Chapter 2- Innate Immunity- The Immediate Response to Infection

Question 1

Innate immunity

Answer 1

The host defense mechanisms that act from the start of infection. They do not adapt to a specific pathogen or generate immunological memory

Question 2

Commensal microorganisms

Answer 2

Microorganisms that colonize the skin and mucosal surfaces of healthy individuals. They deter infection because a pathogenic organism must compete successfully with the resident commensals for nutrients and space. Before birth, babies have no commensal microorganisms. Starting at birth and contact with the mother’s vagina, the infant’s skin and mucosal surfaces begin to be populated by commensals acquired from family members, friends, and pets. The gut contains more commensal bacteria than the skin because it is a good source of food

Question 3

Microbiota

Answer 3

A population of commensal microorganisms

Question 4

Extracellular infections

Answer 4

Invasion of the body by pathogens that live outside cells in extracellular spaces, on the surface of epithelia, or in the blood. These pathogens are accessible to soluble, secreted molecules of the immune system

Question 5

Intracellular infections

Answer 5

Invasion of the body by a pathogen that can replicate inside human cells. These pathogens are not accessible to soluble, secreted molecules of the immune system. To kill these pathogens, the immune system kills the cells the pathogens are replicating in. This exposes the pathogens inside the cells to the soluble molecules of the immune system.

Question 6

Complement/complement system

Answer 6

A collection of soluble plasma proteins that act in a cascade of reactions to attack extracellular pathogens in extracellular spaces and in the blood. Pathogens are coated with complement proteins, which can directly kill the pathogen or facilitate its engulfment by phagocytes (neutrophils, macrophages). The complement system is activated in the presence of infection and is involved in both adaptive and innate immunity. Many bacteria resist phagocytosis if they aren’t coated by complement/

Question 7

Zymogens

Answer 7

Inactive forms of proteolytic enzymes (proteases) that circulate in the blood, lymph, and tissues. Many complement components exist in this form and must be cleaved by another protease to become active

Question 8

Complement activation

Answer 8

A cascade of enzymatic reactions where each protease cleaves, and therefore activates, the next protease in the pathway. Complement activation is induced by infection. Each protease is specific for the complement component it cleaves. Cleavage usually occurs at one specific site

Question 9

Complement component 3 (C3)

Answer 9

An important complement protein- people lacking C3 have the most severe immunodeficiencies. It is cleaved into C3a and C3b in complement reactions. C3b is the larger molecule that covalently binds to the surface of the pathogen, also called complement fixation. It tags the pathogen for phagocytosis and organizes the formation of protein complexes that damage the pathogen’s membrane. C3a acts as a chemoattractant that recruits phagocytes and other effector cells from the blood at the site of infection

Question 10

Complement fixation

Answer 10

The covalent attachment of C3b or C4b to pathogen surfaces. This is important because it facilitates phagocytosis of the pathogen

Question 11

C3 cleavage

Answer 11

C3 has such potent functions due to a high-energy thioester bond in the glycoprotein. When C3 enters the blood in an inactive form, the thioester is stable in the hydrophobic interior of the protein. When C3 is cleaved, the bond is exposed, and undergoes hydrophilic attack by a water molecule or by the amino and hydroxyl groups of proteins and carbohydrates on pathogen surfaces. The reaction causes a small fragment of C3b to become covalently bound to the pathogen. However, most C3b molecules are attacked by water, which causes them to stay in solution in an inactive form.

Question 12

3 pathways of complement activation

Answer 12

Alternative pathway, lectin pathway, and the classical pathway. All 3 pathways lead to C3 activation, C3b binding to the pathogen surface, and recruiting other effector mechanisms to destroy the pathogen

Question 13

Alternative pathway of complement activation

Answer 13

It is activated at the start of infection, but does not involve antibodies. Triggered by direct binding of complement components to the microbial surface. The early stages that cause the cleavage of C3 involve iC3b, factor B, and factor D. There is spontaneous hydrolysis and activation of C3

Question 14

Lectin pathway of complement activation

Answer 14

Activated when a mannose-binding lectin (present in blood plasma) binds to mannose-containing peptidoglycans (carbohydrates) on bacterial surfaces. This pathway is part of the innate immune response, but takes time to gain strength

Question 15

Classical pathway of complement activation

Answer 15

Contributes to both adaptive and innate immunity. It is triggered by binding of the C1 plasma protein to antibody (e.g., IgM, IgG1 and IgG3) coating the microbial surface.

Question 16

Where is C3 made?

Answer 16

The liver C1 recognizes a microbial structure directly or binds to CRP or antibodies bound to a pathogen

Question 17

iC3

Answer 17

The product formed when the thioester bond of C3 is hydrolyzed by water. This hydrolysis reaction is the first step in the alternative pathway

Question 18

Which factors accelerate iC3 production?

Answer 18

The environment near the surface of some pathogens (mostly bacteria) accelerates the rate of C3 hydrolysis of iC3. A high concentration of C3 in the blood also facilitates iC3 production

Question 19

Factor B

Answer 19

Plasma complement protein that is part of the alternative pathway. It binds to iC3 or C3b and is cleaved to form part of the alternative C3 convertases (iC3Bb and C3bBb)

Question 20

Factor D

Answer 20

A protease that cleaves factor B to Bb and Ba in the alternative complement pathway.

Question 21

Cleavage of Factor B

Answer 21

Factor D cleaves Factor B into smaller fragment Ba and larger fragment Bb. Ba is released, while Bb has protease activity and remains bound to iC3

Question 22

iC3Bb complex

Answer 22

A protease that specifically cleaves C3 into C3a and C3b fragments, which exposes the thioester bond in C3b. When C3 is activated in large quantities, some C3b fragments are covalently attached to the amino and hydroxyl groups on the pathogen’s outer surface

Question 23

C3 convertases

Answer 23

Any of the proteolytic enzymes that are formed during complement activation and cleave C3 to C3b and C3a, which allows C3b to covalently bond to antigens

Question 24

C3bBb

Answer 24

The C3 convertase of the alternative pathway. The convertase is situated at the pathogen’s surface, resulting in more C3b fragments becoming fixed to the pathogen. It is made of C3b bound to Bb. It cleaves C3 into C3a and C3b

Question 25

Complement control proteins

Answer 25

Any of a diverse group of proteins that inhibit complement activation at different stages and by different mechanisms. There are 2 broad categories. One category is made of plasma proteins that interact with C3b attached to human and microbial cell surfaces. The other category contains membrane proteins on human cells that prevent complement fixation at the cell surface

Question 26

Properdin (factor P)

Answer 26

A plasma protein that increases complement activation by binding to C3bBb on microbial surfaces, therefore preventing its degradation by proteases. Part of the alternative pathway

Question 27

Factor I

Answer 27

A plasma serine protease. It regulates complement action by cleaving C3b and C4b into inactive forms. Fragment iC3b can’t assemble a C3 convertase, so the combined effect of factors H and I is to decrease the amount of C3 convertase on the pathogen’s surface

Question 28

Factor H

Answer 28

A complement regulatory plasma protein that counters the effect of properdin. It is a plasma protein that binds to C3b and facilitates its further cleavage to iC3b by factor I.

Question 29

Decay-accelerating factor (DAF)

Answer 29

A cell-surface protein that prevents complement activation on human cells. DAF binds to C3 convertases of both the alternative and classical pathways of complement activation. By displacing Bb and C2a, it prevents their action

Question 30

Membrane cofactor protein (MCP)

Answer 30

A membrane-associated complement regulatory protein on human cells that promotes the inactivation of C3b and C4b by factor I

Question 31

Complement control protein (CCP) modules

Answer 31

A family of structurally similar protein modules found in many of the proteins that regulate complement activity

Question 32

Regulators of complement activation

Answer 32

A group of proteins that regulate the activity of complement and contain one or more copies of a particular structural motif of around 60 amino acid residues called the CCP motif

Question 33

Kupffer cells

Answer 33

The macrophages found in the liver

Question 34

Macrophages

Answer 34

The first cells of the immune system a pathogen encounters when it invades a tissue are the resident macrophages. Macrophages are prevalent in the connective tissues, linings of the GI and respiratory tracts, liver, and alveoli. Macrophages are long-lived phagocytic cells that contribute to both innate and adaptive immunity. They can phagocytose microorganisms in a nonspecific fashion, but their efficiency in improved by macrophage cell-surface receptors

Question 35

Complement receptor 1 (CR1)

Answer 35

A macrophage receptor that binds to C3b fragments that were deposited on a pathogen’s surface during the activation of the alternative pathway. When C3b fragments on a pathogen interact with CR1, it facilitates the engulfment and degradation of the pathogen. CR1 also protects the surface of cells on which it is expressed. It disrupts the C3 convertase by making C3b susceptible to cleavage by factor 1. Some of a macrophage’s CRI molecules have this protective role during phagocytosis

Question 36

Opsonization

Answer 36

The coating of the surface of a pathogen or other particle with any molecule that makes it more readily ingested by phagocytes. Phagocytic cells carry receptors for antibody and complement, making opsonization of extracellular bacteria essential for phagocytosis by neutrophils and macrophages

Question 37

Complement receptor 3 (CR3)

Answer 37

A receptor found on macrophages and other cells that binds the iC3b fragment of complement if it is present on a pathogen surface. This aids in the phagocytosis of the pathogen. It is an integrin (cell-surface glycoprotein)

Question 38

Complement receptor 4 (CR4)

Answer 38

A receptor present on macrophages and other cells that binds the iC3b fragment of complement if it’s present on a pathogen surface. This aids in the phagocytosis of the pathogen (cell-surface glycoprotein)

Question 39

Membrane attack complex (MAC)

Answer 39

The complex of terminal complement components (C5, C6, C7, C8, and C9) that forms a pore in the membrane of the target cell. It damages the membrane and leads to cell lysis and death. The pore can be formed in both bacterial and eukaryotic pathogens

Question 40

C5

Answer 40

Structurally similar to C3, but lacks a thioester bond and has a different function. It is activated by the alternative C5 convertase

Question 41

Alternative C5 convertase

Answer 41

Consists of two C3b fragments and one Bb fragment, and is therefore called C3b2Bb. It activates and cleaves C5 into a smaller C5a and larger C5b fragment

Question 42

C5b

Answer 42

Its function is to initiate MAC formation. C6 and C7 bind to C5b in succession. These interactions expose a hydrophobic region of C7, which then inserts into the lipid bilayer. Additionally, the same thing occurs in C8, which is also inserted into the lipid bilayer. These events initiate polymerization of C9 and MAC formation

Question 43

S protein

Answer 43

The soluble regulatory protein of complement that prevents the soluble complex of C5b with C6 and C7 from associating with cell membranes

Question 44

Clusterin

Answer 44

A complement-regulatory protein that prevents the soluble complex of C5b with C6 and C7 from associating with cell membranes

Question 45

Factor J

Answer 45

A soluble complement control protein that prevents the complex of C5b with C6 and C7 from associating with host-cell membranes and initiating an attack on them

Question 46

Homologous restriction factor (HRF)

Answer 46

A cell-surface complement control protein that prevents the recruitment of C9 by the complex of C5b, C6, C7, and C8 and formation of the membrane-attack complex

Question 47

Protectin (CD59)

Answer 47

A protein on the surface of human cells that prevents assembly of the complement membrane-attack complex on cell surface. It protects human cells from complement-mediated lysis

Question 48

Paroxysmal nocturnal hemoglobinuria (PNH)

Answer 48

DAF, HRF, and CD59 attach to the plasma membrane by a glycosylphosphatidylinositol lipid tail. Impaired synthesis of the tail causes PNH. This disease is an immunodeficiency characterized by episodes of complement-mediated lysis of erythrocytes. With no DAF, HRF, or CD59 on their surfaces, erythrocytes aren’t protected from complement. A monoclonal antibody called eculizumab is used to treat this disease. It is specific for C5 and prevents its cleavage and activation by C5 convertases

Question 49

Anaphylatoxins

Answer 49

A general name for complement fragments C3a and C5a, which are produced during complement activation. They induce inflammation, recruiting fluid and inflammatory cells to sites of antigen deposition. In some circumstances, they can induce anaphylactic reactions- an acute and powerful inflammatory reaction. C5a is more potent and stable than C3a

Question 50

Effects of anaphylatoxins

Answer 50

They induce contraction of smooth muscle and degranulation of mast cells and basophils. These cells release histamine and other substances that increase capillary permeability and changing blood flow. These changes facilitate the exit of plasma proteins and cells from the blood and their passage to sites of infection in the tissues. C5a induces neutrophils and monocytes to adhere strongly to blood vessel walls. It induces phagocytes to migrate toward sites of complement fixation

Question 51

Coagulation system

Answer 51

A collection of enzymes and other proteins in the blood that function to form blood clots. The coagulation system is activated by damage to blood vessels. Pathogens can be immobilized in blood clots so they can’t enter the blood or lymph

Question 52

Kinin system

Answer 52

An enzymatic cascade of plasma proteins that is triggered by tissue damage and helps to facilitate wound healing due to the production of bradykinin. Bradykinin reduces hypertension, dilates blood vessels, and relaxes smooth muscle in the damaged tissue

Question 53

Protease inhibitors

Answer 53

Proteins such as alpha 2 macroglobulin that can bind to proteases and inhibit their enzymatic activity. Many pathogens make or acquire protases that inactivate antimicrobial proteins and degrade human tissues. Human plasma contains protease inhibitors to counteract pathogenic proteases

Question 54

Alpha 2 macroglobulins

Answer 54

A protease inhibitor in plasma that is a component of innate immunity. It inhibits proteases that are produced or acquired by bacteria to aid their invasion

Question 55

Defensins

Answer 55

Any member of a large family of small antimicrobial peptides 35-40 amino acids long that can penetrate microbial membranes and disrupt their integrity. Defensins can also prevent disease by denaturing microbial toxins. They are present at epithelial surfaces and in neutrophil granules. There are 2 classes. Defensins have both hydrophobic and hydrophilic regions, which allows them to penetrate microbial membranes and cause lysis

Question 56

Alpha-defensins

Answer 56

There are 6 types- 4 of them are components of neutrophil granules and are named human neutrophil proteins (HNP) 1-4. They participate in the innate immune response in infected tissues and organs. The other two are human defensins (HD) 5 and 6. They are secreted by the Paneth cells of the intestinal epithelium and defend against infections of the gut mucosa

Question 57

Beta-defensins

Answer 57

More numerous and less studied than alpha-defensins. There are 30 beta-defensin genes

Question 58

Defensin function

Answer 58

When a defensin binds to a microbial toxin, it makes the toxin unfold, which destabilizes its 3D structure. It also makes the toxin susceptible to an attack by human proteases. The toxins made by pathogens can vary in their protein sequence, but defensins can eliminate many different toxins

Question 59

Pentraxins

Answer 59

Pentameric proteins that circulate in the blood and lymph and can bind to the surfaces of a variety of pathogens and target them for destruction, facilitating phagocytosis. C-reactive protein is an example. There are two subfamilies: short pentraxins and long pentraxins. Function as bridging molecules that bind pathogens on one binding site and cell surface receptors of phagocytes to another.

Question 60

Chemoattractant

Answer 60

Agents that cause immune cells to move toward the site of inflammation; chemokines and complement proteins

Question 61

Where is complement made?

Answer 61

Made constitutively by the liver and present in blood, lymph, and extracellular fluids. Makes up around 5% of serum protein

Question 62

4 activities of complement

Answer 62

1. Lysis
2. Opsonization
3. Activation of inflammatory response
4. Clearance of immune complexes

Question 63

Phagocytosis mechanism (5)

Answer 63

1. Bacterium becomes attached to membrane evaginations called pseudopodia
2. Bacterium is ingested, forming a phagosome
3. The phagosome fuses with the lysosome
4. Lysosomal enzymes digest captured material
5. Digestion products are released from the cell

Question 64

Platelets

Answer 64

A major component of blood clots release prostaglandins, hydrolytic enzymes, growth factors, and other mediators that help in antimicrobial defense, wound healing and inflammation

Question 65

Chemical defenses of innate immunity (5)

Answer 65

1. Skin- sebum
2. GI tract- acidity, enzymes (proteases)
3. Respiratory tract- lysozyme is nasal secretions
4. Urogenital tract- acidity in vaginal secretions and spermine and zinc in semen
5. Lysozyme is tears

Question 66

Sebum composition

Answer 66

Fatty acids, lactic acid, lysozyme

Question 67

Lysozyme

Answer 67

Antimicrobial peptide which facilitates the hydrolysis of a β-1-4-glycosidic bond between N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) in bacterial cell walls. It is abundant in secretions (tears, saliva, breast milk, and mucus)

Question 68

Defensin structure

Answer 68

Composed of short segment of α-helix resting against 3 strands of antiparallel β-sheet (green) generating an amphipathic peptide having charged residues

Question 69

Paneth cells

Answer 69

Immune cells in the intestine. The α-defensins HD5 and HD6, also known as cryptdins are made only by paneth cells