Chapter 2- Innate Immunity- The Immediate Response to Infection Flashcards
Innate immunity
The host defense mechanisms that act from the start of infection. They do not adapt to a specific pathogen or generate immunological memory
Commensal microorganisms
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
Microbiota
A population of commensal microorganisms
Extracellular infections
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
Intracellular infections
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.
Complement/complement system
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/
Zymogens
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
Complement activation
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
Complement component 3 (C3)
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
Complement fixation
The covalent attachment of C3b or C4b to pathogen surfaces. This is important because it facilitates phagocytosis of the pathogen
C3 cleavage
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.
3 pathways of complement activation
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
Alternative pathway of complement activation
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
Lectin pathway of complement activation
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
Classical pathway of complement activation
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.
Where is C3 made?
The liver C1 recognizes a microbial structure directly or binds to CRP or antibodies bound to a pathogen
iC3
The product formed when the thioester bond of C3 is hydrolyzed by water. This hydrolysis reaction is the first step in the alternative pathway
Which factors accelerate iC3 production?
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
Factor B
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)
Factor D
A protease that cleaves factor B to Bb and Ba in the alternative complement pathway.
Cleavage of Factor B
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
iC3Bb complex
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
C3 convertases
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
C3bBb
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
Complement control proteins
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
Properdin (factor P)
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
Factor I
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
Factor H
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.
Decay-accelerating factor (DAF)
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
Membrane cofactor protein (MCP)
A membrane-associated complement regulatory protein on human cells that promotes the inactivation of C3b and C4b by factor I
Complement control protein (CCP) modules
A family of structurally similar protein modules found in many of the proteins that regulate complement activity
Regulators of complement activation
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
Kupffer cells
The macrophages found in the liver
Macrophages
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
Complement receptor 1 (CR1)
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
Opsonization
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
Complement receptor 3 (CR3)
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)
Complement receptor 4 (CR4)
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)
Membrane attack complex (MAC)
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
C5
Structurally similar to C3, but lacks a thioester bond and has a different function. It is activated by the alternative C5 convertase
Alternative C5 convertase
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
C5b
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
S protein
The soluble regulatory protein of complement that prevents the soluble complex of C5b with C6 and C7 from associating with cell membranes
Clusterin
A complement-regulatory protein that prevents the soluble complex of C5b with C6 and C7 from associating with cell membranes
Factor J
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
Homologous restriction factor (HRF)
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
Protectin (CD59)
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
Paroxysmal nocturnal hemoglobinuria (PNH)
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
Anaphylatoxins
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
Effects of anaphylatoxins
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
Coagulation system
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
Kinin system
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
Protease inhibitors
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
Alpha 2 macroglobulins
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
Defensins
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
Alpha-defensins
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
Beta-defensins
More numerous and less studied than alpha-defensins. There are 30 beta-defensin genes
Defensin function
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
Pentraxins
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.
Chemoattractant
Agents that cause immune cells to move toward the site of inflammation; chemokines and complement proteins
Where is complement made?
Made constitutively by the liver and present in blood, lymph, and extracellular fluids. Makes up around 5% of serum protein
4 activities of complement
- Lysis
- Opsonization
- Activation of inflammatory response
- Clearance of immune complexes
Phagocytosis mechanism (5)
- Bacterium becomes attached to membrane evaginations called pseudopodia
- Bacterium is ingested, forming a phagosome
- The phagosome fuses with the lysosome
- Lysosomal enzymes digest captured material
- Digestion products are released from the cell
Platelets
A major component of blood clots release prostaglandins, hydrolytic enzymes, growth factors, and other mediators that help in antimicrobial defense, wound healing and inflammation
Chemical defenses of innate immunity (5)
- Skin- sebum
- GI tract- acidity, enzymes (proteases)
- Respiratory tract- lysozyme is nasal secretions
- Urogenital tract- acidity in vaginal secretions and spermine and zinc in semen
- Lysozyme is tears
Sebum composition
Fatty acids, lactic acid, lysozyme
Lysozyme
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)
Defensin structure
Composed of short segment of α-helix resting against 3 strands of antiparallel β-sheet (green) generating an amphipathic peptide having charged residues
Paneth cells
Immune cells in the intestine. The α-defensins HD5 and HD6, also known as cryptdins are made only by paneth cells
