Innate Immunity

Question 1

Learning Objectives

Answer 1

1. list the innate immune defenses of the human body
2. describe how the epithelial layers act as barriers to infection
3. describe how the mucociliary escalator (airway barriers) work
4. list the cells of the innate immune system
5. diagram a molecular mechanism that allows neutrophils to extravasate and transmigrate into infected tissues
6. diagram the process of neutrophil phagocytosis and describe the oxidative burst

Question 2

Mammalian immunity

Answer 2

immunity functions to keep most bateria at bay or relegate them to controlled areas (control where bacteria can/cannot grow in the body)
two main “branches”:
1. Innate immune system
2. Adaptive immune system

Question 3

Innate immune system

Answer 3

generalized, rapid defense response
defenses against infection ready for immediate activation prior to attack by a pathogen
no learning or memory (does not get stronger after initial infection)
non-specific and target any foreign pathogens/substances
begins to develop at conception and fully developed at birth
includes physical, chemical and cellular barriers (i.e. skin, microbiota, mucosal membranes, complements, chemokines and cytokines, and cell-mediated immunity)

Question 4

Adaptive immune system

Answer 4

slower, amplified and specific defense response

Question 5

The Immune System: 3 Lines of defense

Answer 5

Innate/natural immunity (non-specific responses)
1st line:
1. skin
2. mucous membranes and secretions
3. normal flora (microbiota in gut or other tissues)

2nd line:
1. innate immune cells
2. inflammation
3. complement
4. antimicrobial substances (i.e. defensins)

Adaptive/acquired immunity (specific responses)
3rd line: specialized lymphocytes
1. B cells (produce antibodies - bind to atiges ad receptors of innate immune cells)
2. T cells (Helper and Killer T cells)

Question 6

Epithelia (epithelial layers)

Answer 6

cells that cover all of the external and internal surfaces of the body that are exposed to the environment (i.e. skin, stomach and gut lining)
large variation between locations (with some commonalities) and different areas of epithelia have specialized defense mechanisms
protected by an array of innate and adaptive defenses

Question 7

Mucosal epithelia

Answer 7

internal surface areas are comprised of only one epithelial layer and lined with mucus

Question 8

Surface associated lymphoid tissue (SALT)

Answer 8

made up of lymphocytes, plasma cells, dendritic cells and macropahges that contributes to the immune barrier

Question 9

Langerhans cells

Answer 9

dendritic cells in skin and mucosal tissues that process invading bacteria and activate specific defenses
also professional antigen presenting cells

Question 10

Mucociliary escalator

Answer 10

composed of mucous-producing globet cells and ciliated epithelium
cilia continuously beats and push microorganisms trapped i the mucous layer out of the body
covers most of the bronchi, bronchioles and nose

a major barrier against infection

Question 11

Microbiota

Answer 11

resident, commensal microbiota help protect against infection by filling a niche and outcompeting potential pathogens
some commensals produce bactericidal compounds (i.e. bacteriocins, antibiotics, type IV effector proteins)

Question 12

Colicins

Answer 12

a type of bacteriocin produced by E. coli that kills other E.coli strains
produced under conditions of nutritional or environmental stress to eliminate closely related strains (control growth of pathogenic strains)
has a narrow spectrum (only against E.coli)

Question 13

Lugdunin

Answer 13

an antibiotic (cyclic-peptide) produced by S. lugdenensis to prevent colonization of S. aureus (including MRSA) and other Gram-positive bacteria
control growth of other competitors in niche (the nose in this case)
i.e. when examining numbers in the nose (niche), S. lugdenensis and S. aureus population has an inverse relationship, indicating that they compete against each other

Question 14

Bte1 and Bte2

Answer 14

Bacteroidetes fragilis T6SS effectors
proteins that are secreted by the T6SS, effectors are toxic against other bacteria and eukaryotic host
mediate competition with other microbiota in the mammalian gut

Question 15

Type VI Secretion System (T6SS)

Answer 15

an ATP-dependent type of secretion system used by a wide range of Gram-negative bacteria to transport effectors across the membrane (periplasm+outer membrane) into adjacent target cell

Question 16

Categories of Innate immune cells

Answer 16

1. phagocytes (“eaters”)
- neutrophils
- monocytes (circulate in blood stream and differentiate into macrophages and dendritic cells (DCs) in tissues)
2. natural killer cells
3. mast cells
- eosinophils
- basophils
non-phagocytic, congregate in blood vessels, and perception of invaders by releasing granules of histamine (allergic response)

Question 17

Polymorphonuclear leukocytes (PMNs)

Answer 17

include neutrophils, eosinophils and basophils

Question 18

What are the differences between innate immune cells?

Answer 18

1. Localization
- dendritic cells are fixed in defined locations
- PMNs and monocytes migrate through blood stream

2. Cell Census
- more PMNs than monocytes
- PMNs are short-lived comapred to monocytes (which differentiate into macrophages in bloodstream)

3. Cell Differentiation
- monocytes differentiate to macrophages and dendritic cells upon entering tissues
- PMNs activated by bacteria to enter tissue but no differentiation

Question 19

Histamine

Answer 19

released by mast cells and basophils, causes vasodilation that allows PMNs/monocytes to enter infected tissues

Question 20

Cellular communication

Answer 20

communication via cell surface receptors allows immune cells to respond
signaling pathways activate neutrophils to undergo extravasation/transmigration
adhesion molecules allow cells to snare passing phagocytes needed in tissue
usage of chemotaxis (complement, bacterial molecules, cytokines) to localize in on site of infection

Question 21

Cytokines

Answer 21

chemical messengers that attracts PMNs such as neutrophils to the site on infection via chemotaxis (act as a chemical gradient)

Question 22

Extravasation/Transmigration

Answer 22

the movement of neutrophils into tissues from the blood vessels
two routes for transmigration into tissues:
1. paracellular (between endothelial cells)
2. transcellular (through endothelial cells)

Question 23

What is the process of neutrophil recruitment to the site of infection?

Answer 23

1. chemokines guide neutrophils to the site of infection - tethering
2. selectins and integrins (cell-surface adhesion receptors) bind to receptors on neutrophils - slow rolling
3. chemokine binding to neutrophils induce conformational changes in integrins, allow neutrophils to adhere to vasculature - firm adhesion and intraluminal crawling
4. neutrophils actively choose sites for transmigration and extravasate into site of infection

Question 24

Opsonization

Answer 24

the process of marking or “tagging” a pathogen for phagocytosis, faciilitates molecular recognition of a microbe by a neutrophil
mediated by opsonins (antibodies or other substances like complements), which bind to foreign microorganisms and make them more susceptible to phagocytosis
opsonins are recognized by receptors on the surface of neutrophils:
antibodies > FcR (bind to Fc (non-variable) region of antibodies)
C3b (complement) > C3bR

Question 25

Phagocytosis

Answer 25

1. **ingestion** of bacteria into a phagosome 2. **fusion** of phagosome and lysosomes 3. phagolysosome releases lysozyme, proteases, defensins, production of peroxides, superoxides, hypochlorous acid, and nitric acid to **degrade and kill** bacteria 4. **release** of bacterial fragments

Question 26

Oxidative burst

Answer 26

**production of toxic compounds** in neutrophil **phagolysosome**: - **hypochlorous acid** (by **myeloperoxidase** or "MPO") - **superoxide anion** (by **NADPH oxidase**) - **reactive oxygen species** (singlet oxygen, hydrogen peroxide and hydroxyl radicals) - **reactive nitrogen species** such as nitric oxide (by **nitric oxide synthase** or "NOS")