Bioms: Innate Immunity

Front 1

skin - mechanical defense

Back 1

1. flow of fluid
2. perspiration
3. sloughing off skin

Front 2

skin - chemical defense

Back 2

1. sebum
2. defensins

Front 3

GI tract - mechanical

Back 3

1. flow of fluid
2. mucus
3. food
4. saliva

Front 4

GI tract - chemical

Back 4

1. acidity
2. enzymes
3. defensins

Front 5

Respiratory tract - mechanical

Back 5

1. flow of fluid
2. mucus
3. air flow

Front 6

Respiratory tract - chemical

Back 6

1. lysozyme in nasal secretion
2. defensins

Front 7

Urogenital tract - mechanical

Back 7

1. flow of fluid
2. urine
3. mucus
4. sperm

Front 8

Urogenital tract - chemical

Back 8

1. acidity in vagina secretions
2. spermine
3. zinc in semen

Front 9

eyes- mechanical

Back 9

1. flow of fluid
2. tears

Front 10

eyes - chemical

Back 10

1. lysozyme (in tears)
2. defensins

Front 11

ubiquitous responses of innate immunity

Back 11

1. 0-4 hours
2. Infection
3. recognition by preformed, nonspecific effectors
4. removal of antigen
eg. complement

Front 12

induced response of innate immunity

Back 12

1. 4-96 hours
2. infection
3. recruitment of effector cells
4. recognition, activation of effector cells
5. removal of antigen
eg. APR (Acute Phase Response)

Front 13

adaptive response

Back 13

1. infection
2. transport antigen to lymphoid organs
3. recognition by naive B and T cells
4. clonal expansion/differentiation to effector cells
5. removal of antigen

Front 14

protective immunity

Back 14

1. reinfection
2. recognition by preformed antibodies and effector T cells
3. removal of infectious antigen

Front 15

immunological memory

Back 15

1. reinfection
2. recognition by memory B and T cells
3. rapid expansion and differentiation to effector cells
4. removal of infectious agent

Front 16

the complement system

Back 16

main objective: C3b attachment

Front 17

Phases of Immunity

Back 17

1. Ubiquitous responses of innate - preformed, nonspecific effectors
2. induced responses of innate - cell secreted effectors
3. adaptive response
4. protective immunity
5. immunological memory

Front 18

Bordet experiment

Back 18

1. discovery of complement system
2. antiserum vs. inactivated serum vs normal serum + inactivated serum
3. Adding normal serum to antiserum restored
lysis, or “complemented” the activity of the
antibodies in the antiserum

Front 19

C3b attachment

Back 19

1. most important component
2. C3 is cleaved into C3a (small) and C3b (big)
3. C3b opsonizes particles for engulfment by macrophages
4. C3a recruits phagocytes

Front 20

macrophages and C3b relationship

Back 20

macrophages have receptors for C3b and engulfs particles it tags

Front 21

C3a

Back 21

1. chemotactic (recruits) neutrophils and macrophages

Front 22

C3b bond

Back 22

1. covalent
2. when cleaved from C3, thioester bond is exposed
3. nucleophlic attack on thioester bond creates soluble C3b (attacks water) or binds to pathogen surface (attack by amine or alcohol)

Front 23

3 pathways of complement activation

Back 23

1. alternative pathway
2. lectin pathway
3. classical pathway

Front 24

alternative pathway

Back 24

1. pathogen surface instigates complement activation
2. first pathway to act
3. complement activation and following steps

Front 25

complement activation

Back 25

1. C3 → C3a + C3b
2. C3b covalently binds to surface components of pathogen
3. recruitment of inflammatory cells
4. opsonization of pathogens (phagocyte kills)
5. perforation of pathogen membranes
6. steps 3-5 all lead to death

Front 26

lectin pathway

Back 26

1. mannose-binding lectin binds to pathogen surface
2. second to act
3. complement activation

Front 27

classical pathway

Back 27

1. c-reactive protein or antibody binds to specific antigen on pathogen surface
2. third to act
3. complement activation

Front 28

detail: initiation on alternate pathway

Back 28

1. C3 in plasma binds
2. C3 + H20 → iC3
3. iC3 + B → iC3B
4. iC3B + D → iC3BD
5. iC3BD - D → iC3Bb (convertase) + Ba + D
6. iC3Bb + C3 → C3b + C3a (step is repeated for additional C3)
7. C3b binds to pathogen surface

Front 29

regulations of complement cascade (inactivate)

Back 29

1. soluble factors
a. H factor is high in animal-specific sialic acid
b. H factor binds to C3b and recruits factor I
c. Factor I cleaves C3 → iC3b (inactive)
d. bacteria lack sialic acid and so C3b remains active
2. membrane-bound factors : DAF and MCP disrupt C3bBb (convertase) causing Bb to dissociate resulting in iC3b (when cleaved by factor I) or DAF-C3b complex

Front 30

factor I deficiency

Back 30

1. factor I cleaves C3 → iC3b (inactive)
2. autoimmune disease
3. depletion of complement
4. when bacterial infection occurs, no complement able to tag bacteria

Front 31

Complement Killing Mechanism: phagocytosis

Back 31

1. complement activation → C3b accumulation on bacterial cell surface
2. CR1 (receptor) on macrophage binds to C3b
3. endocytosis of bacteria
4. membrane-bound vesicle is created with bacteria inside (phagosome)
5. lysosomes fuse with phagosome and form phagolysosome (kill bacteria)

Front 32

cleavage of iC3b enhances adaptive response how?

Back 32

1. complement activations covers pathogens in C3b
2. factor I cleaves C3b → C3d
3. C3d is recognized by CR2 on FDC and B lymphocytes and retains them on surface

Front 33

detail: Lectin Pathway

Back 33

1. cytokines tell liver to secrete MBL to enhance complement fixation
2. MBL binds mannose on the surface of bacteria
3. MASPs bind to MLB, start cleavage
4. MASP-2 cleaves C4 → C4a + C4b
5. some C4 binds covalently to pathogen surface
6. MASP-2 also cleaves C2 → C2a + C2b
7. C2a binds to surfaced C4b → C4b2a (covertase)
8. C4b2a + C3 → C3a + C3b
9. C3b then covalently binds to C3 surface

Front 34

C1 complex

Back 34

1. looks and behaves like MBL/MASP
2. C1q is pathogen/antibody sensor
3. C1r and C1s are proteases
4. binds to either CRP or IgM

Front 35

CRP

Back 35

1. C-reactive protein
2. induced in the liver by cytokines secreted at infection site
3. binds and recruits C1

Front 36

IgM

Back 36

1. antibodies produced by B cells
2. binds and recruits C1
3. adaptive response required to make IgM
4. low affinity but very efficient in activating complement
5. conformation dependent binding

Front 37

detail: Classical pathway

Back 37

1. IgM/CRP binds and recruits C1
2. C1 cleaves C4 and C2 and makes convertase C4bC2a bind to the pathogenic surface
3. covertase cleaves C3 to C3b which binds to surface
4. more convertase generated via alternative pathway

Front 38

amplification of classical pathway (via alternative pathway)

Back 38

1. C1 binds to antigen/antibody complex
2. deposition of C4b by C1
3. deposition of C3b by C4b2a
4. deposition of C3b by C3bBb

Front 39

conformation dependent binding of IgM

Back 39

1. by C1
2. planar conformation: C1q sites are not exposed
3. staple conformation: exposes C1q binding sites

Front 40

C1 binding of IgM v IgG

Back 40

1. IgM: pentameric molecules binds to antigen on sufrace and then adopts staple form and C1 binds to 1 IgM molecule
2. IgG molecule binds to antigen on surface and then C1q binds to 2+ IgG molecules

Front 41

Membrane Attack Complex (MAC)

Back 41

C5 activation by the alternate C5 convertase

Front 42

Complement Killing Mechanism: Direct Lysis (MAC attack)

Back 42

1. lysis of bacterium through generation of holes
2. has soluble and membrane bound regulatory mechanism to prevent lysis of host cells

Front 43

what happens when barrier is breached?

Back 43

1. innate immunity:
2. cytokines secreted and circulated in blood
3. cytokines trigger responses from various tissues (APR)

Front 44

Cytokines elicit what responses to what organs?

Back 44

1. liver (CRP, MBL, acute phase proteins → activation of complement/opsonizaiton)
2. bone marrow endothelium (neutrophil mobilizations → phagocytosis)
3. hypothalamus (increase body temp → decreased viral and bacterial replication)
4. fat, muscle (same as #3)
5. together they elicit inflammation of the tissue

Front 45

inflammation (steps)

Back 45

1. healthy skin not inflammed
2. surface wounds introduce bacteria
3. bacteria activate resident effector cells to secrete cytokines
4. vasodilation and increased vascular permeability allow ICs to leave blood and enter tissue
5. infected tissue becomes inflamed

Front 46

cardinal signs of inflammation

Back 46

1. swelling
2. redness
3. heat
4. pain
5. loss of function

Front 47

vascular permeability in innate response (steps)

Back 47

1. tissue damage → vasoactive and chemotactic factors trigger increase in blood flow and capillary permeability
2. capillaries have influx of fluid and cells
3. phagocytes migrate to inflammation site (chemotaxxis)
4. phagocytes and antibacterial exudate destroy bacteria

Front 48

defensins

Back 48

1. constitutively secreted antimicrobials
2. amphipathic
3. positively charged peptides
4. associate with negatively charged surfaces of bacteria (defensins are cationic)
5. create membrane pores (assemble into rings)
6. attack bacteria, viruses, and fungi
7. ancient defense: found in eurkaryotes

Front 49

α-defensins secreted by Paneth cells

Back 49

1. main source of defensins in the intestines
2. HD6/HD5 defensins (granule components)
3. nanonets (HD6) involved in mucosal immunity
4. Paneth cells secrete granules containing α-defensins HD5 (antibacterial) an HD6 (nanonets)

Front 50

Defense mechanism: extracellular, interstitual spaces/blood/lymph

Back 50

1. complement
2. macrophages
3. neutrophils

Front 51

Defense mechanism: extracellular, epithelial surfaces

Back 51

antimicrobial peptides

Front 52

Defense mechanism: intracellular cytoplasmic

Back 52

NK cells

Front 53

Defense mechanism: intracellular vesicular

Back 53

activated macrophages

Front 54

what are the granulocytes?

Back 54

1. basophil
2. eosinophil
3. neutrophil
myeloid progenitors

Front 55

what are the monocytes?

Back 55

1. macrophage
2. mast cell
3. dendritic cell
myeloid progenitors

Front 56

cells derived from lymphoid progenitors?

Back 56

1. B cells→plasma cells
2. NK/T cells (T cell → effector T cells; NK cell)

Front 57

detection of microbes

Back 57

1. PRR (pattern recognition receptors)
2. MAMPS/PAMPS (microbial associated molecular patterns)

Front 58

PRR-MAMP: Phagocytosis

Back 58

1. PRR trigger uptake
2. bacteria engulfed
3. phagosome → phagolysosome kills bacteria

Front 59

PRR-MAMP: cytokine secretion

Back 59

toll like receptors (TLRs)

Front 60

TLRs

Back 60

1. toll-like receptors
2. activate innate cells, indirectly influence adaptive immunity
3. located in endosomes and plasma membrane (of phages)
4. sense microbial products inside and outside cell
3. induce dendritic cell maturation

Front 61

LPS

Back 61

1. lipopolysaccharide
2. cell wall of bacteria
3. recognized by complex of TLR4, MD2, and CD14

Front 62

TLR4, MD2, CD14, LPS complex pathway

Back 62

1. complex is assembled at macrophage surface
2. MyD88 binds to complex, kinase cascade activates IKK
3. transcription of inflammatory cytokines is signaled
4. cytokines synthesized in cytoplasm and secreted via ER

Front 63

Proinflammatory cytokines

Back 63

TNF-α
IL-β
CXCL8
IL-12

Front 64

IL-β

Back 64

1. proinflammatory cytokine
2. activates vascular endothelium
3. activates lymphocytes
4. local tissue destruction
5. increases access of effector cells
6. fever (systemic effect)

Front 65

TNF-α

Back 65

1. proinflammatory cytokine
2. activates vascular endothelium/permeability
3. entry of complements
4. fluid drainage to lymph nodes
5. fever, metabolite mobilization, shock (systemic effects)
6. induces adhesion molecule expression on endothelial cells

Front 66

CXCL8

Back 66

1. proinflammatory cytokine
2. recruits neutrophils and basophils to site

Front 67

IL-12

Back 67

1. activates NK cells
2. stimulates them to make IFN-γ
3. produced by macrophages

Front 68

TLRs and dendritic cell maturation

Back 68

1. dendritic cells carry most all TLRs
2. TLR activates cells to uptake CCR7 and move to lymph
3. promotes up-regulation of MHC and B7 so that cell is mature and activated to present antigens to T cells

Front 69

mast cells

Back 69

1. initiators of adaptive response
2. granulated macrophages
3. express multiple TLRs and receptors for C3a and C5a
4. reside in connective tissue near blood vessels
5. activated by bacteria and complement
6. break down membrane phospholipisd (to make vasoactive and chemoattractive molecules)

Front 70

neutrophils

Back 70

1. leave bone marrow and travel via blood to infection sites
2. stored in bone marrow
3. engulf/kill bacteria directly (or via complement)
4. die in tissue and degraded by macrophages
5. attracted to endothelial cells near infection
6. fuse with phagosome

Front 71

adhesion molecules

Back 71

1. bind to neutrophils
2. allow neutrophils to migrate between cells and tissue

Front 72

respiratory burst

Back 72

1. ezymatic reactions involving superoxide and hydrogen peroxide
2. generates extremely potent reactive species
3. species do NOT preferentially attack microbe, causes a lot of collateral damage (tissue damage)

Front 73

challenges of viruses to innate system

Back 73

1. obligate intracellular microbes
2. require cellular machinery to replicate
3. look like host cells to innate immune cells

Front 74

how does innate immune system detect viruses?

Back 74

1. damaged host tissues release TLR/PRR ligands
2. PRRs detect viral proteins
3. conserved features at distinct locations

Front 75

viral host defense

Back 75

1. interferon (interfere with viral replication)
2. lysis (cytotoxic T cells/NK cells) of infected cell
3. antibodies (bind and wipe out virus/ tag them for phagocytosis or lysis)

Front 76

interferon

Back 76

1. alpha or beta response
2. resistance to viral replication
3. increase expression for receptors on NK cells
4. activate NK cells cytotoxicity
5. induced through TLRs
6. almost always produced in response to virus infection

Front 77

Natural Killer Cells

Back 77

1. cytotoxic (promoted by IFN-α/β or IL-12)
2. produce IFN-γ (activate macrophages)
3. kills cells infected with viruses
4. display various receptors (not all identical)
5. recognize presense/absense/variation MHC
6. inhibitory receptors control NK activity

Front 78

MHC class I

Back 78

inhibit signals from activating receptors (negative signal) which prevent NK from lysing normal cell

Front 79

MIC-A/MIC-B

Back 79

1. expressed by normal cells when stressed
2. activating receptors bind these
3. will lyse via NK

Front 80

Timing of viral host defense

Back 80

1. ~ 2 days produce IFN
2. ~3 days NK cell killings
3. 6-7 days T cell killing