Chapter 2 Immunology

Name 2 immediate defensive mechanisms of innate immune system?

1. Antimicrobial enzymes such as lysozyme begin to digest bacterial cell walls. 2. ANTIMICROBIAL PEPTIDES such as DEFENSINS breakdown bacterial cell membranes directly. 3. The COMPLEMENT SYSTEM that targets pathogens both for lysis and for phagocytosis by cells of the innate immune system such as MACROPHAGES Remember that these soluble molecules are present in extracellular fluid, blood, and epithelial secretions . They can either kill the pathogen or weaken its effect.

Two types of antimicrobial agents

1. Antimicrobial proteins: Such as Lysozyme and Secretory Phospholipase A 2. Antimicrobial Peptides: Such as Defensins, Cathelicidins and Histatins

What are the 2 ways the ALTERNATE PATHWAY can be activated?

1. By the action of the lectin or classical pathway. C3b generated by either of these pathways and covalently linked to a microbial surface can bind factor B. This alters the conformation of factor B, enabling a plasma enzyme called factor D to cleave it into Ba and Bb. Bb remains stably associated with C3b, forming the C3bBb C3 convertase. 2. The second way of activating the alternative pathway involves the spontaneous hydrolysis of the thioester bond in C3 to form C3(H2O). This C3(H2O) can bind factor B, which is then cleaved by factor D, producing a short-lived fluid-phase C3 convertase, C3(H2O)Bb. Although formed in only small amounts by C3 tickover, fluid-phase C3(H2O)Bb can cleave many molecules of C3 to C3a and C3b. Much of this C3b is inactivated by hydrolysis, but some attaches to the surfaces of any microbes present. C3b formed in this way is no different from C3b produced by the lectin or classical pathways and binds factor B, leading to the formation of C3 convertase and a stepping up of C3b production.

2 ways COMMENSAL BACTERIA help keep pathogens at bay?

1. COMMENSAL BACTERIA can make antimicrobial substances such as lactic acid and Antimicrobial peptides. 2. Commensal microorganisms also induce responses that help to strengthen the barrier functions of epithelia by stimulating the epithelial cells to produce antimicrobial peptides.

What are the 3 pathways of COMPLEMENT ACTIVATION?

1. Classical pathway of complement activation. This pathway is antibody triggered. 2. ALTERNATIVE PATHWAY of complement activation, which can be activated by the presence of the pathogen alone. 3. LECTIN PATHWAY of the complement activation, which is activated by lectin-type proteins that recognize and bind to carbohydrates on pathogen surfaces.

What are the different ways C1 binds to pathogens?

1. Clq component binds to antibodies that have bound to pathogens 2. Clq can also bind directly to the surface components of some bacteria pathogens. 3.By binding to C-reactive protein, an acute-phase protein in human plasma that binds to phosphocholine residues in bacterial surface molecules.

What are the 2 ways CONVERTASE formation can be prevented?

1. Convertase formation can be prevented by cleaving C3b to an inactive derivative, iC3b. 2. By having , a membrane-attached protein known as decay-accelerating factor (DAF or CD55) competes with factor B for binding to C3b on the cell surface and can displace Bb from a con- vertase that has already formed.

What are 3 important classes of antimicrobial peptides.

1. Defensins 2. Cathelicidins 3. Histatins

What is the difference between GRAM-POSITIVE bacteria and GRAM-NEGATIVE bacteria

1. In Gram-positive bacteria (upper left panel), peptidoglycan forms the outer layer in which other molecules are embedded such as teichoic acid and the lipoteichoic acids that link the peptidoglycan layer to the bacterial cell membrane itself. 2.. In Gram-negative bacteria (upper right panel), a thin inner wall of peptidoglycan is covered by an outer lipid membrane that contains proteins and lipopolysaccharide (LPS). Lipopolysaccharide is composed of a lipid, lipid A (turquoise circles), to which is attached a polysaccharide core (small turquoise hexagons).

2 places where are the inactive Cathelicidins propeptides stored

1. In neutrophils, the inactive cathelicidin propeptides are stored in another type of specialized cytoplasmic granule called SECONDARY GRANULES. 2.In keratinocytes, cathelicidins, like β-defensins, are stored and processed in the lamellar bodies.

What is Lysozyme and how does it work?

1. Lysozyme is an enzyme that attacks the chemical features specific to bacterial cell wall. 2. Specifically, Lysozyme is a glycosidase that breaks a specific chemical bond in the peptidoglycan component of the bacterial cell wall.

Name 2 antibacterial enzymes that attack the chemical features specific to bacterial cell walls?

1. Lysozymes 2. Secretory Phospholipase A2 They are secreted in tears and saliva and by phagocytes.

What are the 4 PATHOGEN RECOGNITION RECEPTORS (PRRs) that can trigger the LECTIN PATHWAY?

1. MANNOSE-BINDING LECTIN (MBL) (liver) 2. L-FICOLIN (liver) 3. M-FICOLIN (lungs/blood cells) 4. H-FICOLIN (liver)

what are the 3 Surface defenses of the immune system

1. Mechanical barriers: such as Epithelial Cell Layers and Mucus 2. Clearing Mechanisms: Such as cila function, coughing, tears, sneezing, peristalsis. ( wave like muscle contractions tha moves stuff) 3. Microbiome: Normal flora that competes with pathogens for nutrients and binding sites

Name 2 protective functions of mucus?

1. Microorganisms coated in mucus may be prevented from adhering to the epithelium. 2. In the respiratory tract, microorganisms can be expelled in the outward flow of mucus driven by the beating of cilia on the mucosal epithelium 3.

The mammalian immune response to invading organisms proceeds in three phases. what are they?

1. The first begins with the immediate innate defenses. The first phase of host defense consists of those mechanisms that are present and ready to resist an invader at any time. 2. Then with the induced innate defensins 3. Finally with the adaptive immunity.

What does Activated MASP-2 do to C4 and C2?

1. When MASP-2 cleaves C4, it releases C4a, allowing a conformational change in C4b that exposes the reactive thioester. 2. Then, C4b bonds covalently via this thioester to the microbial surface nearby, where it then binds one molecule of C2. 3. C2 is then cleaved by MASP-2, producing C2a, that remains bound to C4b to form C4b2a, which is the C3 convertase of the lectin pathway. 4. C4b2a now cleaves many molecules of C3 into C3a and C3b. The C3b fragments bond covalently to the nearby pathogen surface, and the released C3a initiates a local inflammatory response. The complement-activation pathway initiated by ficolins proceeds like the MBL lectin pathway.

What are the 2 types of antimicrobial agents?

1. antimicrobial enzymes 2. antimicrobial peptides

What are the 3 subtypes of defensins

1. defensin α- 2. defensin β- 3. defensin θ- They are distinguished on the basis of amino acid sequence, and each subtype has members with distinct activities. Some being active against Gram-positive bacteria and some against Gram-negative bacteria, while others are specific for fungal pathogens.

What happens when MANNOSE-BINDING LECTIN (MBL) binds to pathogens?

A conformational change occurs in MASP-1 that enables it to cleave and activate a MASP-2 molecule in the same MBL complex. Then Activated MASP-2 can cleave the complement components C4 and C2

What are PHOSPHOLIPASE A2 and what do they do?

A highly basic enzyme that can enter the bacterial cell wall to access and hydrolyze phospholipids in the cell membrane, killing the bacteria.

what is a phagosome?

A membrane-bound vesicle in a phagocyte containing the phagocytized material.

What must happen for pathogen to establish infection?

A microorganism must first invade the body by binding to or crossing an epithelium.

Disease occurs when...

A microorganism succeeds in evading or overwhelming innate host defenses to establish a local site of infection, and then replicates there to allow its further transmission within our bodies.

Why does the adaptive immunity occur after the innate immune response?

Adaptive immunity occurs late, because the rare B cells and T cells specific for the invading pathogen must first undergo clonal expansion before they differentiate into effector cells that migrate to the site of infection and clear the infection.

How are antimicrobial peptides like defensin made?

All the antimicrobial peptides, including the defensins, are generated by proteolytic processing from inactive propeptides

Define PROTEASE?

An enzyme that breaks down proteins and peptides.

what is a PROTEASE?

An enzyme that breaks down proteins and peptides.

How does C1 allow the CLASSICAL PATHWAY to function in both the innate immunity and adaptive immunity?

Because C1 can interact with pathogens and antibodies. This is what allows the classical pathway to function in both the innate immunity and adaptive immunity.

Why does RegIIIα s preferentially kill Gram-positive bacteria?

Because the Lipopolysaccharides (LPS) of Gram-negative bacteria inhibits the pore-forming ability of RegIIIα, further enforcing the selectivity of RegIII proteins for Gram-positive bacteria.

What is C1 composed of?

C1 complex is composed of a large subunit (C1q), which acts as the pathogen sensor, and (C1r and C1s), which are initially in their inactive form C1r and C1s are closely related to MASP-2

When does C2 become susceptible to cleavage by C1s?

C2 becomes susceptible to cleavage by C1s only when it is bound by C4b.

what do C3a and C5a do when they are cleaved and released?

C3a and C5a act as chemoattractants that recruit immune-system cells to the site of infection and cause inflammation (bottom left).

What does C3b bind to?

C3b binds covalently to adjacent molecules on the pathogen surface. Otherwise it is inactivated by hydrolysis.

What happens once C3b binds to pathogen?

C3b bound to a pathogen acts as an opsonin, enabling phagocytes that express receptors for C3b to ingest the complement-coated microbe more easily (bottom center).

What happens when C3b when it binds to C3 CONVERTASE?

C3b can also bind to the C3 convertases produced by the classical and lectin pathways and form another multisubunit enzyme, the C5 convertase.

once C3 CONVERTASE cleaves C3 , what happens to C3b and C3a?

C3b is left bound to pathogen , while C3a is released and does not bind to pathogen. C3b that is not covalently coupled to a surface is rapidly inactivated by hydrolysis.

What does C5 CONVERTASE do?

C5 convertase cleaves C5, liberating the highly inflammatory peptide C5a and generating C5b. C5b initiates the 'late' events of complement activation, in which additional complement proteins interact with C5b to form a membrane- attack complex (MAC) on the pathogen surface, creating a pore in the cell membrane that leads to cell lysis (see Fig. 2.15, bottom right).

How is C5 CONVERTASE formed in both the CLASSICAL AND LECTIN PATHWAYS?

C5 convertase is formed by the binding of C3b to C4b2a to make C4b2a3b.

How are inactive Cathelicidins made active?

Cathelicidin is activated by proteolytic cleavage only when primary and secondary granules are induced to fuse with phagosomes, where it is cleaved by neutrophil elastase that has been stored in primary granules of Neutrophils.

Where are Cathelicidins made and why?

Cathelicidins are made constitutively by neutrophils and macrophages. Cathelicidins are made in response to infection by keratinocytes in the skin and epithelial cells in the lungs and intestine. They are made as inactive pro- peptides composed of two linked domains and are processed before secretion

How are β-Defensins (and some α-defensins) produced lungs?

Center panel: Type II pneumocytes in the lung alveoli (not shown) also produce and secrete antimicrobial defensins. In the lung, the airways are lined by ciliated epithelium. Beating of the cilia moves a continuous stream of mucus (green) secreted by goblet cells outward, trapping and ejecting potential pathogens.

What happens when the C3 COMPLEMENT PROTEIN is cleaved?

Cleavage of C3 produces a small protein fragment called C3a and the remaining larger fragment, C3b. The larger fragment for other factors is designated by the suffix b, with one exception. For C2, the larger fragment was named C2a by its discoverers,

What is the COMPLEMENT SYSTEM/COMPLEMENT?

Complement is a collection of soluble proteins present in blood and other body fluids. COMPLEMENT originally evolved as part of the innate immune system and that it still provides protection early in infection, in the absence of antibodies, through more ancient pathways of complement activation.

What molecules do H-FICOLIN recognize on pathogens?

D-FUCOSE and GALAZTOSE, and has only been linked to activity against the Gram-positive bacterium Aerococcus viridans.

What is Defensin?

Defensin is a antimicrobial peptide that breakdowns cell walls of bacteria directly.

What are defensins and how do they function?

Defensins act within minutes to disrupt the cell membranes of bacteria and fungi, as well as the membrane envelopes of some viruses. The mechanism is thought to involve insertion of the hydrophobic region into the membrane bi-layer and the formation of a pore that makes the membrane leaky

What are Defensins?

Defensins are short cationic peptides of around 30-40 amino acids that usually have three disulfide bonds stabilizing a common amphipathic structure—a positively charged region separated from a hydrophobic region.

Since the cellular responses of the innate immunity act over several days, what happens to the adaptive immune response during this time?

During this time, the adaptive immune response may also begin if antigens derived from the pathogen are delivered to local lymphoid tissues by dendritic cells.

How are epithelia protected from pathogens?

Epithelia are also protected by many kinds of chemical defenses, including antimicrobial enzymes and peptides.

What are the two chemical defenses that are protected by the Epithelia?

Epithelia are protected by many kinds of chemical defenses, including: 1. antimicrobial enzymes 2. antimicrobial peptides.

What is the EPITHELIA comprised of?

Epithelia comprise the skin and the linings of the body's tubular structures— the respiratory, urogenital, and gastrointestinal tracts.

What does Epithelia consist of?

Epithelia consists of the skin and the linings of the body's tubular structures Ex. The respiratory, urogenital, and gastrointestinal tracts.

Where do antimicrobial peptides come from?

Epithelial cells secrete these antimicrobial peptides into the fluids bathing the mucosal surface, whereas phagocytes secrete them in tissues.

How are Antimicrobial Peptides secreted?

Epithelial cells secrete these peptides into the fluids bathing the mucosal surface, whereas phagocytes secrete them in tissues.

What does FACTOR H bind to?

Factor H binds preferentially to C3b bound to vertebrate cells because it has an affinity for the sialic acid residues present on their cell surfaces (see Fig. 2.18). Thus, the amplification loop of the alternative pathway is allowed to proceed on the surface of a pathogen or on damaged host cells, but not on normal host cells or on tissues that express these negative regulatory proteins

What is FACTOR H?

Factor H is another complement-regulatory protein in plasma that binds C3b. Like CR1, it is able to compete with factor B to displace Bb from the convertase In addition, it acts as a cofactor for factor I.

Are there more MANNOSE-BINDING LECTIN (MBL) or FICOLIN in plasma?

Ficolins are more abundant than MBL in plasma and so may be more important in practice

Define Glycosidase.

Glycosidase is an enzyme that catalyzes the hydrolysis of a bond joining a sugar of a glycoside to an alcohol or another sugar unit

where are antimicrobial peptides called HISTATINS made? (3 places)

Histatins are constitutively produced in the oral cavity by the parotid, sublingual, and submandibular glands.

What is IgM?

IgM is the class of antibody most efficient at binding C1q, making natural antibodies an effective means of activating complement on microbial surfaces immediately after infection and leading to the clearance of bacteria before they become dangerous

In the absence of infection, what does the COMPLEMENT SYSTEM DO?

In the absence of infection, these proteins circulate in an inactive form. In the presence of pathogens or antibodies bound to pathogens, the complement system becomes 'activated.'

How is the ALTERNATIVE PATHWAY of the COMPLEMENT SYSTEM initiated?

In the alternative pathway (top right), soluble C3 undergoes spontaneous hydrolysis in the fluid phase, generating C3(H2O), which is augmented by the action of factors B, D, and P (properdin).

How is the COMPLEMENT SYSTEM activated?

In the complement system, activation by breaking down proteins into amino acids by enzymes is essential, with many of the complement proteins being broken down by enzymes that successively cleave and activate one another.

How are α-defensins (cryptdins) and the antimicrobial lectin RegIII produced in the intestines(gut)?

In the intestine, Paneth cells (specialized cells deep in the epithelial crypts) produce several kinds of antimicrobial proteins: α-defensins (cryptdins) and the antimicrobial lectin RegIII.

What is Commensal Bacteria?

Is nonpathogenic bacteria that helps keep pathogens at bay.

briefly describe the COMPLEMENT SYSTEM?

It directly kills some microorganisms and interacts with others to promote their removal by phagocytic cells

What is the alternative pathway C3 convertase is composed of?

It is composed of C3b itself bound to Bb, which is a cleavage fragment of the plasma protein factor B. This C3 convertase, designated C3bBb, has a special place in complement activation because, by producing C3b, it can generate more of itself.

What is the Mucosal Ephithelia

It is the internal epithelia that secretes mucus. Mucus contains many glcoprotiens called Mucins

What pathogen sensor does the CLASSICAL PATHWAY use ?

It uses a pathogen sensor known as the C1 complex, or C1.

What is a key feature of the ALTERNATIVE PATHWAY?

Its key feature is its ability to be spontaneously activated. It has a unique C3 convertase, the alternative pathway C3 convertase, that differs from the C4b2a convertase of the lectin or classical pathways

What is Lysozyme?

Lysosyme is an antimicrobial enzyme that digests the cell wall of bacteria.

How do LYSOZYMES digest the cell wall of bacteria.

Lysozyme cleaves β-(1,4) linkages between GlcNAc and MurNAc, creating a defect in the peptidoglycan layer and exposing the underlying cell membrane to other antimicrobial agents. Lysozyme is more effective against Gram-positive bacteria because of the relatively greater accessibility of the peptidoglycan

How does Lysozyme breakdown bacterial cell walls?

Lysozyme selectively cleaves the glycan linkage between N-acetylglucosamine and N-Acetylmuramic acid (two sugars) and is more effective in acting against Gram-positive bacteria, in which the peptidoglycan cell wall is exposed, than against Gram-negative bacteria, which have an outer layer of LPS covering the peptidoglycan layer.

What exactly do lysozymes do?

Lysozyme selectively cleaves the β-(1,4) linkage between these two sugars and is more effective in acting against Gram-positive bacteria, in which the peptidoglycan cell wall is exposed, than against Gram-negative bacteria, which have an outer layer of LPS covering the peptidoglycan layer

What are Lysozymes and what do they do?

Lysozymes are a glycosidase that breaks a specific chemical bond in the peptidoglycan component of the bacterial cell wall.

How does MANNOSE-BINDING LECTIN (MBL) bind to microbial surfaces?

MBL has a low affinity for mannose, fucose, and N-acetylglucosamine (GlcNAc) which are found on the surfaces of some pathogens. So in order MBL to bind to them, these carbs have to be repetitive in order for them to bind. Thus MBL has high total binding strength

What happens to MANNOSE-BINDING LECTIN (MBL) in plasma?

MBL in plasma forms complexes with the MBL-associated serine proteases MASP-1, MASP-2, and MASP-3.

Where is MANNOSE-BINDING LECTIN (MBL) made and where does it reside?

Made in the liver and circulates in the blood in low concentrations. But in the presence of an infection,it's production is increase during acute phase response.

What are PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPs)?

Molecules specifically associated with groups of pathogens that are recognized by cells of the innate immune system

What happens to most microorganisms that succeed in crossing the epithelial surface?

Most of the microorganisms that succeed in crossing an epithelial surface are efficiently removed by innate immune mechanisms that function in the underlying tissues, preventing infection from becoming established. I

Are θ-defensins found in the the human body?

No because, the single human θ-defensin gene has been inactivated by a mutation.

Does COMPLEMENT only influence the innate immune system?

No, besides acting in innate immunity, complement also influences adaptive immunity.

Are C1q, C1r, andC1s the cleavaged products of C1?

No, these are not cleavage products of C1 but are distinct proteins that together comprise C1

When does the adaptive immune system start to respond to pathogens?

Only if an infectious organism breaches these first two lines of defense will mechanisms be engaged to induce an adaptive immune response—the third phase of the response to a pathogen.

what is OPSONIZATION?

Opsonization is a term that refers to an immune process where particles such as bacteria are targeted for destruction by an immune cell known as a phagocyte . The process of opsonization is a means of identifying the invading particle to the phagocyte.

How does COMPLEMENT influence the adaptive immune system?

Opsonization of pathogens by complement facilitates their uptake by phagocytic antigen-presenting cells that express complement receptors; this enhances the presentation of pathogen antigens to T cells. B cells express receptors for complement proteins that enhance their responses to complement-coated antigens,

What are PANETH CELLS?

PANETH CELLS are specialized epithelial cells in the base of the crypts in the small intestine that secrete many antimicrobial proteins into the gut. Specifically LYSOZYMES AND PHOSPHOLIPASE A2.

What happens when COMPLEMENT PROTEINS interact with each other?

Particular complement proteins interact with each other to form several different pathways of complement activation, all of which have the final outcome of killing the pathogen, either directly or by facilitating its phagocytosis, and inducing inflammatory responses that help to fight infection.

Is PROPERDIN a positive or negative regulatory protein?

Positive regulatory protein.

Where are PROPERDINS made?

Properdin is made by neutrophils and stored in secondary granules. It is released when neutrophils are activated by the presence of pathogens.

what is proteolytic processing

Proteolytic processing is a major form of post translational modification which occurs when a protease cleaves one or more bonds in a target protein to modify its activity. This processing may lead to activation, inhibition or destruction of the protein's activity.

what is RegIIIα?

RegIIIα kills bacteria directly by forming a hexameric pore in the bacterial membrane (Fig. 2.12). RegIII family proteins preferentially kill Gram-positive bacteria, in which the peptidoglycan is exposed on the outer surface.

Define constitutively

Relating to the synthesis of a protein or an enzyme at a constant rate regardless of physiological demand or the concentration of a substrate.

What protects healthy host cells from the injurious effects of inappropriate complement activation on their surfaces?

Several negative regulatory proteins, present in plasma and in host-cell mem- branes, called Complement regulatory proteins.

How do Defensins disrupt cell membranes of microbes?

Since defensins have charged and hydrophobic regions (separated),this allows the defensins to interact with the charged surface of the cell membrane and become inserted in the lipid bilayer. Although the details are still unclear, a transition in the arrangement of the defensins in the membrane leads to the formation of pores and a loss of membrane integrity.

The lipoteichoic acids of Gram-positive bacterial cell walls and the lipopolysaccharide of the outer membrane of Gram-negative bacteria are not present on animal cells. why is this important?

Since they are not found in animal cells, it is one way that the innate immune system is able to recognize bacteria.

Where are L-FICOLIN and H-FICOLIN made and where do they reside once made?

Synthesized by the liver and circulate in the blood.

What happens when C3 CONVERTASE is generated?

The C3 convertase is bound covalently to the pathogen sur- face, where it cleaves C3 to generate large amounts of C3b, the main effector molecule of the complement system; and C3a, a small peptide that binds to specific receptors and helps induce inflammation.

How is C5 CONVERTASE formed by the ALTERNATIVE PATHWAY?

The C5 convertase of the alternative pathway is formed by the binding of C3b to the C3bBb convertase to form C3b Bb.

Describe the Complement System?

The Complement System directly kills some microorganisms and interacts with others to promote their removal by phagocytic cells.

What is the Complement System?

The Complement System is a system of plasma proteins that targets pathogens both for lysis and for phagocytosis by cells of the innate immune system such as macrophages.

Besides producing LYSOZYMES AND PHOSPHOLIPASE A2, what else do the PANETH CELLS of the intestines produce?

The PANETH CELLS of the gut constitutively produce α-defensins, called cryptdins, which are processed by proteases such as trypsin in humans, before being secreted into the gut lumen.

Describe what PRIMARY GRANULES are?

The PRIMARY GRANULES of neutrophils are specialized membrane enclosed vesicles, rather similar to lysosomes, that contain a number of other antimicrobial agents as well as defensins

How do anatomical barriers help against infection?

The anatomic barriers are fixed defenses against infection and consist of the epithelia that line the internal and external surfaces of the body along with the phagocytes residing beneath all epithelial surfaces. These phagocytes act directly by engulfing and digesting invading microorganisms

Describe the anatomic barriers found in the innate immune system?

The anatomic barriers are fixed defenses against infection and consist of: 1. The epithelia that line the internal and external surfaces of the body, along with the phagocytes residing beneath all epithelial surfaces.

Define proteolysis

The breakdown of proteins or peptides into amino acids by the action of enzymes.

How is the CLASSICAL PATHWAY of the COMPLEMENT SYSTEM initiated

The classical pathway (top center) is triggered by binding of C1 either to the pathogen surface or to antibody bound to the pathogen.

How are the cleavage products of the ALTERNATIVE PATHWAY designated?

The cleavage products of the ALTERNATIVE PATHWAY are also designated by the addition of lowercase a and b. Thus, the large fragment of B is called Bb and the small fragment Ba.

How are COMPLEMENT PATHWAYS triggered?

The complement pathways are triggered by proteins that act as pattern recognition receptors to detect the presence of pathogens. This detection activates an initial zymogen, triggering a cascade of proteolysis in which complement zymogens are activated sequentially, each becoming an active enzymes that cleaves and activates many molecules of the next zymogen in the pathway, amplifying the signal as the cascade proceeds.

What is COMPLEMENT SYSTEM composed of and where are they produced?

The complement system is composed of more than 30 different plasma proteins, which are produced mainly by the liver.

How does the COMPLEMENT SYSTEM recognize microbes and then mark them for destruction?

The complement system recognizes features of microbial surfaces and marks them for destruction by coating them with C3b.

When a pathogen breaches the host's epithelial barriers and initial antimicrobial defenses, it next encounters a major component of innate immunity known as...

The complement system, or complement.

The response to an initial infection occurs in three phases. What are they?

The first two phases rely on the recognition of pathogens by germline-encoded receptors of the innate immune system. Where as the third phase, incorporates the adaptive immunity's variable antigen-specific receptors that are produced as a result of gene segment rearrangements.

How are the glycan of a yeast surface protein different than that the glycan of a vertebrate cell?

The glycans of yeast surface proteins commonly terminate in mannose residues rather than the sialic acid residues (N-acetylneuraminic acid) that terminate the glycans of vertebrate cells These difference are how the LECTIN PATHWAYS recognize these pathogens.

What happens if the immediate defense of the innate immune system fail?

The innate immune cells become activated by pattern recognition receptors (PRRs) that detect molecules called pathogen-associated molecular patterns (PAMPs) (see Section 1-5) that are typical of microbes. The activated innate cells can engage various effector mechanisms to eliminate the infection.

how is the innate immune system able to detect infections and distinguish between pathogens and host tissues?

The innate immune system uses a limited number of secreted proteins and cell-associated receptors to detect infections and to distinguish between pathogens and host tissues.

What is the MUCOSAL EPITHELIA?

The internal epithelia are known as mucosal epithelia because they secrete a viscous fluid called mucus, which contains many glycoproteins called mucins.

What is the key feature of C3b?

The key feature of C3b is its ability to form a covalent bond with microbial surfaces, which allows the innate recognition of microbes to be translated into effector responses.

How is the LECTIN PATHWAY of the COMPLEMENT SYSTEM initiated?

The lectin pathway is initiated by soluble carbohydrate binding proteins -mannose-binding lectin (MBL) and the ficolins—that bind to particular carbohydrate structures on microbial surfaces. Specific proteases, called MBL-associated serine proteases (MASPs), that associate with these recognition proteins then trigger the cleavage of complement proteins and activation of the pathway

What is the main effect of COMPLEMENT activation?

The main effect of complement activation is to deposit large quantities of C3b on the surface of the infecting pathogen, where the C3b forms a covalently bonded coat that can signal the ultimate destruction of the pathogen by phagocytes

What happens after C3b coats pathogens?

The next step in the complement cascade is the generation of the C5 convertases.

How are proteins of the ALTERNATIVE PATHWAY designated?

The proteins of the alternative pathway are designated by different capital letters, for example, factor B and factor D.

How does C1 activate the CLASSICAL PATHWAY?

The recognition function of C1 resides in the six globular heads of C1q. When two or more of these heads interact with a ligand, itcauses a conformational change in the C1r:C1s complex, which leads to the activation of C1r. Then activated Clr cleaves Cls to activate it. The activated C1s acts on the next two components of the classical pathway, C4 and C2. Specifically, C1s cleaves C4 to produce C4b, which binds covalently to the pathogen surface. Then C4b binds one molecule of C2, which is cleaved by C1s to produce C2a. This produces the active C3 convertase (C4b2a), which is the C3 convertase of both the lectin and the classical pathways.

The convertase of the lectin and classical pathways, C4b2a, and the convertase of the alternative pathway, C3bBb, initiate what?

The same subsequent events they cleave C3 to C3b and C3a.

How is the spread of a pathogen initially countered?

The spread of a pathogen is often initially countered by an inflammatory response that recruits more effector cells and molecules of the innate immune system out of the blood and into the tissues, while inducing clotting in small blood vessels further downstream so that the microbe cannot spread through the circulation

How do Antimicrobial Peptides work?

Their Cationic regions ( positively charged area) binds to negatively charged pathogen membrane.Once they are in membrane they form pores within membrane, which in turn allows for an opening in the cell wall making it leak. That in turn kills pathogens. The mechanism is thought to involve insertion of the hydrophobic region into the membrane bi-layer and the formation of a pore that makes the membrane leaky.

What make the innate receptors of the innate immune system unique?

These are called innate receptors because they are inborn; they are encoded by genes directly inherited from an individual's parents, and do not need to be generated by the gene rearrangements used to assemble antigen receptors of lymphocytes .

How are the LECTIN AND CLASSICAL PATHWAYS of COMPLEMENT activated?

These pathways are initiated by proteins that bind to pathogen surfaces It is important that activating events are confined to this same site, so that C3 activation also occurs on the surface of the pathogen and not in the plasma or on host-cell surfaces. This is achieved principally by the covalent binding of C4b to the pathogen surface.

What do HISTATINS do?

These short, histidine-rich, cationic peptides are active against pathogenic fungi. More recently histatins were found to promote the rapid wound healing that is typical in the oral cavity,

Besides providing a physical barrier to infection, what else does our surface epithelia do?

They also produce a wide variety of chemical substances that are microbicidal or that inhibit microbial growth. EX: the acid pH of the stomach and the digestive enzymes, bile salts, fatty acids, and lysolipids present in the upper gastrointestinal tract create a substantial chemical barrier to infection

How are Proteins that belong to the classical pathway designated?

They are designated by the letter C followed by a number.

what are Lipopolysaccharides (LPS)?

They are large molecules consisting of a lipid and a polysaccharide composed of O-antigen. They are found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses in animals.

What are COMMENSAL BACTERIA?

They are non-pathogenic bacteria that help keep pathogens at bay. .

How are α-defensins stored once they are made?

They are stored in the PRIMARY GRANULES of Neutrophils.

Are C3 convertases C3bBb and C3(H2O) Bb short lived or long lived?

They are very short-lived.

How are short lived C3 convertases C3bBb and C3(H2O) Bb stabilized?

They are, stabilized by binding the plasma protein properdin (factor P). Which in turn enhances the effectiveness of the alternate pathway.

How do FICOLINS bind to pathogens?

They bind to fucose, and N-acetylglucosamine (GlcNAc) , but don't bind to mannose-containing carbohydrates.

What roles do MANNOSE BINDING LECTIN (MBL) and FICOLIN play when it comes to the LECTIN PATHWAY?

They can recognize some of the pathogen-specific carbohydrates that are unique to some pathogens Such as Mannose and Fucose residues found of pathogen surface.

What happens once inactive Cathelicidins become active Cathelicidins ?

They either remain in the phagosome or are released from the neutrophil by exocytosis.

What do these COMPLEMENT-REGULATORY PROTEINS interact with to protect host cells from being damaged by complement activation on their surfaces?

They interact with C3b and either prevent the convertase from forming or promote its rapid dissociation.

What happens after COMPLEMENT PATHWAYS are triggered?

This results in activation of three distinct effector pathways 1. Inflammation 2. phagocytosis 3. membrane attack that help eliminate the pathogen. In this way, the detection of even a small number of pathogens produces a rapid response that is greatly amplified at each step.

How are e β-defensins and cathelicidins produced in the epidermis of the skin?

Top panel: the epidermis has multiple layers of keratinocytes in different stages of differentiation arising from the basal layer of stem cells. Differentiated keratinocytes in the stratum spinosum produce β-defensins and cathelicidins, which are incorporated into secretory organelles called lamellar bodies (yellow) and secreted into the intercellular space to form a waterproof lipid layer (the stratum corneum) containing antimicrobial activity.

What happens when any of the COMPLEMENT PATHWAYS interacts with a pathogen surface?

When any of the pathways interacts with a pathogen surface, the enzymatic activity of a C3 convertase is generated.

what happens when COMMENSAL MICROORGANISMS are killed by antibiotics treatments?

When commensal microorganisms are killed by antibiotic treatment, pathogens frequently replace them and cause disease

The spread of a pathogen is often initially countered by ...

an inflammatory response that recruits more effector cells and molecules of the innate immune system out of the blood and into the tissues, while inducing clotting in small blood vessels further downstream so that the microbe cannot spread through the circulation

Where are β-defensins stored once they are made?

are packaged into lamellar bodies (see Fig. 2.6), lipid-rich secretory organelles that release their contents into the extracellular space to form a watertight lipid sheet in the epidermis and the pulmonary surfactant layer in the lung.

This C3 convertase, designated C3bBb, has a special place in complement activation because...

by producing C3b, it can generate more of itself. This means that once some C3b has been formed, by whichever pathway, the alternative pathway can act as an amplification loop to increase C3b production rapidly.

What is C4b2a also called

classical C3 convertase

The enzymes of the complement system are synthesized as ...

inactive pro-enzymes, or zymogens, which become enzymatically active only after proteolytic cleavage, usually by another complement protein.

what is a peptidoglycan?

is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of most bacteria, forming the cell wall. Peptidoglycan is an alternating polymer of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), strengthened by cross-linking peptide bridges

what is the COMPLEMENT SYSTEM?

it is a system of plasma proteins that targets pathogens both for lysis and for phagocytosis by cells of the innate immune system.

What is the process of OPSONIZATION?

opsonization, refers to coating a pathogen with antibodies and/or complement proteins so that it can be more readily taken up and destroyed by phagocytic cells.

What molecules do H-FICOLIN and M-FICOLIN recognize on pathogens?

recognizes acetylated sugars such as GlcNAc and N-acetylgalactosamine (GalNAc), and particularly recognizes lipoteichoic acid, a component of the cell walls of Gram-positive bacteria that contains GalNAc.

After initial complement activation by any pathway, the extent of amplification via the alternative pathway is critically dependent on what?

the stability of the C3 convertase C3bBb.

Several mechanisms ensure that complement activation will proceed only on ...

the surface of a pathogen or on damaged host cells, and not on normal host cells and tissues.

what are propeptides?

they are inactive proteins/peptides that can be turned into an active form by post-translational modification. The name of the precursor for a protein is often prefixed by pro

What is the main function of Clq in the immune response?

to bind to the constant, or Fc, regions of antibodies that have bound pathogens via their antigen-binding sites.

How are α-defensins made?

α-defensin is made by neurophils. Oncce made they are stored in the PRIMARY GRANULES of Neutrophils.

How are β-defensins made?

β-defensins are made by epithelia outside the gut, primarily in the respiratory and urogenital tracts, skin, and tongue. Specifically by keratinocytes in the epidermis and by type II pneumocytes in the lungs