAMPs by Tissue Macrophages

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream
(2) Activation of Tissue Macrophages

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream
 (2) Activation of macrophages induces increased
phagocytosis (ingestion) and killing of ingested
pathogen
Macrophages (MF) are
professional phagocytes

Wikipedia: phagocyte
(2) Activation of Tissue Macrophages

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream
 (3) Expansion: Activated Macrophages Recruit
Neutrophils

Macrophages: (MF)
Chemoattractants
recruit neutrophils

Neutrophils: (PMNs)

Blood Stream
Neutrophils are phagocytes and far
more toxic than macrophages

Also called PMNs: Polymorphonuclear neutrophiles.

Activated neutrophils begin ingesting bacteria

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream
(4) Resolution as neutrophils and macrophages die
Note: Pus is primarily dead neutrophils

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream
 Stages of Innate Immune Responses
1. Recognition of the infection (binding of
receptors to PAMPs or DAMPs)
2. Activation of the innate immune cells
– Become better phagocytes
3. Expansion of the response by recruitment of
new cells from the blood
– Rapid
– Limits pathogen growth
4. Resolution of the response by death of the
immune cells
Adequate Protection
Requires BOTH
the Innate and
Adaptive Arms of the
Immune System
 Adaptive Immunity
• It is delayed
• It is specific
• It provides memory

• It consists of:
– B cells (produce antibody)
– T cells
adaptive immune cells also have
receptors

Foreign
Antigen
Human-infecting virus families

https://www.antiviralintelistrat.com/1/viral_taxonomy
Human RNA virus families

Felix Rey
Nature 468, 773–775
(09 December 2010)
Adaptive Immune Responses can be
specific for anything
Hives
• Example: People can
develop allergies to
synthetic substances
like sulfonamides –
which are the basis
of many drugs.
– How??
Random Diversity
Random diversity is produced by random
gene recombination
1 2 3 4

A B C
Gene Segments are
combined at random to
a b g produce whole genes

2 A a

Generates greater than

Complete gene for
immune receptor >109 different
specificities!
 4 stages of the adaptive immune response
B cell Repertoire:
>109 potential specificities

- Pre-existing diversity

- Very few cells with an

individual specificity

Slide adapted from Dr. Manser

 4 stages of the adaptive immune response
B cell Repertoire:
>109 potential specificities

1. Recognition

2. Activation

3. Expansion

4. Resolution

Slide adapted from Dr. Manser

 Random Diversity and Selection of the
appropriate cell
B cell Repertoire:
>109 potential specificities

1. Recognition: specific
Antigen

2. Activation

Slide adapted from Dr. Manser

 Random Diversity and Selection of the
appropriate cell
B cell Repertoire: Individual cells proliferate to
>109 potential specificities produce identical progeny: a clone

1. Recognition: specific

Antigen
2. Activation

3. Expansion: Clonal
This is the cause of the delay. It
takes time to expand specific
Immune cells from few to many.
Response
Slide adapted from Dr. Manser
 Random Diversity and Selection of the
appropriate cell
B cell Repertoire:
>109 potential specificities

memory

Antigen

effectors

Immune
Response
Slide adapted from Dr. Manser
Where are lymphocytes activated?

Secondary Lymphoid Organs

• Lymph nodes, spleen,
tonsils, Peyer’s Patches
 B cells
• B cells express the “B cell receptor” (BCR),
which is a membrane-bound version of an
antibody
• Proteins, sugars etc. (anything really) bind
directly to the BCR and initiated B cell
activation.
B cell antigen recognition

Foreign
Antigen
 T cells
• T cells recognize foreign molecules presented in
MHC (major histocompatibility complex) on an
antigen presenting cell (APC)

• T cells do not recognize 3-D antigens, but rather

small protein fragments called peptides (8-12
amino acids).

• This requires collaboration between innate and

adaptive cells.
 T cell activation: depends on MHC
Peptide (antigen)

MHC = major histocompatibility complex

 T cell receptor
Processed Antigen (TCR)
Fragment

MHC
Antigen Presenting Cell (APC)
 Summary:
• B cells recognize 3-D antigens freely

• T cells recognize peptide antigens displayed in

MHC.
Antibodies and T cells facilitate clearance
Specific antibodies

Specific T cells

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream
Pathogen is cleared!

Macrophages: (MF)

Neutrophils: (PMNs)

Blood Stream

Drs. Snyder and Manser, Sept 11th

(4) Resolution of Adaptive Immunity:
Lymphocytes Die
B cell Repertoire:
>109 potential specificities

memory

Antigen

effectors

Immune
Response
(4) Resolution of Adaptive Immunity:
Lymphocytes Die
B cell Repertoire:
>109 potential specificities

memory

effectors
 Memory cells enable rapid immune
responses to re-infection
B cell Repertoire:
>109 potential specificities Re-infection

memory

effectors
 How is the immune system better than
Norton anti-virus?
1. Huge diversity + Selection
of specific cells = Adaptive
to anything

2. Memory of previous
infectious = life-long
immunity.
 Summary
• Immune responses take place in 4 stages:
– Recognition, Activation, Expansion, Resolution
• Innate immune cells respond within hours.
– Innate immune responses are activated by
patterns.
• Adaptive immune responses are specific
because of the huge available diversity and
clonal selection.
– Respond in days to weeks.
• Collaboration is needed to clear the pathogen.