Mmg 522: Lecture # 3 Innate Immunity

Front 1

The first line of denfense that occurs naturally without induction

Present constantly, deals with broad range of targets

Back 1

Innate Immune Response

aka: native or natural immunity

Front 2

What are some of the physicial barriers of the innate immune system?

Back 2

1. Skin
2. Mucous
3. Membranes
4. Respiratory cilia

Front 3

What are some of the chemical barriers of the innate immune system?

Back 3

Secretions from sebeacous glands which inhibit bacterial growth
Low pH
Lysozyme
Fatty acid

Front 4

A biological barrier of the immune system.

Involves small peptides that disrupt microbial membranes/ion channels and quickly kill bacteria by producing antibodies

Back 4

Defensins

Front 5

How does killing of microbes occur by intraepithelial lymphocytes?

Back 5

A type of innate immune response.

They recognize lipids and attack.

Front 6

What are the cellular barriers of innate immune response?

Back 6

Gamma and delta T cells

Normal T cells are alpha and beta

Front 7

What is the most abundant leukocyte?

It is the 1st cell that responds to an infection (not microbe).

Short life span

Back 7

PMN or Neutrophils

Front 8

What chemokine recruits PMN to the site of infection?

Back 8

IL-8

Front 9

What stimulates production of PMN in bone marrow?

Back 9

Cytokine Granulocyte Stimulating Factor

Front 10

What is the primary function of PMN?

Back 10

Phagocytosis

Front 11

What are the first cells that respond to a microbe (not infection)?

Back 11

Macrophage

Front 12

What are the dual names for macrophages?

Back 12

Monocyte in blood
Macrophage in tissue

Front 13

What are the dual roles of macrophages?

Back 13

Phagocyte
APC

Macrophages serve as a critical link between innate & adaptive bc functions as APC (innate) and secretes cytokines (adaptive)

Front 14

Short life span or long life span for macrophages?

Do macrophages produce cytokines?

Back 14

Longer life span than PMN

Yes, major producer of cytokines

Front 15

What are some other names for macrophages based on their locations in the body?

Back 15

Microglia (CNS)
Kupffer cells (liver)
Alveolar macrophages (lung)
Osteoclasts (bone)

Front 16

How do phagocytes (PMN and macrophages) recognize microbes?

Back 16

Via Pattern Recognition Receptors (PRR)

Found in pathogens but not in normal tissues of the body. Found on the cell surface of phagocytic cells.

1. LPS: part of gram - cell wall
2. Flagellin (bacteria)
3. Lipopeptide or glycolipid
4. Terminal mannose on glycoprotein (bacteria)
5. Unmethylated CpG nucleotides found in bacterial DNA
6. dsRNA (virus)

Front 17

Pattern Recognition Receptors

Back 17

Different microbes can be recognized by one PPR

PPRs from same lineage are the identical.

Front 18

How does phagocytosis occur?

Back 18

1. Microbe binds to phagocyte receptors
2. phagocyte receptor zips up around microbe.
3. Microbe ingested in phagocyte
4. Fusion of phagosome with lysosome
5. Killing of microbes by lysosomal enzymes in phagolysosomes.

Front 19

What are some lysosomal enzymes in phagolysosomes that kill microbes?

Back 19

ROI-reactive oxygen intermediate
NO

Front 20

What are some additional macrophage responses?

Back 20

1. Killing of microbes via ROI and NO

2. Inflammation, enhanced adaptive immunity via cytokines (TNF, IL-12)

3. Increased MHC (major histocompatibility complex) molecules that enhance antigen presentation

Front 21

Natural killer recognition

What are the receptors that determine killing?

Back 21

NK cells recognize cells that are not expressing MHC class I molecules.

Activating, Inhibiting, ITIM (stops signal transduction)

Front 22

What are the function of Natural Killer cells?

Back 22

1. Cytotoxic

2. Secrete IFN-gamma to stimulate killing by macrophages

Front 23

What is the opposite of IFN-gamma?

Back 23

IFN-GAMMA goes from NK to macrophage while IL-12 secreted from macrophages and activates NK.

Front 24

What is the cytokine that macrophages secrete to stimulate NK?

What is the cytokine that NK secrete to stimulate macrophages?

Back 24

IL-12



IFN-gamma

Front 25

A series of proteis found in serum which form an enzymatic cascade.

Back 25

Complement

Front 26

How does a complement work?

Back 26

1. Activation trigger (mannose) activates protease

2. This active protease then cleaves the second complement protein in the pathway

etc.

Front 27

The enzymatic cascade continues until what occurs?

Back 27

1. Opsonization
2. Complement-mediated cell lysis
3. Chemoattraction
4. B cell activation

Front 28

Opsonization explained

Back 28

During the cascade, a protein called C3 is cleaved into C3a and C3b.

C3b has affinity for lipid bilayers and attach to cell membrane of pathogen. So c3b is an opsonin.

Opsinized bacteria are more readily phagocytosed by macrophages and PMN.

Front 29

Complemented-mediated cell lysis

Back 29

If the cascade continues to completion, final complement binds around C3b and forms a pore through the bacteria causing the bacteria to lyse.

Front 30

What are 2 proteins used for opsonization?

Back 30

IgG

C3b

Front 31

What are the 3 pathways used to activate complement?

Back 31

alternative & lectine pathways-innate because do not require antibodies

Classical pathway-adaptive because initated by antibodes.

Front 32

What are types of extracellular pattern recognition molecules?

Back 32

Type I and II interferons

Front 33

Type I interferon

Back 33

Alpha and Beta

Alpha secreted by macrophages
Beta secreted by fibroblasts

Increases MHC expression so macrohages recognize them.

Diffuse to a neighboring cell and binds to IFN receptor which induce neighboring cell to produce a protein that will inhibit viral replication. So the neighboring cell is protected.

Front 34

type II interferon

Back 34

Gamma

Secreted by NK and T

Involved in innate and adaptive

Activate macrophage

Stimulate B cell antibody production & increases MHC expression

Front 35

Acute Phase Protein (APP) purpose

Back 35

Proteins secreted by liver upon infection such as CRP and MBL

Involved in immune response

CRP acts as opsonin
MBL activates complement pathway

Front 36

Migration of Leukocytes

Back 36

1. Macrophages with ingested microbes secrete cytokines

2. Stimulates endothelium to express adhesion molecules that facilitate attachment of leukocytes

3. Integrin activated by chemokines

4. Diapedisis when cells migrate between the endothelial cells.

Front 37

Accumulation and activation of leukocytes and plasma proteins and permeability of vasculature

Renders protection as well as tissue damage

Back 37

Inflammation

Front 38

What are the 4 cardinal signs of inflammation?

Back 38

Red, swollen, fever, pain

Front 39

What are the cytokines involved in inflammation?

Back 39

Secreted by activated macrophage

IL-1, IL-6 and TNF-a cause fever

IL-1, TNF-a and IL-6 induce APP synthesis in liver

IL-8 recruits PMN and TNF-a activates them (TNF is secreted by macrophages to stimulate PMN)

Massive amount of TNF causes septic shock

Front 40

Caused by endotoxin, LPS

Massive production of IL-1 and TNF-alpha

Back 40

Septic shock

Front 41

What are the consequences of Septic shock?

Back 41

1. Vascular collapse (low blood pressure)

2. Disseminated intravascular coagulation (DIC, massive, severe clotting)

3. Metabolic disturbance (diarrhea)

4. Fever and APP production (CRP as indicator)

5. Potential vital organ failure including heart, kidney, lung and liver

Front 42

Memorize what?

Back 42

Cytokines in innate immunity table on slide 28

Front 43

What are some mechanisms for microbrial evasion?

Back 43

1. Resistance to defensin- modifieds LPS

2. Resistance to Complement activation

3. Resistance to phagocytosis

4. Resistance to fusion with lysosome -
a. By staying within a vesicle inhibiting lysosome, break phagosome and go into cytoplasm so enzymes in lysosome will not work.

b. By breaking the vesicle and enter cytoplasm

5. Resistance to ROI - via catalase