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Immunity > Innate Immunity - Langer 3/31/16 > Flashcards

Innate Immunity - Langer 3/31/16 Flashcards

1
Q

Elie Metchnikoff

A

noticed that marine invertebrates displayed mobile ameboid cells that surrounded the site of a “poke”

found that these mobile ameboid cells could actually ingest things too → phagocytosis

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2
Q

innate immunity: functions

A
  1. initial response to microbes to prevent, control, eliminate infection
  2. stimulates subsequent adaptive immune response
    * can influence or tailor it to specific type of microbe
  3. can recog some pdts of damaged/dead host cells and eliminate them + initiate tissue repair
    * often able to do this without inflammatory response
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3
Q

properties of innate immunity

A
  • always functional, immediately available
  • responds to common features of classes of microbes
  • key molecules are encoded in genome (NOT PDTS OF ANTIGEN-SPECIFIC genetic rearrangements)
  • stimulates adaptive immunity
  • DOES NOT retain memory of antigens/pathogens encountered previously
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4
Q

properties of adaptive immunity

A
  • requires exposure to antigen/pathogen; time lapse between exposure and immune response
  • highly specific response (vs. general response of innate)
  • generates memory based on past infection
  • focuses and potentiates innate response
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5
Q

pathgen recognition in innate immunity

  • players and what they recognize
  • location
  • effect of recognition
A

pattern recognition receptors (PRRs) recognize molecules on pathogens that have specific molecular patterns not seen in healthy hosts

  • PAMPs : pathogen-assoc mol patterns - on pathogen/produced by pathogen
  • DAMPs : danger/damage-assoc mol patterns - “unmasked” or unusual host components

PRRs locations:

  1. on cell membrane to sense PAMPs outside cell
  2. on endosomal membrane to sense PAMPs brought in by endocytosis
  3. in cytoplasm to sense PAMPs in cyto

binding of PRRs can…

  • directly affect pathogen
  • trigger cascade of molecular, cellular, global responses in host
    • ​acute inflammation
    • antiviral response
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6
Q

origin of innate immunity

A

long evolutionary need for organisms to find protective mechanisms against common classes of pathogens (bacteria, viruses, fungi, parasites) → evolution of molecules that recognize and protect hosts

  • now, manifest as hard-wired molecules expressed in cells and protective responses that form rapid response to pathogens
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7
Q

functional outcomes of innate immune responses

A

1. acute inflammation (usually against microbes)

  • against microbes; also in resp to damaged/dead cells, accumulation of abnormal substances in cells or tissues
  • critical for would healing BUT chronic is bad/pathological

2. antiviral response

3. possible initiation of longer-term, specific adaptive immune response

  • generation of antigen-specific T and B cells and antibodies
  • whether or not occurs depends on pathogen, how much pathogen was encountered, and how quickly initial infection was resolved
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8
Q

PAMPs and DAMPs

what are they?

A

allow host organisms to recognize microbes and damaged/unusual self cells

PAMPs : pathogen-associated mol patterns

  • unique molecules often essential for microbial survival
    ex. single, double stranged RNA (viruses); pilin, flagellin protein (bacteria); cell wall lipids (bacteria); carbohydrates (fungi, bacteria)

DAMPs: damage-associated mol patterns

  • produced by host cell damage (not as a result of apop)
    ex. HSPs, monosodium urate crystals, HMGB1 (nuclear protein)
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9
Q

cell-associated PRRs

A

greatest variety expressed by phagocytes (macrophages, neutrophils) and dendritic cells

  • epi and endo cells might also express

binding → activates signal transduction pathways leading to anti-microbial and pro-inflammatory responses

include. ..
1. Toll-like receptors
2. cytoplasmic PRRs

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10
Q

Toll-like receptors

TLRs

A

cell surface TLRs recognize various PAMPs from bacteria or fungi

  • part of intact pathogen
  • shed by pathogen
  • released following phagocytosis by macrophages, killing by neutrophils

endosomal TLRs recognize patterns of endocytosed pathogens (ex. viral RNA, unmethylated CpG dinucleotide motif of bacterial DNA)

binding → signal transduction cascade resulting in activation of transc factors in nucleus → key for inflammatory and antiviral responses

  • infl response? NF-kappaB

​→ production and secretion of “pro-inflammatory” cytokines: TNF alpha, IL-1, interleukin 6

  • antiviral response? Interferon Response Factor family (INF)

→ production and secretion of Type I interferons (IFN-alpha, IFN-beta) - crucial to early antiviral defense

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11
Q

cytoplasmic PRRs

  • 5 groups (descriptions, basic mechanisms of action)
A

imp bc some pathogens/viruses have parts of their life cycle take place in cytoplasm or escape from phagocytic vesicles and hang in cytoplasm (bacteria, parasites)

NOD-like receptors (NLRs) : immune infl, epithelial barrier cells

  • binding of NLRs to PAPMPs or DAMPs → intracellular signaling cascade

key: activation of NF-kB (tf for infl genes), activation of infl cytokine IL-1

cytoplasmic sensors for RNA and DNA

  • RIG-I RNA sensor senses viral RNA (doesn’t bind cellular mRNA bc of the 5’ cap!)
  • DNA sensors may recognize bacterial DNA or host DNA showing stress or damage signs

bacterial carbohydrate receptors (C lectin family)

  • lectins are proteins that bind carbs (C = Ca-dependent)
  • aid in phagocytosis of microbes and can also stimulate signaling pathways

scavenger receptors

  • cell surface receptors with broad specificity (ex. oxidized lipoproteins); mediate phagocytosis

FMLP (f-Met-Leo-Phe) receptor

  • responds to N-term of bacterial proteins (fMet)
  • unlike other receptors, these are Gprotein-coupled receptors
  • activation of cell and cytoskeletal/cell surface changes that facilitate chemotais towards bacterial infection and entry into infected tissue
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12
Q

NOD-like receptors (NLRs)

A

major family of cytoplasmic PRRs occuring in immune, infl, epithelial barrier cells

binding of NLRs to PAMPs or DAMPs → intracellular signaling cascade

key: activation of NF-kB (tf for infl genes), activation of infl cytokine IL-1

*misreg of NLRs might be involved in pathogen of gut diseases (IBD)

*activation of NLRs and infl cytokines might be related to other infl disease (gout, pseudogout, lung disease from silica/asbestos exposure

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13
Q

cytoplasmic sensors for RNA and DNA

A

RIG-I RNA sensor senses viral RNA (doesn’t bind cellular mRNA bc of the 5’ cap!)

DNA sensors may recognize bacterial DNA or host DNA showing stress or damage signs

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14
Q

bacterial carbohydrate receptors

A

C lectin family

  • lectins are proteins that bind carbs (C = Ca-dependent)
  • aid in phagocytosis of microbes and can also stimulate signaling pathways
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15
Q

scavenger receptors

A
  • cell surface receptors with broad specificity (ex. oxidized lipoproteins); mediate phagocytosis
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16
Q

FMLP (f-Met-Leo-Phe) receptor

A
  • responds to N-term of bacterial proteins (fMet)
  • unlike other receptors, these are Gprotein-coupled receptors
  • activation of cell and cytoskeletal/cell surface changes that facilitate chemotais towards bacterial infection and entry into infected tissue
17
Q

cell types involved in innate immunity

A
  • phagocytes (macrophages, neutrophils)
  • dendritic cells
  • NK dells
  • mast cells
18
Q

role of epithelial barrier

A

first line of defense

skin and mucosa of respiratory, GI, GU tracts = main sites of interaction with microbes

  • play part of physical barriers to infection, are immunologically active, incorp several surveillance/effector cells, produce secretions/antimicrobial molecules
    • defensins have direct antimicrobial toxicity, activate cells involved in the infl response
    • cathelicidins have microbicidal activity, immune activation fx
  • ​intraepithelial T lymphocytes : T lymphocytes typically associated with adaptive response, however, some have fixed/ltd antigen specificity to recognize common PAMPS
19
Q

phagocytes

A
  • first line of defense after physical barriers
  • engulf, kill/process microbes

two primary types:

  1. macrophages
  2. neutrophils
20
Q

macrophages

A

type of phagocyte

arise from circulating monocytes that migrate into tissues and differentiate → residential macrophages

alveolar macrophages (lung), microglia (CNS), Kupffer cells (liver), osteoclasts (bone) : all phagocytic, some have tissue-specific fx

primary fx: surveillance

activation via…

  1. binding of microbes to TLRs or other macrophage cel-surface PRRs
  2. signaling from other activated immune cells (ex. cytokine IFN-gamma from NK cells)

effects of activation:

  • more efficient phagocytosis (expression of addt’l cell-surface PRRs)
  • killing molecules/mechs upreg’d to better knock out phagocytized microbes (ROS and NO producing mechs in cells)
  • production of “pro-infl” cytokins (TNF, IL1, IL6) upreg’d → activate other immune cells, change vascular permeability, initiate/propagate infl response

*macrophages also have roles in adaptive immunity

21
Q

neutrophils

A

type of phagocyte

aka polymorphonuclear leukocytes (PMNs)

  • make up 60% of white cells in blood; number goes up during infection
    • first cells to infiltrate areas of bacterial and fungal infection
    • dominant cells in tissue with acute infl
    • phagocytose bacteria in circulation/in tissues
  • short half-life (do not provide long-lasting defense)
22
Q

natural killer cells

A

NK cells

originate from same lymphocyte lineage as T cells and B cells, but have distinguishing features/fx

  • large cells with numerous cytoplasmic granules containing cell-killing substances
    • perforin: facilitates entry of other NK cell contents into target cells
    • granzymes: enzymes that enter the cytoplasm of target cells and initate signaling cascades → apoptosis
  • also binding of antigen Fas to NK cell Fas ligand

*growth/activation can be stimulated by cytokines (IL12, IFN 1) from other cells or from environment

main fx

  1. kill virus-infected cells in early stage of viral infection
  2. kill cells with intracellular microbes
  3. release IFN-gamma → acivates macrophages for more efficient phagocytosis

how do NK cells know which cells to kill?

integration of cytoplasmic signaling pathways triggered by inhibitory and activating receptors

  • inhibitory receptors recog Class I MHC mols (normally on surface of healthy nucleated cells)
    • when viruses or stress hit, MHC mols involved in antigen presentation can be downreg’d → fewer inhibitory receptors engaged…
  • activating receptors recognize diverse ligands
23
Q

dendritic cells

  • two types
  • functions and how they carry them out
A

form a surveillance and antigen-capture network in epithelia and subepithelial tissues in several organs

1. “conventional DCs” (majority, incl Langerhans cells in skin)

fx: recognize and/or capture antigen (microbes or free antigen) via array of TLRs and other PRRs

once recog/capture antigen, 2 major effects (which can vary depending on antigen):

  • produce pro-infl cytokins (TNF, IL1, IL6, IL12)
  • leave resident tissue, travel to lymph node, mature and present antigen to naive T cells → crank up antigen-specific response by T cells
    • link between innate and adaptive immunity!

2. plasmacytoid dendritic cell (pDC) (rarer, v critical)

high levels of TLR 3, 7, 9 iin endosome which allows them to response to ss/dsRNA and DNA (viruses) with high sensitivity

fx: recog RNA/DNA to start high level production of antiviral-family of type 1 IFN (IFN-alpha, IFN-beta), which (contrast to IFN-gamma)…

  • have direct anti-viral effects → stimulate genes in nearby/distal cells to make them more virus-resistant
  • modulate cellular reactions in other immune cells
    • link between innate and adaptive immunity!
24
Q

mast cells

A

primarily associated with immunity to multicellular parasite and allergy and asthma…but prob also have a role in innate immunity

  • present in skin and mucosal epi, often adj to microvasculature and nerves
  • numerous cytoplasmic granules (infl mediators like histamine, vasoactive amines, proteolytic enzymes)
  • produce lipid mediators (prostaglandins) and cytokines (TNF)
  • contain number of PRRs (most TLRs)

location of mast cells and presence of key PRRs suggests imp role in innate immunity - as yet not well understood

25
Q

soluble recognition and effector molecules of innate immunity

A

found in serum and tissues, help tag and destroy pathogens via 2 main fx:

1. opsonization : act as opsonins - tag microbes to enhance recognition by cellular receptors on macrophages, neutrophils, dendritic cells

2. initiate or promote infl responses : attract phagocytes and/or participate in direct killing of pathgens

26
Q

complement system

  • basics
  • 3 pathways
  • 3 outcomes
A

best known, most imp soluble recog/effector molecules comprising approx 20 proteins, mostly produced in liver

  • “complement” serum antibodies and help them kill cells under approp conditions
  • activated via 3 pathways - classical, alternative, lectin - differ in early events, but all converge at critical C3 protein
    • classical involves pathogen-specific antibodies (adaptive)
    • alt/lectin do not depend on patho-specific antibodies - fully active in immunologically naive host (innate)

efficient/potent system with 3 primary outcomes:

  1. opsonize microbes for phagocytosis and killing
  2. mobilize and recruit phagocytes to sites of infection
  3. directly kill pathogens
27
Q

alternative pathway (complement)

A

complement C3 is present in high conc in serum and tissue

  • alt pathway is initiated by spontaneous hydrolysis of C3 → C3b and C3a
  • C3b is highly reactive, binds to bacterial or fungal polysacchs or proteins
    • if no targets nearby, reactive group on C3b hydrolyzes → C3b inactivated
    • if targets nearby, C3b binds to cells → binds serum protein Factor B, which is cleaved by plasma protease to form Bb → bacteria bound to C3bBb complex
  • C3bBb is a potent protease (aka C3 convertase) → further cleaves C3 → C3b

major consequences:

  1. pathogens are tagged with multiple C3b → targets for phagocytes which have C3b complement receptors
  2. complement pathway can run to finish → final recruitment of membrane attack complex (C5b, 6, 7, 8, 9) which can lyse some cells
  3. cleavage events release smaller fragments C3a and C5a → key roles in inflammation
  • mobilize and recruit phagocytes, promote inflammation via binding to specific neutrophil C3a/C5a receptors (in GPCR family) → chemotaxis of neutrophils to infected site
  • bind to receptors on mast cells →release of inflammatory mediators (incl histamine, leukotrienes) - critical effects in acute infl
  • additional direct effects on cells (ex. sm muscle cells)

C3a, C5a aka anaphylatoxins bc can cause anaphylaxis

28
Q

lectin pathway (complement)

A
  • hinges on fact that carbs on surface of healthy human cells are diff from those on pathogens
  • carbs are recognized by collectins, family of lectins incl MBL, pulmonary surfactant proteins A and D (SP-A, SP-D)

ex. mannose-binding lectin/mannan-binding lectin (MBL) recognizes terminal mannose/fructose residues on bacteria/fungi glycolipids or glycoproteins (not found on human cells)
* once bound, MBL recruits MBL-assoc serine proteases (MASPs) → cleave early proteins in complement pathway (C4, C2) → form a C3 convertase → cleaves C3 into C3a and C3b

primary outcomes:

  1. opsonization by C3b for binding to phagocytes
  2. potential assempty of membrane attack complex → cell lysis
  3. generation of C3a and C5a → infl response
29
Q

classical pathway (complement)

A

relies on antibody for pathogen recog → involves both complement (innate) and antibodies (from B cells, adaptive)

generally only engaged on repeat/prolonged encounter with pathogen, once speicifc antibodies have been produced

  • antibody-antigen complexes are bound by complement C1 to form protease → activates components C2 and C4 to form C3 convertase → cleaves C3 to C3a and C3b
  • also, C4b,2a,3b complex acts as C5 convertase → cleaves C5, whose products can go on to bind and form membrane attack complex

antibody can also serve as an opsonin (independent of C1)

30
Q

important aux features of complement system

  • self cell protection
  • immune complexes
A

self-cell protection

  • host cells are protected from complement reactions via regulatory proteins at several point in pathway
    ex. decay accelerating factor/DAF, CD59/protectin, protein I (inhibitor of C3b in serum/tissue)

​immune complexes

  • plays role in clearing antigen-ab complexes (immune complexes) from body: RBCs have complement receptors and bind immune complexes → phagocytosed and destroyed by macrophages in liver/spleen
    • if trapped in lymph nodes…stimulated immne resp!
  • immune complexes lodged in tissue create damage via complement activation (major target: kidney, which filters complexes from blood)
    • autoimmune diseases lead to continuous formation of immune complexes → kidney damage
31
Q

pentraxins

A

soluble recog/effector molecule of innate immunity

  • incl some proteins produced during infl (acute-phase proteins, acute-phase reactants)
    ex. C-reactive protein, serum amyloid protein → can activate complement C1, feeding complement pathway
  • sometimes serve as key biomarkers for infl
32
Q

cytokines

A

proteins that act as signals within imune system (and during devpt, etc)

major pro-inflammatory cytokines: TNF alpha, IL1 beta, IL6

viral infection cytokines: Type 1 interferons (most common: IFN-alpha, IFN-beta

33
Q

major outcome of innate immune response:

1. inflammatory response

  1. antiviral response
A

response to bacteria, physical objects, fungi, parasites

includes…

  • recruitment of leukocytes
  • phagocytosis and killing of microbes by phagocytes
  • stimulating elements of adaptive immunity to produce stronger response and initiate immunological memory
34
Q

major outcome of innate immune response:

  1. inflammatory response

2. antiviral response

A

response to viruses

dependent on production of Type 1 IFN (IFN alpha and IFN beta)

***IFN-gamma is NOT A TYPE 1 IFN!!! doesnt have a role in antiviral response. involved elsewhere***

  • nucleated mammalian cells can respond via PRRs
  • plasmacytoid dendritic cells (pDCs) [high levels of endosomal TLR7, TLR9] are sensitive, specialized to respond to viruses → pump out Type 1 IFNs, which in turn…
  1. bind to neighboring cells (paracrine) to induce synthesis of several proteins → confer braod viral infection resistance (“antiviral state”)
    * can extend thorugh circ as endocrine effect
  2. secreted IFN can feed back to infected cell’s IFN receptor → induce apoptosis
  3. Type 1 IFN stimulates cells’ innate and adaptive immune systems to change in a way that confers strong short-/long-term antiviral response
  • increased class I MHC/HLA presentation
  • maturation of dendritic cells and upreg of class II MHC/HLA
  • stimulation of B cell class-switching → production of higher affinity/more effective antibodies

Immunity (18 decks)

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