2. Innate Immunity, Cell Migration, and Phagocytosis Flashcards
(90 cards)
1
Q
innate (constitutive) response is the __ response to injury; mediated mainly by __ cells, also __ and __ __ __; has some specificity and no __.
A
initial, myeloid, NK, innate lymphoid cells (ILC), memory
2
Q
adaptive response is mediated by __ __ ___ (T and B cells); highly specific for __; has __; takes a long time to get started
A
clonally selectable lymphocytes, antigens, memory
3
Q
innate immunity response time
A
hours
4
Q
innate immunity specificity
A
limited and fixed “pattern recognition”
5
Q
innate immunity response to repeat infections
A
always the same
6
Q
innate immunity major components
A
- physical barriers
- phagocytes
- pattern recognition receptors
7
Q
innate immunity genes
A
constitutive
8
Q
adaptive immunity response time
A
days-weeks
9
Q
adaptive immunity specificity
A
diverse, improves during response
10
Q
adaptive immunity response to repeat infections
A
faster, stronger, longer-lasting
11
Q
adaptive immunity major components
A
- T and B cells
- antigen-specific receptors
- antibodies
12
Q
adaptive immunity genes
A
altered by somatic recombination (VDJ)
13
Q
5 physical barriers
A
- skin: acidic, anti-microbial peptides
- mouth: enzymes, anti-microbial peptides, directional flow of fluid to stomach
- stomach: low pH, digestive enzymes, fluid flow to intestine
- intestine: mucus, anti-microbial peptides, normal microbiota compete for niches
- airways and lungs: cilia, mucus, anti-microbial peptides, coughing/sneezing
14
Q
4 steps of early immune/inflammatory responses
A
- tissue damage causes release of vasoactive and chemotactic factors that trigger a local increase in blood flow and capillary permeability
- permeable capillaries allow an influx of fluid (exudate) and cells
- phagocytes migrate to site of inflammation (chemotaxis)
- phagocytes and antibacterial exudate (complement, C-reactive protein) destroy bacteria
15
Q
4 main innate immune cell types
A
- neutrophils
- macrophages
- dendritic cells
- natural killer cells
16
Q
3 functions of neutrophils
A
- phagocytosis
- reactive oxygen and nitrogen species
- antimicrobial peptides
17
Q
6 functions of macrophages
A
- phagocytosis
- inflammatory mediators
- antigen presentation (to T cells) (less effective than DC)
- reactive oxygen and nitrogen species
- secrete inflammatory cytokines and other mediators
- complement proteins
18
Q
5 functions of dendritic cells
A
- antigen presentation (to T cells)
- costimulatory signals
- reactive oxygen species
- interferon
- cytokines
19
Q
3 functions of natural killer cells
A
- lysis of viral-infected cells
- interferon
- macrophage activation
20
Q
these cells are the first line of defense (earliest cells recruited to infected or wounded site)
A
neutrophils
21
Q
neutrophils doing phagocytosis
A
- foreign microbes are engulfed into phagosomes
- more efficient if microbes are opsonized by Abs and/or complement
22
Q
neutrophils doing killing
A
- oxidative: ROS and RNS
- non-oxidative: cationic proteins, enzymes
23
Q
IFNgamma cytokines can activate which cell type
A
macrophages
24
Q
which cell type is the main APC in primary immune response (in peripheral tissue, esp skin and mucosae)
A
dendritic cells
25
these cells are phagocytic cells (related to macrophages?) that ingest microbes, Ag through innate receptors
dendritic cells
26
TLR signals activate dendritic cells to do 3 things:
- upregulate MHC-II (presents processed Ag peptide to T cells)
- upregulate T-cell co-stimulatory molecules (CD40L, CD80, CD86)
- induce migration to draining lymph nodes
27
how do macrophages, dendritic cells, and other innate immune cells recognize foreign microbes in a naive host before adaptive responses have developed?
patterns (recognized on receptors)
28
TLR (cell surface or internal compartments) target/source
microbial components not found in hosts
29
TLR (cell surface or internal compartments) effect of recognition
induces innate response
30
where was the gene for Toll first found? and what does it do?
drosophila; directs dorsal-ventral axis formation
31
TLR are also known as
pattern recognition receptors (PRR); they distinguish microbes from host cells (recognize patterns)
32
true or false: TLR recognize microbial components not found in the host
true
33
true or false: TLR are not critical for immunity
false; TLR are critical for immunity!
34
3 examples of TLR
- TLR4 recognizes lipopolysaccharride (LPS) on gram-negative bacteria
- TLR5 recognizes bacterial flagellin
- various intracellular TLRs recognize ss or ds (viral) RNA, bacterial DNA (CpG motifs)
35
TLR structure
leucine-rich repeats on extracellular domain recognize ligands
36
TLR signaling
"TIR" domain (box 1, 2, 3) on cytoplasmic domain activates inflammatory signaling pathways
37
TLRs activate two pathways:
- extracellular pathogens: activate "MyD88-dependent" pathway --> turn on pro-inflammatory cytokines (TNFalpha, IL-1, IL-6)
- intracellular pathogens: activate anti-viral cytokines --> turn on IRF transcription factors and lead to expression of type I interferons (IFNs)
38
which pathway do most TLRs signal through?
MyD88
39
what is NF-kB
an inflammatory transcription factor
40
multiple inflammatory signals converge on __ which binds to promoter elements in target pro-inflammatory genes such as:
blank: NF-kB
- inflammatory cytokines: IL-1, IL-6, TNFalpha
- proteins that facilitate antigen presentation and T cell activation
- acute phase response genes
- anti-microbial proteins
- other inflammatory mediators: prostaglandins, iNOS
41
intracellular PRR (pattern recognition receptor)
nucleotide-binding oligomerization domain (NOD) proteins
42
what do NODs do?
- recognize microbial components found in cytosol
- bind peptidoglycan in bacterial cell walls
- lead to activation of caspase-1 --> cleavage of inactive forms of IL-1
- mutations in NOD genes associated with inflammatory bowel disease, asthma
43
types of interferons (IFNs)
- IFN-gamma
- IFN-alpha
- IFN-beta
44
IFN-alpha and IFN-beta (type 1 interferons) have direct ___ activity
anti-viral
45
IFN-alpha and IFN-beta activate genes that __ polyA mRNA and __ initiation of mRNA translation
degrade, inhibit
46
which IFN is the "immune interferon"
IFN-gamma
47
what does IFN-gamma activate
NK cells and macrophages
48
what does IFN-gamma upregulate
MHC-II on APC
49
what is IFN-gamma made by
CD4+ Th1 cells, CD8+ T cells, NK cells
50
general steps of inflammation and local response
- activated innate cells trigger inflammation
- acute vs chronic
- local vs systemic
- inflammatory cytokines (recruit other cells to the site, trigger systemic innate defenses)
51
systemic acute phase response
local inflammatory response accompanied by systemic APR
52
what occurs in systemic APR
- fever
- ACTH and hydrocortisone production increases
- acute phase proteins synthesized by the liver
- C-reactive proteins promote phagocytosis of microbes
- complement proteins
- fibrinogen, MBP, serum amyloid A, etc
- induced by inflammatory cytokines
- IL-6, TNFalpha, IL-1
53
types of antimicrobial peptides
- defensins
- cathelicidins (LL-37)
- S-100 proteins (calprotectin)
- Reg-IIIgamma
- Lipocalin-2
54
defensins
- small cationic peptides (~20 kDa) typically found in mucosal secretions (gut, mouth, etc)
- directly kill microbes
- similar proteins found in frogs, invertebrates, plants, etc.
55
other innate antimicrobial factors
- lysozyme
- lactoferrin
- peroxidase
- histastins
*all found in saliva
56
lysozyme as an antimicrobial factor
- muramidase hydrolyses bacterial peptidoglycan
- cationic protein (pI > 10)
57
lactoferrin as an antimicrobial factor
binds free iron down to pH 4
58
peroxidase as an antimicrobial factor
uses H2O2 to oxidize SCN- to OSCN-; inhibits bacterial metabolism
59
histatins as an antimicrobial factor
small His-rich peptides are active against Candida
60
interplay of innate and adaptive immune systems
- TLRs recognize components on microbes (triggers release of inflammatory cytokines like TNFalpha, IL-1, IL-6, IL-8; upregulates costimulatory molecules on APC --> activate T cells)
- DC ingest bacteria, present antigens to T cells
- TNFalpha and IL-8 upregulate adhesion molecules on vascular endothelium --> recruit neutrophils and lymphocytes
- cytokines secreted by various cells shape the T cell response
61
what is IL-12 secreted by and how does it shape the T cell response?
- secreted by macrophages and dendritic cells
- Th1: antibacterial Ab and CMI
62
what is IL-4 secreted by and how does it shape the T cell response?
- secreted by mast cells
- Th2: mainly antiparasitic immunity
63
what is IL-6 secreted by and how does it shape the T cell response?
- secreted by macrophages
- Th17: immunity to fungi, extracellular bacteria
64
what is TGFbeta secreted by and how does it shape the T cell response?
- secreted by many cells
- Th17: immunity to fungi, extracellular bacteria
- Treg: immune regulation
65
involvement of ___ links innate immunity to adaptive immunity
TLR
66
what is cell migration induced by
injury (vasoactive and chemotactic factors are released in response to bacteria from tissue damage injury)
67
immune cell migration is a property common to all __, is preferential __ of different cells to different sites, and is essential for the capacity of the immune system to protect __
leukocytes, migration, tissues
68
3 steps in neutrophil migration (emigration of neutrophils from circulation into tissues)
- cell "rolling" (adhere to endothelium instead of floating by; think of velcro shoes on velcro floor)
- firm adhesion (tight binding)
- diapedesis (skeletal changes to squeeze through the wall
*all steps are catalyzed by a variety of adhesion molecules
69
4 steps of lymphocyte migration
1. naive lymphocytes move from primary lymphoid tissues, via circulation, to secondary lymphoid tissues (this is where Ag processing and presenting)
2. activated lymphocytes move from spleen and lymph nodes into circulation
3. circulating activated lymphocytes migrate into other lymphoid organs, or cross vascular endothelium into other tissues
4. antigen presenting cells migrate to lymphoid organs, carrying antigen from the periphery
70
chemotaxis is the
directed movement of leukocytes along a concentration gradient of chemoattractants
71
chemoattractants may be derived from
the tissue or from infecting organisms
72
chemotaxis stimulates
leukocytes by binding to receptors on the neutrophil surface
73
4 examples of neutrophil chemoattractants
- N-formyl-methionyl peptides (FMLP)
- complement fragment C5a
- leukotriene B4 (LTB4)
- interleukin-8
74
adhesion molecule numbers can be modulated by
- recruitment from intracellular stores
- novel synthesis
- both
75
3 families of adhesion molecules
- immunoglobulin superfamily (Ab, TCR, MHC, T cell components, etc)
- integrins
- selectins
76
3 major beta2-integrins (very important adhesion molecules!)
- CD11a/CD18 (aka LFA-1)
- CD11b/CD18 (aka Mac-1)
- CD11c/CD18 (aka p150,95)
*CD18 subunit is critical to these integrins
77
what is CD11a/CD18 (LFA-1) expressed by
T and B cells, NK cells, granulocytes, and macrophages
78
what are the ligands for CD11a/CD18 (LFA-1)
ICAM-1 and ICAM-2
79
what does LFA-1 mediate
it mediates the adhesion of T cells to various other cell types including APC
80
what are CD11b/CD18 (Mac-1) and CD11c/CD18 (p150,95) expressed by
myeloid cells but not by the majority of T cells
81
what are the ligands for CD11b/CD18 (Mac-1) and CD11c/CD18 (p150,95)
C3Bi and others
82
what do CD11b/CD18 (Mac-1) and CD11c/CD18 (p150,95) play an important role in
adhesion and emigration of leukocytes to extravascular sites
83
leukocyte adherence deficiency is a defect in
the gene for CD18
84
leukocyte adherence deficiency causes
defective expression of all three beta2-integrins at the cell surface
85
leukocyte adherence deficiency results in
clinical condition, often fatal
86
during opsonization, __ are activated by __, via specific surface receptors for __
phagocytes, immunoglobulins, Fc
(FcgammaR (I, II, III); FcalphaR)
87
in opsonization, distinction of bound from free Ig is achieved through __ binding of Igs on __ surface (i.e. crosslinking of FcR)
multivalent, Ag
88
what receptors are involved in opsonization
complement, CR3 (CD11b/CD18 - Mac-1)
89
6 steps in phagocytosis
1. adherence (enhanced by opsonins)
2. ingestion (uptake into phagosome)
3. fusion of lysosomes to form phagolysosome
4. activation of respiratory burst
5. destruction and digestion by lysosomal contents and reactive oxygen species
6. exocytosis of remains (APC will save some remains and give to T cells)
90
3 steps of respiratory burst
1. increase in oxidative metabolism of phagocytes following uptake of opsonized particles (NADPH, oxidized to generate O2-)
2. production of bactericidal reactive oxygen/nitrogen intermediates (O2- --> H2O2; iNOS --> NO)
3. myeloperoxidase uses H2O2 to oxidize Cl- to OCl-
