Physiology (Immunology 1)

Question 1

History of Innate Immunity

Answer 1

Innate immunity is highly conserved
- Compared to the adaptive which is only in vertabrates
- Drosphilla = have innnate immunity
- Startfish = have macrophages
- Frogs + Zebra fish = models of immune system (have a similar immune system to humans but it is more simple)

Question 2

Challenge for innate immunity

Answer 2

Innate immunity has to recognize many classes of organisms of wide variety that can cause problems
- Recognizes things of varying sizes (Small - Virsus -> Bacteria –> Protoza –> Fungi –> Parisites)
- Have four main chatagories = viruses + bacteria + protozoa + fungi AND each catagory has many different specieis
- All different in shape and size
- Have extracellular and intracelular things + different species have different replcation stradegies + RNA vs. DNA

Example -
Small - Have to recognize viruses that hijak cell machinery
Large - Have to recognize larger exrtacellular bacteria + have to recognize fungi that cause cause tissue daamge

Question 3

Goal of the innate immune system

Answer 3

Overall: To swiftly and effeciently idetfy potential health threats

1. Slow and halt the invasion of the threat
2. Alter he adaptive immune system
3. Minimize damage to the organism (Damage control)

Question 4

Is the innate immune system effective?

Answer 4

RESULT of innate - because the innate immune system is so effective –> the majority of potential threats are no threat at all
- We are exposed to things all of the time but most threats don’t reasult in anything because immune system is good at controling them

Question 5

Innate Vs. Adaptive immune

Answer 5

Innate - INflimation + complement activation + phagocytosis + destruction of the pathogen
- Tyical time after infection to start a response = minautes
- Duration of the response = Says

Adaptive = Specilized actors
- Typical time to initiate = hours - days - weeks

Question 6

Main Pillars of Innate immunity

Answer 6

1. Avoidance
2. Resistence
3. Tolerance

Question 7

Innate immunity (Avoidence)

Answer 7

Avoid things using chemical and physical barriers - avoid the ability of the pathogen to get in and establish infections (prevent infection)

Uses:
1. Epithelial barriers (EX. Skin, intesitines etc.)
2. Mucus (Ex. oral mucosa)
3. Enzymes
4. pH (Ex. change in pH organism can’t handle)
5. Commernsal microflora

Question 8

Innate immunity (Resistnce)

Answer 8

Innate immune tries to resist infection - Profesional profilers

Uses:
1. Humoral components
2. Cellular components

Question 9

Innate immunity (Tolerance)

Answer 9

Prevention of damage (tolerance of the tissue to be damaged to a certain extent and still be able to heal)
- IF you get an infection = you tolerize the area to make sure the area is not too sensitive

Ex. Liver is very tolerant to damage - sees many microoranisms but it can still heal and recover

Question 10

Cellular components of the adaptive immune system

Answer 10

1. Macrophages
2. Dendritic cells
3. Nuetrophils
4. Eosenophils
5. Basophils
6. Mast cells
7. NK cells

Question 11

Macrophages

Answer 11

Overall: Phagocytosies and activation of bactericidal mechanisms + antigen presentation
- Eating machine (eat everything it comes into contact with that shows signs of being forign)
- Engulf and kill pathogens = first line of defense (primary source of blockade of infection because the are in tissues and most infections occur in tissues)
- Destroy pathogens with oxidative reagents
- Put out chemokines and cytokines to tell other cels = prevents other cells from getting infected AND draws in cells to help
- Once infection happens - they complete tissue repair post infection (Ex. when wound gets red –> heals –> because macorphages healed it) ; can heal well or can cause fibrosis = not healing properyly = get organ dysfunction

Location - resident in most tissues ; found in every tissue in body

Arise during emrogensis + get new ones through monocyte differentiation

Long lived cells (Ex. Microglia)

Question 12

Monocytes vs. macrophages

Answer 12

Monocytes + macrophaes BOTH phagocytose but most infectsion occur in tissues where macrophages already are = macrophages is the #1 phagocytic cell

Question 13

Dedritic cells

Answer 13

Overall - Antigen uptake in peripheral sites + Antigen presentation
- 2nd class of phagocytic cells
- Mostly do mucoperocytosis = drinking around the are a
- Have long dedirtic extenstions
- Complete survelince in tissue (at the first line of defense) - survery for infection –> leave first line of defense and report infection to specilize cells in lymph nodes (leave the tissue after infection)

Question 14

Dendrites vs. Macrophage

Answer 14

Macrophages = take things up to kill them

Dendirtic = take up things to tell suroundings to help + to present things to the lymphoid organs

Question 15

Granulocytes

Answer 15

Nuertophils (majority) + Eossenphis + Basophiles

Work horses of immunity

In H and E stain = have very big granuales

Question 16

Nuertophils

Answer 16

Overall - Phagocytosis (destroy pathogen) and activation of bactericidal mechanisms
- Important in initial response
- Catches pathogens around them and destorys them
- Produce cytokines and kemokines to pull in more cells
- Not present in tissue prior to infection (makes them different from macrophages)
- Kill selves — spill out insides – surrounds area = kills everything around it
- 24 hour life cycle - Leave bone marrow at night –> die at the end of the day

Question 17

Eosenophils

Answer 17

Overall - Killing of antibody coated parisites
- Also affects allergy repsonse

Question 18

Basophils

Answer 18

Overall - Promotion of allergic repsonses and augmentaion of anti-parasiic immunity

Question 19

Mast cells

Answer 19

Overall - Release of granials contaiing histamine and active agents
- Affects allergies
- Engaged with IgE –> in response release histamine

Question 20

NK cells (natural killer cell)

Answer 20

Overall - Release of lytic granuals that kill some virus infected cells
- Bridge between the innate and adaptive immune system
- Has more specificity than other innate cells but not as much specificty as adapative cells (looks like adaptive cell but functions like innate cell because has broad affects)
- Looks for cells that are not showing self (no MHC I prsenting healthy peptide) = kills them
- Released granzymeB to kill pathogens
- Kill tumor cells

Question 21

Circulating innate immunity

Answer 21

1. Nuertrophis
2. Basophils
3. Eosenphils
4. Mast Cells
5. Monocytes (because become macorphages)
6. NK cells
7. Platlets - express receptors on surface + bind AB + bind to monocytes and facilitate monocyte entry to the brain

Question 22

Tissue/Cavity innate immunity

Answer 22

1. Macrophages
2. Dendritice cells (found in lymphid tissue + in gut)
3. Innate-like lymphocytes - cells that look like lymphocytes (adaptive) but have innate function becayse they are not very specific
   Includes:
   
   • ILCs (in gut)
   • NK T Cells - Mix of NK cell and T cell (have TCR but not variant + kill like NK cells)
     -Gamma delta T cells (skin defense) - very invarinat responses = only respond certain way = innate like
   • B-1 B Cells (mouth + cavity Defense/tooth decay)

Question 23

Antigen presenting cell

Answer 23

Macrophages + Dendrtites - both antigen presenting cells
- Link adaptive and innate immune systems (transition from innate to adaptive response)
- Present antigens to B and T cells t get adaotive response –> B cells will induces AB and T cells will have specific responses

Question 24

How does the immune system identify potential threats?

Answer 24

The immune system recognizes many things through Patterns Recognition Receptors (PRRs)

Question 25

Partern Recognition Receotors

Answer 25

Overall - allow the innate system to repsond within hours 1. Optimize speed and efficiencey - invarint in the genome = don't need recombination to be made/functional = can be made faster - consituntly expressed (always expressed in most immune cells - don't need activation signal) - Inherited through passage of gene - Trigger imediatley to responses when see repsonse 9might ned mutiple reposne becaue dont want innate triggering to everything 2. Accutley idetofy threates - Recognize sturctural patterns common/conserved on pathogens = recognize PAMPs (pathigen associated molecular patterns)

Question 26

Pathigen Assocated Molecular patterns (PAMPs)

Answer 26

Bacteria - Lipteichoic acid (LTA) + Peptodoglycan (PGN) + Lipoporteins + DNA + Flagellin + Lipopolysaccridies (LPS) - Tend to be bacteria cell walls (Ex. LSP) Virus - Coat protein or nucelic acid that is expressed in virus Parasite - GPI anchor Yeast - Zymosan (beta-glucan) --> cell wall of yeast ALL building blocks of pathigens that can't go away (invariant they can't change) = innate immune system co-evoloved to recignize them - very senstive - small amount of PAMPs causes cell to react

Question 27

Pathogens avoiding Innate system

Answer 27

Some pathogens can get around innate system's ability to recognize PAMPs Example - viruses have envelope or bacteria hide in cell - Example - Salmonella hides inside vacuale inside macrophages and then leaks out of the cell

Question 28

Types of PRRs

Answer 28

1. Humoral 2. Ceullular

Question 29

Humoral PRRs

Answer 29

Includes: 1. Ciruclating (in blood) - causes a bacteria = bacteria die bevause they losse the Na+ gradient - Includes - C1 complex of compliments (main circulating) + Monnose Binding lectin (MBL) + C reactive protein 2. Surfactant proteins A and D (in lung) - causes a pore in envelope = bacteria die bevause can't replicate - Degrade bacetria that it comes into contact with - Like enzymes in the lungs Made in the liver

Question 30

C1 complex

Answer 30

First compoenent of compliment- binds to AB that are biund to a bacteria/virus --> triggers pathway of complememt End of pathway - cause pores in cell wall of bacteria or infected cell = causes cell death MBL = also intiates complement but it doesn't bind to AB - binds to mannose on bacteria cell wall =intiates compliment C reactive = signal that there is something going - also binds to bacteria and intitaes compliemnt cascade)

Question 31

Ceullular PRRs

Answer 31

Includes: 1. Extraceullar memebrane bound - found on cell surface -> primari;y respond to bacteria and parisites because outside the cell - Have phagocytic receotors (Macrophage mannose receptor + Scavanger receperts) - invraints receotors that binds to parts f bacteria/viruses --> pulls Pathogen in to be phagocytosed - Have signaling receptors (Toll like Receptors (TLR) 1, 2, 4, 5, 6) - found on DCs + NK cells + Macrophages - reacts to 2. Intracellular - Have membrane bound (TLRs 3, 7, 8, 9) - found on endosomal vesicles + mostly resond to virsues - Have cytosolic (NOD1/2 and Inflamasomes) - NODA1/2 recgnize RNA and DNA inflamasomes react to viruses or general negative climate/off balance of homeostasis

Question 32

Scavenger receptors

Answer 32

Recognize MCL or C reactive pritein or C1 complex of compliments bound to cells

Question 33

TLRs

Answer 33

TLRs = react to specific PAMPs - Bind to many ligands BUT the ones listed are primary ligands TLRs = extra or intracellular in endocytes vesicles or in cytolsol --> virsues get into cytosol or has envelope --> TLR recognizes RNA/DNA - Intraceullar = recgonise virsues --> viruses is negative - TLRs recignize years + bacteria + fungu + virsues best known TLRs: 1 and 2 form heterodimer - on surface - bind to proteins found on yeast + bacteria 2 and 6 form heterodimer on surface - bind to proteins found on yeast + bacteria 4 + CD14 + MD2 = recongnizes LPS (gram neg) or lipotratic acid (gram pos) 5 = Recognize flagelin 3 = recognize dsDNA 7 = recognize ssRNA 8 = recginizes G-Rich oligionucleotides 9 = Unmethylated DNA Look a red boxes in picture

Question 34

Downstream of TLRs

Answer 34

Multiple pathways depedning on whcih TLR is signal = get multiple responses depending on TLR signals Have TLR 4 --> LPS binds --> Get MYD88 cascade --> Get NF kapp B Dimers --> make pro-inflmatory cytokines OR Have TLR 4 --> LPS binds --> get TRIF cascade --> Get interferon production OR TLR 7 --> reacts to vriuses --> different STAT pathway --> Get NF Kappa B --> get cytokines When TLR is engaged it turns on transcription to get cytokines (Ex. inteferons or NF Kappa B) - Downstream response of inflimation - always result in pro-inflamatory cytokines

Question 35

What happens when a PAMP binds to a PRR

Answer 35

1. Destruction of PAMP's source (destroy invading pathogen) 2. Recruitment of other cells 3. Priming of PRR bearing cell ALL occuring simultanously

Question 36

Destruction of PAMP's source

Answer 36

Occurs through: 1. Phagocytosis 2. Cytotoxin Killing 3. Secreation Tyoe I IFNs: IFN alpaha + IF beta 4. Inducing "climate change"

Question 37

Destruction of PAMP's source (Phagocytosis)

Answer 37

Opsonization vs. Direct cell-cell - Opsonization - bind bacteria with AB --> macrophages phagocytose - Direct cell-cell -- macrophages to bacteria --> phagocytose bacteria --> destory with enzymes in lysosome (destroy in phagolysasome) Done by Nuertrophils and macrophages - Macrophage have phagocutic receptors that bind microbes (mannose receptor + complement receteptor + lipid receptor + Dectin 1 + Scavanger receptor) - Nuertophils --> phagoctose bacetria into phagosome --> instead of using lysosome it will make hagosome intercat with granuales that it uses to kill extracellular bacteria Uses Irreversible oxidative destuction - Example - Bacteria binds to compleent receptor --> Phagoytose --> merge phagosome will lysosome --> forms phagolysosome --> low pH --> have oxidation destructive pathway = destroy pathogen

Question 38

Destruction of PAMP's source (cytotoxic killing)

Answer 38

Cytotoxix killig = direct killing of infected cells or bacteria Done through complement membrane attack complex - series of C proetins that go down a chain of domains --> go down activate copplement cascade --> get formation of a pore = pathogen dies because all of the Na leaves the pathogen + all pressure is lost + things spill out of cell (cell can do apoptosis or necrosis) NK cells can do this - recognize when cell is not presenting self --> kills cells by releasing perforin and granzyme --> kills cell - Perforin acts on target cell membrane - Granzyme and granyulin --> leads to apoptosis - Not 100% specific = can harm bystanding cells it is next to

Question 39

Receptors on NK cells

Answer 39

NK cells have positive and negative receptors --> if have many positive receptors to kill then NK cell in engage --> Kill pathigen - If positive receotors engage more than negative = get hole in memebrane --> pathogen dies because loses Na gradient

Question 40

Destruction of PAMP's source (Secretion of Type 1 IFNs)

Answer 40

Infected cells sees virus in cell --> signals IFN beta ---> INF beta signals to surrounding cells --> Bind IFN receptor to surrounding cells --> tells cells to turn on PKR Kinase + Mx + restiction factor + IFN beta/IGN alpha --> continues cascade down = increase host defense - Inhibits viral replication + silos replication (IF viruses can't get into cells to replicate = virus dies) - IFN goal = prevent further viral replication + protect surrounding cells - bystander cells become resistnt to viral infection because upregulate kinases + Mx genes + rescitictiono factors = will traget viruses when enter cells = inhibits furtehr viral replication in bystander cells IFN alpha + INF Beta = potent cytokines

Question 41

Destruction of PAMP's source (Inducing Climate change)

Answer 41

Induce fever --> get global climate change to prevent further infection Macorpages (induce fever) --> IL1beta, IL6, TNFalpahe --> Liver makes acute phase protein synthesis when mannose binds to complement + hypothalumus increases temperture + fat and mulscile cells enter catabolic state

Question 42

IL1beta, + IL6 + TNFalpaha

Answer 42

Act on Liver - Make actute phase protens (R-recative proteins, MBL) --> get activatation of complement opsonization Act on bone marrow --> Get Nuetrophil mobilization (get immeidate release of nuertophils) --> Nuertophils phagocytose pathogen Act on hypothalumus --> increases body tempertature - Prevents replication of bacteria/virus (don't replicate well at high body temps) - Increases antigen process - Increases specific immune repsonse Acts on Fat/muscles - Break down fast/muscle for protein and anergy (allow increased body temp) Acts on Dedritic cells -- TNF alpha stimulates DCs ro leave infection and migrate to lymoh nodes and maturation --> get adpative immune repsonse

Question 43

Recruitment of other cells when PAMPs bind to PRR

Answer 43

1. Vasoactive peptides and cytokines 2. Activating cytokines and kemokines 3. End result: Rolling and Diapedesis

Question 44

Recruitment of other cells when PAMPs bind to PRR (Vasoactive peptides and cytokines)

Answer 44

Mast cells + monocytes + platlets - When increase Vasoactive peptides and cytokines = Mast cels + monocytes + platelets respond to histmanine and sertaonoins and cytokine s= leave blood and go to area where infection occurs Vasodilation - Histaine and seratonin - Monocytes in the endothelium bind to seratonin and integrin = roll off (immune cells recognize cytokines and kemokienes and go out of blood) TNF-Alpha --> Increase selectins and integrins (markers on vasculature or cells - increase expression alows cells to stick to vasuclature and leave the blood) TNF-Alpha --> Increase vascular permability (makes tight juctions wider) Have Nuetrophils and monocytes in the blood (Stay there unless have issue) -- have vasoactive peptides and cytokines --> dilated the blood vessle = blood essel becomes leaky = the cell can leave the blood vessel near infection

Question 45

Recruitment of other cells when PAMPs bind to PRR (Activating Cytokines and Chemokines)

Answer 45

Cytokines and chemkins pulls specifc cells out of blood Chemokines: - Monocytes + macrophages + DCs --> CCL2 --> pull Monocytes to site of infection --> monocytes become macrophages - Macorphages and endothelal cells --> XKCL8 (IL8) : pull nuertophils and T cells to site of infection - Cells being pulled out of blood --> see increase recetport --> go in direction of cytokines = pulls cell to site of inflimation Cytokins: - Platlets --> RANTES --> Pulls Monocytes - Macrophages --> produce IL-12 --> Pull NK cells - Macrophages --> produce IL1B and IL6 --> Pulls lymphocytes - RANTES + IL12 + IL1Beta and IL6 = drive respective cells to inflamation (drive cells down pathway that is needed)

Question 46

Intercellular vs. extra ceullarly chemokines

Answer 46

A and B = intercellular C = extracellilar --> cytikines pull specilized cells to the site of infection Epxression of cytokines determine if needs to be anti or pro ifnmatory response - based on how far down line inefction is going - Lots of iFN gamma = infection is ongoing = signal T cells to respond ; More IL4 or Il5 = signals ingfection so it quiets infection

Question 47

Use of chemokines and cytokines

Answer 47

Need chemokines and cytokines to get the cells you want at site of infection

Question 48

Recruitment of other cells when PAMPs bind to PRR (End result)

Answer 48

End result of Vasoactive peptides and cytokines + Chemokines = to get cells to enter site of infection (Called "Rolling and Diapedesis") Overall: Get cells to slow down in blood vessle and follow cytokines to site of infcetion Selectins - When have increase in selectins --> nuertophils see inrease --> slows down --> recignizes cytokine --> goes out of Blood vessel Integrins Diapedesis - cell binds and starts to move through the endothelium Migration to site of infection

Question 49

Binding if damps to PRR - Prmining of PRR bearing cell

Answer 49

Overall - Cell with PRR needs to be primed - focus on presenting cells 1. Upregukation of MHC II or MHC I 2, Induction of Co-stimulatory molecules 3. Migration to Lymph node

Question 50

Prmining of PRR bearing cell (Upresgulation of MHC II and I)

Answer 50

Priming increases MHC II or I - upregulation allows T cells when enter site of infection to know if cell is infected or not MHC II - On APC --> macrophages and DCs -MHC II - T cell recognizes and generates a receptor + helps B cells geneerate AB - Present CD4 T cells what help is needed MHC I - All cells except RBCs and nuerons MHC I - T cells kills infected cell MHCs = present peptides to adaptive immune = adaptive can specifically target infection

Question 51

Presentation of peptides to T cells

Answer 51

Phgocytic cells take pathigen --> show T cell the protein Present the peptide o T cell in complex (T cells can't kill every time it sees a papetide because there would be too much autoimmunity) - MHC II/I AND inrtdouction of costimulatory molcules = activates T cell (can't activate T cell with only 1 you need at least two but usually 3 signalls) - Occurs in lymph nodes - DCs go to the closest lymoh nodes

Question 52

Prmining of PRR bearing cell (Induction of Ci-stimulatory molecules)

Answer 52

CD80 and CD86 --> Get Signal 2 T cel comes to APC with MHCII but no co stim = T cell won't do anything Induction of Co-stimulatory = shows T cell it needs to respond

Question 53

T cells and DCs in lymph nodes

Answer 53

In lymphnodes there are T cells curculating --> DCs are preseting as mich as they can (lots of MHCII) --> naive T cell will pump into DC and recognize it --> T cell stops moving -- T cell binds to antigen --> T cell differentiates

Question 54

Prmining of PRR bearing cell (Migration to Lumph nodes)

Answer 54

DCs otravel through afferent lymoh vessles to get to lymph node --> go to T cell zone (paracortex) and encounter naive T cell --> Activate naive T cell Have increase in T cells after inflamatory resonse = response can happen faster

Question 55

Overarching goal of innate system

Answer 55

Hold infection at bay until the cells can get help