INNATE IMMUNITY Flashcards

Question 1

Q

What is the purpose of Innate immunity? What cells are involved in this kind of immune response?

Answer

A

innate immunity- the immediate response to infection. dendritic cells, marcrophages, NK cells are involved.

Question 2

Q

Describe the physical/mechanical, chemical and microbiological barriers to pathogens that are seen in skin, gut, lungs and eyes/nose.

Answer

A

In the skin, gut, lungs and eyes/nose, EPITHELIAL CELLS are joined by tight junctions (sealed system barrier for organism)
-Skin: Mechanical- longitudinal flow of air or fluid
Chemical- fatty acids and antimicrobial peptides
microbiological- normal microbiota
-Gut; Mechanical barrier: longitudinal flow of air or fluid. Chemical- low pH (acidic), and antimicrobial enzymes and peptides. Microbiological: normal microbiota
-Lungs: Mechanical- movement of mucus by cilia
Chemical: Pulmonary surfactant and antimicrobial peptides. Microbiological: normal microbiota
-Eyes/nose/oral cavity: Mechanical- tears and nasal cilia. Chemical: antimicrobial enzymes in tears and saliva. Microbiological: normal microbiota

Question 3

Q

When does someone acquire commensal microorganisms and why are they important?

Answer

A

Commensal microorganisms (microbiota) are acquired starting at birth.
They are important as the development of the immune system is influenced by microbiota (they develop together).
Also, humans depend on commensal microorganism for survival (symbiotic relationship)
> 1000 species of bacteria inhabit the human gut.

Question 4

Q

What is the simplest way to prevent pathogens?

Answer

A

To prevent surface area (not allow a space for pathogens to enter).

Question 5

Q

Describe the importance of the 4 different Lung surfactants. What are the mechanisms involved in antibacterial host defense

Answer

A

4 different lung surfactants:
SP-A and SP-D are large molecules that are primarily involved in HOST DEFENSE.
Th SP-B and SP-C are small and hydrophobic,
These surfactants (especially SP-A and SP-D) agglutinate pathogens (bind to surface of pathogens, opsonize (coat viruses and bacteria) and induce PHAGOCYTOSIS by alveolar macrophages
The mechanisms involved in host defense are growth inhibition, aggregation, or neutralization, or indirect killing by phagocytosis.

Question 6

Q

Compare and contrast the different immune response required for extracellular vs intracellular pathogens.

Answer

A

Extracellular pathogens- pathogens that are on the outside surface of infected cell or are taken up as vesicles into the cell. They can be opsonized and then targeted by secreted molecules.
Intracellular pathogens- like viruses can get inside human infected cells and replicate themselves and assembly which can KILL the HOST cell. (once virus is inside infected cell, it can replicate and avoid attack by soluble immune proteins), It’s viral replication can kill host cell.

Question 7

Q

What is a complement system and how are they used. Where are complements made and where are they present in human bodies?

Answer

A

A complement- system of plasma proteins that mark pathogens for destructions. These soluble proteins are produced in the LIVER and are made through spontaneous hydrolysis.
Complements are found in the blood, lymph and extracellular fluids.
complements contain proteases and zymogen (inactive form of proteases) for cleavage.
They coat the surface of pathogens and target them for destruction (opsonization). This is a simple an effective way to distinguish human from microbial cells.

Question 8

Q

What occurs during complement activation and what are the components involved? What is complement fixation?

Answer

A

Complement activation in response to pathogen: is the proteolytic cleavage of complement protein C3. C3 protein will be cleaved into a larger fragment C3b and smaller fragment C3a.
C3b will then be chemically reactive and be covalently bound to surface of pathogen.
Complement fixation- process that describes C3b being covalently attached to pathogen surface, which tags or marks the pathogen for destruction by phagocyte.
C3a then recruits phagocytic cells to the site of infection.

Question 9

Q

Compare and contrast the activity of C3 before and after it has been cleaved, and what occurs to components of the complement protein.

Answer

A

Before, C3 is cleaved, C3 enters circulation in an inactive form with thioester bond stabilized and attached to hydrophobic region of C3 protein. After cleavage of C3 into to C3b and C3a, it will expose the thioester bond (high-energy) that is attached, and the bond will be subject for nucleophilic attack by water (keep C3 inactive in solution) or by amino or hydroxyl groups that are on pathogen surfaces. (majority of bonds attacked by water).

Question 10

Q

What are three pathways that lead to complement activation and what do these pathways have in common?

Answer

A

Alternative pathway, Lectin pathway, and classical pathway.
All three pathways lead to Complement C3 activation and cleavage of C3 to C3a and C3b; where C3b is covalently bound to surface of pathogen and recruiting similar mechanisms for destruction, and death of pathogen

Question 11

Q

Which complement pathways always occurs at the Start of an infection?

Answer

A

At start of an infection, complement activation proceeds by ALTERNATIVE pathway.

Question 12

Q

What is a complement?

Answer

A

Complement is a system of plasma proteins that mark pathogens for destruction.

Question 13

Q

What are the different outcomes for the three pathways that lead to complement activation?

Answer

A

Three pathways:
Alternative Pathway outcome- recruiting INFLAMMATORY cells
Lectin Pathway outcome- opsonization of pathogens, facilitating uptake and KILLING OF PHAGOCYTES
- Classical Pathway- Perforation (destruction) of pathogen cell membranes

Question 14

Q

What is the order of pathways to act in an immune system?

Answer

A

Alternative is the first pathway to act from beginning of an infection, second is Lectin pathway (induced by infection, requires time), and third to act is classical pathway (involved in innate and adaptive immunity)

Question 15

Q

What factors initiate each of the three pathways for complement activation?

Answer

A

Alternative- initiated when pathogen creates local environment conducive to complement activation (innate immunity)
Lectin pathway- mannose-binding lectin binds to pathogen surface (that contains mannose-carbohydrates); innate immunity
Classical pathway- initiated by C-reactive protein (innate immunity) binding to bacterial surface, or antibody (adaptive) binds to specific antigen on pathogen surface

Question 16

Q

What is the C3 convertase and factors that either increase or decrease/inhibit pathway activation for Alternative, Lectin-binding and Classical pathway?

Answer

A

Alternative C3 convertase- IC3Bb

I will come back to this

Question 17

Q

What are the steps in the alternative pathway of complement activation and component involved? What is the C3 convertase?

Answer

A

Steps of Alternative Pathway:
First Soluble C3 protein is made in the liver and eventually enters aqueous environment to become active and expose thioester bond.
1. in plasma near microbial surface, This C3 spontaneously reacts with water (hydrolysis) to form iC3 (or iC3C3(h20) ). This step initiates complement activation
2. The iC3 binds to Factor B (inactive complement protein).
3. Factor D (serine protease) then cleaves Factor B into small fragment Ba and large fragment Bb. A soluble convertase iC3Bb
4. iC3Bb (protease) then cleaves C3 into C3a and C3b fragments (exposes thioester bond in C3b).
5. some fragments of C3b become covalently attached (to amino or OH) of pathogen surface.

Question 18

Q

Describe the positive feedback that occurs once C3b has been bound to pathogen surface.

Answer

A

C3b that is bound to surface of pathogen (like soluble iC3Bb) can also bind to factor B and B will get cleaved by factor D.
Factor D will cleave Factor B and then release Ba and C3bBb complex on microbial surface
This C3bBb is the C3 convertase of alternative binding pathway.
The C3bBb will bind to C3 and cause it to cleave into C3a and C3b (activate thioester bond).
This C3 convertase (C3bBb) will keep cleaving more C3 and fixing more C3b at microbial surface, leading to more C3 convertase being made (as well as C3a for attracting phagocytic cells) and positive feedback created.

Question 19

Q

Describe how the alternative C3 convertase C3bBb are termed as “Runaway reactions” and the regulatory proteins that are involved to help regulate the reactions?

Answer

A

One molecule of alternative convertase C3bBb can catalyze formation of many of the same C3bBb molecules to keep reaction occurring over and over.
regulatory proteins: Properidin, Factor H, factor I, DAF, MCP all help to regulate reaction

Factor P (Properidin) binds to C3bBb to prevent degradation (stabilizes the convertase) and increase cleavage of C3 into C3a and C3b.
Factor H binds to C3b and Induces cleavage to iC3b by factor I to decrease the amount of C3b on PATHOGEN surface. iC3b cannot be converted to convertase (so positive feedback won’t occur)

-DAF (decay accelerating factor)- binds C3b and causes dissociation and inactivation
MCP (membrane cofactor)- binds C3b and makes it susceptible to cleavage by factor I into iC3b.
DAF and MCP are on HUMAN CELL surface

Question 20

Q

What is opsonization?

Answer

A

Opsonization- process of coating of a pathogen with a protein that facilitates phagocytosis.

Question 21

Q

make a flow chart of the components of the hematopoietic stem cell and the components under common lymphoid precursor and common myeloid precursor.

Answer

A

Hematopoietic stem cell: have two main parts
1. Common lymphoid Precursor: divide into B cell which later forms plasma cell (differentiated cell); as well as NK/T cell precursor: T cell to form effector T cell and NK cell
2. common myeloid precursor (CMP)- granulocyte/macrophage progenitor to form macrophage and dendritic cell precursor: monocyte (which matures macrophage) and dendritic cells; as granulocytes (basophils, eosinophils, neutrophils)
The megakaryocyte/erythroid progenitor forms megakaryocyte (platelets) and erythroblast (form erythrocyte); unknown precursor- forms mast cell.

Question 22

Q

What is the first line of cellular defense against invading microorganism?

Answer

A

Phagocytosis by macrophages.

Question 23

Q

What are the roles of CR1 in phagocytosis?

Answer

A

CR1- Complement receptor 1- a receptor on macrophages that recognizes/binds C3b on bacterium surface. It also PROTECTS expressing cells and makes C3b susceptible to cleavage by factor I

Question 24

Q

Explain the process of Phagocytosis by macrophages and include important components of it.

Answer

A

Phagocytosis process: bacterium is coated with C3b (opsonized) in order to enhance phagocytic activity by macrophages, and degrade pathogens
Steps:
1. complement activation leads to deposition of C3b on bacterial surface (coating)
2. CR1 on macrophage binds C3b on bacterium
3. This binding facilitates the endocytosis of bacterium by macrophage
4. Macrophage membrane fuse, creating a membrane bound vesicle called phagosome (endosome)
5. Lysosomes fuse with phagosome forming phagolysosome and delivering toxins that kill and degrade bacterium.

Question 25

Q

Describe the process of C5 activation by alternative C5 convertase. What is the molecule that represents alternative C5 pathway? How does it differ from C3 convertase?

Answer

A

C5 is activated by the alternative C5 convertase C3b2Bb, (which are 2 C3b fragments and Bb fragment). C3b binds the alternative alternative C3 convertase
This C5 convertase cleaves C5 into a smaller C5a fragment and a larger C5b fragment
C5 convertase differs from C3 convertase because it does not have a thioester bond (like C3)

Question 26

Q

What initiates the Membrane-attack complex (MAC)? What is the purpose of MAC and its components?

Answer

A

The C5b fragment (cleaved by C5 convertase)
initiates the formation of MAC.
MAC (membrane-attack complex) is composed of terminal complement proteins that lyse pathogens by forming membrane pores.
mac- large pore that is assembled and inserted into bacterial membranes to kill bacteria/pathogens by destroying their integrity

Question 27

Q

How is the alternative C5 convertase formed?

Answer

A

C3b binds alternative C3 convertase (C3bBb) to form C3b2Bb, which is C5 alternative convertase.

Question 28

Q

Explain how the MAC is assembled.

Answer

A

MAC is formed using C5, C6, C7, C8 C9 proteins
Process:
1. C5b initiates the assembly of MAC in solution
2. C6 binds to C5b and forms binding site for C7
3. C7 binds to C5b6 and exposes hydrophobic region that attaches to cell membrane (reaches lipid bilayer)
4. C8 binds to C5b67 and exposes hydrophobic region that inserts into cell membrane
5. C9 polymerizes (several polymers) on C5b678 complex to form membrane-spanning channel that disrupts cell’s integrity- result in cell death.

Question 29

Q

Compare and contrast the use of complement components on pathogen cells vs CD59 usage on human cells. How do they differ?

Answer

A

On cells of pathogens, complement components C5-C9 assemble a complex that perforates cell membrane to destroy its integrity
on human cells a PROTECTIN called CD59 binds to the C5b678 complex to prevent recruitment of C9 to form the pore (prevent pore from attacking cell membrane or destroying it).

Question 30

Q

What is the role of CD59 in human cells?

What is another molecule that has a similar function? What do these molecules have in common?

Answer

A

Role of CD59- a protectin or protein that prevents C9 recruitment to C5b678 complex (avoid forming pore/MAC or destructing membrane)
HRF- Homologous restriction factor also works like a protectin (similar to CD59) in preventing C9 from binding to complex and forming MAC pore.
CD59 and HRF are both present on human cells and prevent C9 recruitment to form MAC.
they also both have glycophosphatidylinositol LIPID TAIL

Question 31

Q

What is Paroxysmal nocturnal hemoglobinuria?

Answer

A

Paroxysmal nocturnal hemoglobinuria- rare, life threatening disease due to mutation in bone marrow.
-disease caused by destruction of RBCs, due to impaired synthesis of lipid tail (that both CD59 and HRF have).
people with this disease are missing the protectins CD59 and HRF on their RBC, as they don’t have protecting to prevent C9 from binding to complex and forming MAC.
treatment: gene therapy, bone marrow transplant

Question 32

Q

Which fragments are ligands for receptors on phagocytic , endothelial cells and mast cells?

Answer

A

C3a and C5a fragments-ligands

Question 33

Q

What are Anaphylatoxins and where do they come from? Give examples.

Answer

A

Anaphylatoxins- are the fragments C3a and C5a from complement activation that induce inflammation and
Inflammation- major consequence of innate immune response to infection.
C3a and C5a - also induce an acute and powerful inflammatory reactions that affect tissues throughout the body.

Question 34

Q

What is the major role of anaphylatoxins? What is C5a’s specific role in this?

Answer

A

Anaphylatoxins induce contraction of smooth muscle and degranulation of mast cells and basophils leading to release of histamine and other vasoactive substances.
This increases capillary permeability.
Anaphylatoxins also increase vascular permeability (blood vessels), and blood flow which will allow plasma proteins and and cells to leave blood and enter site of infection.
C5a works as chemoattractant for phagocytes and increases phagocytic capacity (monocytes and neutrophils) to speed up destruction of pathogens.

Question 35

Q

What happens when blood vessels are damaged by pathogens? Describe this process, and include purpose of clotting.

Answer

A

When blood vessels are damaged by pathogens, coagulation system is created.
Coagulation- cascade of enzymes in plasma that cooperates with platelets to form blood clots. pathogen is then immobilized in clot and cannot enter blood.
Clotting- decreases blood and fluid loss. During clot formation, platelets degranulate, release prostaglandins and other agents to recruit immune cells, antimicrobial defenses and tissue repair.

Question 36

Q

What is the kinin system? What are its components?

Answer

A

Kinin system-enzymatic cascade of plasma proteins induced by damaged tissue and leads to production of bradykinin. The bradykinin peptide reduces hypertension, dilates blood vessels and relaxes smooth muscle in the damaged tissue; which all help eliminate invading pathogens, repair damaged tissue?

Question 37

Q

What is the function and components of alpha2-macroglobulin?

Answer

A

Some plasma proteins help limit spread of infection like alpha2-macroglobulin.
alpha2-macroglobulin- is a glycoprotein that works as a protease inhibitor (prevent pathogens from inactivating antimicrobial peptides).
a2-macroglobulin have bait region and thioester bond
process:
1.a2-macroglobulin presents bait region that protease will try cleave
2. microbial protease cleaving bait, causes conformational change in a2-macroglobulin
3. this activates thioester bond, covalently linking protease to alpha-macroglobulin
4. alpha2-macroglobulin then envelopes/enshroud protease and forms complex that will bind receptor on hepatocytes, fibroblasts, macrophages and be cleared.

Question 38

Q

What is the role of antimicrobial peptides? What is one major example?

Answer

A

Antimicrobial peptides are major component of innate immune system.
These peptides kill pathogens by perturbing (disrupting) their cell membrane
A major example are DEFENSINS that neutralize a broad range of toxins.

Question 39

Q

What are defensins? What is their structure and function? Provide a major example of one and how it functions.

Answer

A

Defensins- are peptides of 30-40 aa rich in arginine residues, antiparallel b-sheet
-they have AMPHIPHATIC character (hydrophobic/hydrophilic regions), and charged and uncharged regions. This property allows them to penetrate membranes, disrupt their integrity and cause lysis.
Defensin- alpha and beta ones
EX: Human Beta-1 defensin- is secreted at MUCOSAL surfaces in epithelial cells and neutrophils.

Question 40

Q

What are Paneth cells, and where are they located?

Answer

A

Paneth cells- main source of defensins in intestine. these are alpha-defensins
located in the bottom of crypt in Gut lumen (next to stem cells)
Paneth cells secrete defensins (HD5 and HD6) to provide defense against infections of gut mucosa.

Question 41

Q

What is another word to describe defensins?

Answer

A

Defensins also called anti-chaperone proteins as they promote protein unfolding and denaturation to destroy microbial toxins.
most defensins are constitutive: majority alpha defensin like Human neutrophil proteins 1-4 (neutrophils, NK, B and T cells) others are b-defensins- HD5, HD6-paneth, or HBD1-4 (epithelial, monocytes, dendritic, keratinocytes)

Question 42

Q

Explain how defensins are able to disrupt membranes of pathogens.

Answer

A

Defensins (+) - have hydrophilic/hydrophobic regions which allows them to interact with charged surface of cell membrane and defensins can insert into the lipid bilayer (electrostatic attraction an transmembrane electric field)
once in the lipid bilayer, the defensin peptides form a pore, leading to loss of mem integrity.

Question 43

Q

What are pentraxins and their function? what are the two types?

Answer

A

Pentraxins-plasma proteins of innate immunity that bind microorganisms and target them to phagocytes
-have cyclic multimeric structure that bind surface of pathogens
2 types of pentraxins:
1. Short Pentraxin- serum amyloid P (SAP) made in LIVER hepatocytes; ligand for bacteria ,virus, fungi, PARASITES
2. Long pentraxin- PTX3- seen in monocytes, macrophage, dendritic , endothelial, epithelial cell.

Question 44

Q

What is the role of pentraxins?

Answer

A

Pentraxins- are bridging molecules that bind pathogens to human cells (1 pentraxin binding site for each ) to signal phagocyte to engulf and destroy pathogen.
pentraxins- are like the “antibodies” of innate immune system.

pentraxins and antibodies both bind to same surface- receptor on phagocytes, CD89

Question 45

Q

Describe what occurs in the induced innate immune system,

Answer

A

In induced phase of innate immune system- involves soluble and cellular receptors that detect presence of infecting organisms and recruit leukocytes to make an inflammatory response.
key characteristic: activate effector mechanism that preserve “self” and eliminate “non-self” or altered self.

Question 46

Q

Explain how cellular receptors of innate immunity distinguish non-self from self. What do these equate to? Which cellular receptors are involved?

Answer

A

Non-self- microbes
Self- healthy human cells
Cellular receptors:
1. Macrophage receptors recognize the cell-surface carbohydrates of bacterial cells and bind to them but not those of human cells (macrophage signaled to induce phagocytosis)
2. Natural Killer cell receptors recognize changes at surface of human cells that are caused by viral infection (NK surface receptor bind viral proteins, signal NK to kill infected cell)
innate immune response- based on plasma proteins and cellular receptors that distinguish microbial carbs, lipids, proteins, and nucleic acids from their mammalian counterparts (>100 different receptors)

Question 47

Q

elaborate on the tissue macrophages that carry a battery of phagocytic and signaling receptors.

Answer

A

Macrophages have various, different receptors that recognize a different portion of pathogen.
Most macrophage receptors are phagocytic (mannose, complement, dectin-1, scavenger,)
but the one macrophage receptor that is a SIGNALING receptor is Toll-like receptors (family of 10 receptors with variable specificity for range of pathogens.

Question 48

Q

Which domains characterize the mannose receptors (and also dectin-1 receptor)? What family of receptors do they fall into?

Answer

A

CTLD- Carbohydrate recognition domain- C-type lectin domain, requires calcium (Ca coordinates interaction of carb ligand with protein receptor)
- RTLD- Ricin-type lectin domain- that recognizes sulfated galactosamine residues
CTLD and RTLD are domains that characterize the mannose receptor (sr-e3), and dectin-1 receptors.
These are all among SR-E, class of Scavenger receptors that are lectins
Scavenger receptors- recognize negatively charged microbial ligands.

Question 49

Q

what is the specific role of scavenger receptors in immunity?

Answer

A

Scavenger receptors- trigger processes of phagocytosis, cell adhesion, and intracellular signaling to identify microbes and molecules that could be harmful host, and cause their elimination.

Question 50

Q

Describe how the different macrophage receptors degrade microorganisms.

Answer

A

Process

Different macrophage receptors ( MARCO, Dectin-1, complement, mannose receptor) will recognize components on microbial surfaces
microorganisms are then bound by phagocytic receptors on macrophage surface
microorganisms then internalized by receptor-mediated endocytosis, form endosome.
fusion of endosome with lysosome, forms phagolysosome in which microorganisms are degraded.

Question 51

Q

What does MARCO stand for and what type of receptor is it?

Answer

A

MARCO- Macrophage receptor with collagenous structure- which is a type of scavenger receptor that recognizes bacterial LPS (lipopolysaccharide) and binds to it, to eventually degrade the bacteria.

Question 52

Q

What are Toll-like receptors, and its characteristics?

What is the signaling domain? What is the pathogen recognition domain? Which TLR only homodimerizes?

Answer

A

Toll-like receptors- signaling receptors that are present on immune-system cells and function in innate immunity by responding to a range of microbial and viral products
TLRs;
family of 10 genes- TLR 1-10
-TIR-toll interleukin-1 receptor SIGNALING DOMAIN
-LRR- leucine-rich repeat- 20-29 amino acids: this LRR varies- PATHOGEN RECOGNITION DOMAIN
- TLRS can be homodimers or heterodimers
-TLR4- only homodimerizes (main TLR that recognizes LPS)

Question 53

Q

What happens when TLR4 recognizes LPS? Describe how this process occurs (stepwise)?

Answer

A

recognition of LPS by TLR4 induces CHANGES in macrophage GENE EXPRESSION

steps:
1. first TLR4 recognizes LPS
2. CD14 , a co-receptor binds LPS
3. MD2- adaptor protein binds TLR4 and LPS
- MD2 bridges TLR4
4. MYD88- an adaptor protein binds to TIR domain and IRAK4
5. IRAK4- autophosphorylates (phosphorylates its self), then phosphorylates TRAF6
6. This leads to activation of IKK (inhibitor of IKB)
7. IKK phosphorylates IKB which leads to degradation of IKB and releases NFKB
8. NFKB enters the nucleus and activates transcription of genes for inflammatory cytokines (that are synthesized in cytoplasm) and secreted via ER.

Question 54

Q

What happens to patients with the disease X-linked hypohidrotic ectodermal dysplasia and immunodeficiency or NEMO (NFKB essential modulator deficiency)? What are the abnormalities of this disease?

Answer

A

X-linked hyophidrotic ectodermal dysplasia and immunodeficiency/NEMO:
- disease that arises due to lack of an IKK subunit, and hence results in impaired NFKB response (affects activation of macrophages by TLR4 signaling
NEMO- is on X chromosome (more common in males)
this disease also results in abnormalities in tissues that arise from ectoderm (skin, teeth and hair)

Question 55

Q

What occurs when resident macrophages are activated? Which cellular structures are inducing this inflammation?

Answer

A

Activation of resident macrophages, induces a state of INFLAMMATION at sites of infection
1. IL-1Beta and TNF-alpha- induce blood vessels to become more permeable, allowing effector cells and fluid containing soluble effector cells to enter infected tissue (cause painful, swelling)
2. IL-6- induces fat and muscle cells to metabolize, making HEAT and raising TEMPERATURE in infected tissue (induce fever)
3. CxCL8- recruits neutrophils from the blood and guides them to the infected tissue.
4. IL-12- recruits and activates Natural killer cells that in turn secrete cytokines that strengthen macrophages’ response to infection
the functions of cytokines all lead to Red, painful and hot feeling when someone has an infection.
neutrophils now in tissue (during inflammation)
-macrophages will help clear dead neutrophils

Question 56

Q

What is a NOD receptor? What is its role in immunity?

What is the use of CARD in NOD receptors? What is the importance of RIPK2 and TAKI and what does this lead to?

Answer

A

NOD- nucleotide-binding oligomerization domain- that allow receptors to form oligomers.
NOD-like receptors recognize bacterial degradation products in cytoplasm (degraded peptidoglycan)
CARD- caspase recruitment domain- NOD receptors DO NOT RECRUIT caspases; they recruit proteins with CARD domains
RIPK2- protein kinase that phosphorylates TAKI which phosphorylates and activates IKK- leading to NFKB activation.
process: bacteria is degraded in macrophage phagolysosome, releasing muramyl dipeptide that binds to and dimerizes NOD 2 receptor.
kinase RIPK2 assembles with NOD2 dimer, and phosphorylates and activates TAK1 which phosphorylates/activates IKK, to degrade IKB and release NFKB and lead to macrophage activation.

Question 57

Q

Compare and contrast macrophages and neutrophils.

Answer

A

Macrophages- long-lived; reside in tissues, work from start of infection and have functions other than phagocytosis
Neutrophils- short-lives, dedicated killers that circulate in blood; wait for call from macrophage to come and defend infected tissue.

Question 58

Q

What are the first effector cells recruited to sites of infection?

Answer

A

NEUTROPHILS (dedicated phagocytes)

-neutrophils- most abundant leukocyte.

Question 59

Q

Where are neutrophils recruited from? who recruits them? What happens after they are infected cells?

Answer

A

INFLAMMATORY CYTOKINES recruit neutrophils from the blood to the infected tissue from the BLOOD to the infected tissue

Neutrophils:
They are short-lived, dedicated killer cells
they are highly abundant (bone marrow)
-PUS- creamy substance formed by dead neutrophils

Question 60

Q

Where are Toll-like receptors located? What cells express TLR-4? What does TLR-4 recognize? What is the result of TLR-4 activation?

Answer

A

Toll-like receptors are located in endosome membranes. TLR4- recognizes LIPID A component of LPS (gram-negative bacteria); also signals macrophages to respond to bacterial infection. TLR4- activation results in gene expression for inflammatory cytokines

Question 61

Q

What cells express NOD receptors? What do they recognize? What is the result of activating NOD receptors. Describe the process.

Answer

A

Immune cells (myeolod/lymphoid) and epithelial cells express NOD receptors. NOD receptors recognize degradation products of phagocytized bacteria.
Activating NOD receptors will lead to activation of NFKB (through cascade) which activates macrophages
process: 1. bacteria is degraded in macrophage phagolysosome, releasing muramyl dipeptide that binds to and dimerizes NOD 2 receptor.
2. Protein kinase RIPK2 assembles with NOD2 dimer, and phosphorylates and activates TAK1 which phosphorylates/activates IKK, to degrade IKB and release NFKB and lead to macrophage activation.

Question 62

Q

What cells express cytokines? Under which conditions are cytokines expressed?

Answer

A

macrophages store cytokines IL-1B in its inactive form inside cytoplasm. IL-1a is expressed by healthy cells, like neutrophils, endothelial cells, endothelial cells and macrophages.
Cytokines are expressed during inflammation, or at start of infection

Question 63

Q

What are the target cells of cytokines and what is the result?

Answer

A

target cells of cytokines- T cells, macrophages, tissue cells
result- induce inflammation at site of infection.

Question 64

Q

Explain how the inflammatory cytokines highlighted in the lectures activate the acute-
phase response.
What are the downstream effects that contribute to a state of inflammation?

Answer 64

A

septic shock- life threatening reaction that when bacterial infections spreads from tissue to the blood and becomes systemic.
Constant activation of innate immune response, causes widespread dilation of blood, leakage of fluid in tissues throughout body causing septic shock (lack of blood supply to organs).

Answer 65

A

Inflammasome- protease that cleaves pro-IL-1B (inactive form), and releases active form of IL-1B
Inflammasomes amplify the innate immune response by increasing the production of IL-1B.
IL-1B- major regulator of inflammation and innate immunity.

Answer 66

A

Inflammasome:
IL-1 receptor contains TIRL domain (like TLR)
1. IL-1B binds IL1R (positive feedback)
2. ATP release causes activation of potassium channels to decrease K+ concentration
3. This causes NLPR3 (no CARD) to bind adaptor protein with CARD
4, This adaptor protein binds binds procaspase 1
which leads to formation of inflammasome- high concentration, and autoproteolysis of procaspase1 into active form of caspase.

macrophages are supercharged to make IL-1beta

Answer 67

A

To recruit neutrophils to infected tissue, cytokines use:
1. Chemokines (CXCL8, CCl2)- which direct the flow of leukocytes in the body.
2. Adhesion molecules- attach leukocyte to tissue cell surface. (Vascular addression, C3D4, Selectin, LFA-1 integrin, ICAM-1)
During inflammation, blood vessels dilate and vascular endothelial cells upregulate SELECTINS
TNF- (tumor necrosis factor) increases and vascular endothelial cells upregulate ICAM-1 and ICAM-2 (intercellular adhesion molecules)
These molecules allow neutrophils to attach to vascular endothelium and enter infected tissue.

Answer 68

A

Weak-Selectin Mediated Adhesion allows neutrophils to roll along the endothelium
-During Tight Binding-CXCL8 binding leads to changes in integrins (LFA-1) as it binds ICAM1
in the basement membrane- neutrophils secrete elastase to degrade lamins and collagens.
Neutrophils then follow chemical trail to source of CXCL8 in tissue (macs)

Answer 69

A

1 . Rolling adhesion- neutrophils attach to weak selectin and roll along endothelium

Tight-binding- interaction of LFA on neutrophil attaching to ICAM1 (adhesion molecule on endothelium
Diapedesis - chemokines guide neutrophils to squeeze between endothelial cells
Migration- neutrophils follows CXCL8 gradient to reach site of infection

Answer 70

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NEUTROPHILS- potent killers of pathogens
- They express receptors for many bacterial and fungi
-they then bind bacteria, engulf them and destroy them with toxic contents of neutrophil granules.
After, this occurs they are PROGRAMMED TO DIE (apoptosis)

Answer 71

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Inflammatory cytokines IL-1, IL-6, and TNF-alpha all act on tissues to raise body temperature and activate the liver to make acute-phase response.
The cytokines
1. induce ACUTE-PHASE proteins in LIVER for complement activation and opsonization (coat the pathogen surface, mark for destruction)
2. induce NEUTROPHIL mobilization in the bone marrow, epithelium for phagocytosis.
3. induce an increased body temperature in the HYPOTHALAMUS, to decrease bacterial and viral replication
4. induce metabolism of FAT, MUSCLE- for protein and energy mobilization to increase body temp, and decrease viral/bacterial replication (IL-6)

Answer 72

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Most bacterial and viral pathogens grow and replicate best at temp below body temp (hence fever will help inhibit growth and replication of pathogen)
Adaptive immunity- more potent (powerful) at higher body temps
Human cells- are more resistant to TNF-alpha side effects on body
causes lethargy, somnolence, anorexia ( help conserve energy to fight off pathogen)

Answer 73

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Acute-phase response- SUM of changes in change of concentration of plasma proteins during infection
-results in synthesis of acute-phase proteins that have a change in concentration of greater than or equal to 25%

Answer 74

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Acute-phase proteins- C-reactive protein, Serum Amyloid A, C3 complement, Fibrinogen, Albumin
- all made in the LIVER
In acute-phase(during inflammation)- C-reactive protein and Serum Amyloid A INCREASE largely in concentration; C3 complement and Fibrinogen moderately increase. Albumin (most abundant plasma protein) DECREASES after inflammation.
acute-phase- form of induced innate immune response at start of infection

Answer 75

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C-reactive protein- binds pathogens- opsonin and triggers innate immune response. They may also deliver pathogens to phagocytes
Mannose-binding lectin and LPS binding protein- also aid in pathogen recognition
Complement proteins- pathogen elimination
Serum Amyloid A- aid in INFLAMMATION response by interacting with HDL, binds to TLRs (toll-like receptors) and CD36(induces cytokines)
Fibrinogen- COAGULATION (clotting)

Answer 76

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The mannose-binding lectin initiates Lectin pathway of complement activation
Mannose binding lectin (MBL)- binds mannose-containing carbohydrates on the pathogen
-multipoint attachment is critical (of MBL to pathogen surface)
-Lectin pathway of complement activation is triggered and opsonin induces monocytes in blood to uptake bacteria.

Answer 77

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first, bacteria induces macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins.
C-reactive and Mannose-binding lectin are both BIND pathogens, act as OPSONINS, and COMPLEMENT activators to induce PHAGOCYTOSIS
C-reactive protein binds PHOSPHOCHOLINE on bacterial surfaces.
Mannose-binding lectin binds to carbohydrates on bacterial surfaces

Answer 78

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Lectin pathway;

Activated MASP-2 cleaves C4 to C4a and C4b. Some C4b (exposed thioester bond) binds covalently to microbial surface
Activated MASP-2 also cleaves C2 to C2a and C2b.
C2a binds to surface C4b forming classical C3 convertase C4bC2a
C4bC2a binds C3 and cleaves it to C3a and C3b. C3b binds covalently to microbial surface (C3b also binds to factor b forming alternative c3 convertase- C3bBb)

Answer 79

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C4a- soluble, recruits leukocytes (WEAKER than C3a and C5a)

C4bC2a- the C3 convertase of Lectin pathway (classical convertase)

Answer 80

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In classical: the C3 convertase is C4bC2a
-same convertase for lectin pathway.
Alternative- the C3 convertase is C3bBb
These different C3 convertases both favor cleavage of C3 to C3a and C3b

Answer 81

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The C-reactive protein (part of pentraxin family) triggers classical pathway of complement fixation
C-reactive protein binds Complement 1 on pathogen surface, and C1 becomes an active protease, and cleaves C4.

Answer 82

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TLR1:TLR2: heterodimer, has lipopeptide-gphosphyinositol, ligand, monocytes, dendritic cells, eosinophils/basophils, mast cells carry these receptors, and receptor is in PM.
TLR3- homodimer- double stranded viral RNA- ligand; NK cells carry TLR3 and are located in ENDOSOMES
TLR4- Lipopolysaccharide-ligand; recognizes Gram negative bacteria Macrophages, dendritic cells, mast cells and eosinophils carry it. Receptor is in PM.
TLR5- flagellin ligand; intestinal epithelium carry receptor located in PM
TLR7, TLR8 and TLR9 : homodimers all located in endosomes
TLR7- single stranded viral RNA ligand; plasmacytoid, dendritic cells, NK cells, eosinophils, B cells carry it
TLR8- single stranded vrial RNA ligand, NK cells carry it
TLR9- unmethlyated CPG-rich DNA; same as TLR7 except it has basophils (no NK)
TLR10- basophil/eosinophil, NK cells, plasma-dendritic cells, B cells

TLR1:TLR2- heterodimer located on PM
TLR4- homodimer Located on PM
TLR3- homodimer located in endosome (NK cells)
TLR5- homodimer- PM
TLR6-heterodimer with TLR2 in PM
TLR7, TLR8 and TLR9- homodimers in Endosomes
TLR10- homodimer and heterodimer withTLR1/2

Answer 83

A

All human cells can make Type I interferon
process:
1. Viral replication in cytoplasm produces uncapped RNA with 5’ triphosphate
2. RLR- (RIG-I-like receptors) detect and bind to viral RNA (helicase domain) which induces association with MAVS and dimerization (CARD domain of RNA interacts with MAVS)
MAVS- mitochondrial antiviral viral signaling protein
3. RLR Dimerization initiates signaling pathways that Phosphorylate and activate IRF3 and NFKb
4. IRF3 causes synthesis and secretion of type I interferon, and NFKb causes synthesis and secretion of inflammatory cytokines

Answer 84

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When virus infects cells it leads to production of Interferons (both IFN-alpha and IFN-beta)
The interferon response will:
- induce resistance to viral replication in all cells -increase expression of ligands for receptors of NK cells.
-activate NK cells to kill virus-infected cells.

Answer 85

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Plasmacytoid dendritic cells- factories for making large quantities of type I interferons

quantities are >1000 times of other cells
helps to prevent systemic spread of infection

Answer 86

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NK Cells are the main lymphocytes (STARS) of innate immunity functions of NK cells:

kill cells infected with virus
maintain/increase the state of inflammation (increase phagocytosis)
CD56 positive, lack CD3
5-25% of blood lymphocyte population

Answer 87

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CD56 dim- 90% of BLOOD NK cells- greater capacity for killing
CD56 bright- 80% of NK cells in tissue (great for inflammatory)
greater than 100x10^6 NK cells circulating- primary purpose is to kill human cells

Answer 88

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Virus infection of cells triggers interferon response
Type I interferon drives PROLIFERATION of NK cells.
Type I interferon drives the DIFFERENTIATION of NK cells into cytotoxic effector cells
Effector cells KILL virus-infected cells by inducing them to undergo APOPTOSIS

Answer 89

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TLR7 in endosome binds single stranded RNA (ssRNA) and signals via MyD88 to induce IFN gene expression- lead to synthesis of type I IFN-a and IFN-B
-TLR3 in endosome binds Double stranded RNA (DsRNA) and signals via TRIF to induce IFN gene expression- make type I IFN-Beta

Answer 90

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Macrophage activated by viral infection secretes inflammatory cytokines that recruit and stimulate NK cells.
NK cell and Macrophage form a conjugate pair (juxtacrine) with synapse in which IL-12 and Il-15 activate the NK cell.
NK cells proliferate and differentiate into effector NK cells secreting interferon gamma (IFN-gamma).
Interferon gamma binds to its receptor on macrophages and activates them to increase phagocytosis and secretion of inflammatory cytokines/

Answer 91

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IL-12- secreted by macrophages; activates and recruits NK cells
IL-15- membrane bound- macrophages and NK cells associate- disfavors differentiation into cytotoxic cells. Favors differentiation into EFFECTOR NK cells (produces cytokines type II interferon)

Answer 92

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Dendritic cells can take up or be infected by pathogens- which causes change in protein expression on NK cells
Binding causes dendritic cells to express IL-15 - that induces NK cells to proliferate, differentiate and survive

Answer 93

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Dendritic cells DRIVE (bind NK) activation, proliferation and differentiation of NK cells, which leads to production of effector NK cells that secrete cytokines and kill virus-infected cells
-When NK cells are abundant/outnumber dendritic cells: NK cells can kill dendritic cells (supress dendritic function), clear infection
-When NK cells are SCARCE, and outnumbered by dendritic cells:
they drive dendritic cells to MATURE into a form that initiates ADAPTIVE immunity (occurs when innate immune system failing to terminate infection)
adaptive initiated.

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INNATE IMMUNITY Flashcards

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