Innate Immunity Flashcards
(94 cards)
1
Q
kinetics of innate and adaptive immune response
A
Innate: immediate defense reaction, no memory of aggressors
Adaptive: slow defense reaction. Memory cells enabling vaccination
2
Q
How does the host respond to microbes (bacteria, viruses, fungi, protozoa)?
A
- No response would lead to death
- in the host response, first line of defense is non-specific innate immunity, which induces inflammation
- second line of defense is specific adaptive immunity, which is mediated by humoral immunity (antibodies produced by B cells) and cell-mediated immunity (T cells)
3
Q
How do the innate and adaptive immune systems work together?
A
Innate immune response induces the adaptive immune response, which then uses elements of the innate immune response to clear the infection
4
Q
____ is essential for effective host defense at the early stage of infection
A
innate immunity - especially neutrophils and macrophages
5
Q
___ is essential for microbe clearance
A
adaptive immunity - if microbes cannot be cleared, then microbes will start to grow again
6
Q
innate immune response occurs in these several steps:
A
- recognition of the pathogen by host cells: receptors for pathogen constituents
- recruitment of host cells at the site of infection: mediated by soluble proteins (cytokines, chemokines)
- activation of destructive effector mechanisms: effector cells engulf pathogen and effector cells kill pathogen or pathogen-infected cells
7
Q
how does innate immunity vary according to microorganism type?
A
extracellular infection in interstitial spaces, blood, lymph: complement, macrophages, neutrophils
extracellular infection on epithelial surfaces: antimicrobial peptides
intracellular cytoplasmic infection: NK cells
intracellular vesicular infection: activated macrophages
8
Q
Extracellular vs. Intracellular innate immunity
A
extracellular means the infection is accessible to soluble molecules and phagocyte
intracellular infection requires killing of activation of infected cells
9
Q
how many molecules can the innate immune system recognize?
A
10^3 (compared to 10^7 of adaptive)
10
Q
specificity of innate immunity
A
recognizes structures which are shared by various classes of microbes but are not present on normal host cells
11
Q
Pattern Recognition Receptors (PRRs)
A
proteins on or in cells that recognize specific compounds unique to microbes or tissue damage, allowing the cells to sense the presence of invading microbes or damage
12
Q
receptors of innate immunity
A
PRR is encoded in the germline and possess limited diversity.
PRR distribution is non-clonal: indentical receptors on all cells of the same lineage
13
Q
A skin infection is occurring. What is the first step by which the cells of the innate immunity identify that microbes have invaded the skin?
A
They express receptors with limited diversity allowing them to recognize molecules expressed by microbes
14
Q
Overview of how cells of the innate immunity identify microorganisms?
A
pattern recognition receptors recognize pathogen associated molecular patterns
15
Q
Pathogen-associated molecular patterns (PAMPs)
A
Molecules associated with groups of pathogens that are recognized by cells of the innate immune system;
Molecules expressed and/or produced solely by microbes and recognized by PRR expressed by immune cells
Can be nucleic acids, proteins (ex. flagellin), cell wall lipids (ex. LPS), carbohydrates (ex. glucans)
16
Q
cellular location of pattern recognition receptors (PRRs)
A
PRR expression and ligands are redundant (more than one receptor can recognize the same molecule)
- localized at plasma and endosomal membrane, and in the cytosol
- recognize similar types of ligands
17
Q
PAMPs recognition by Toll-like receptors (TLRs)
A
Expressed on cells that are components of the innate immune system
- macrophages, DC, neutrophils, mast cells, mucosal epithelial cells, endothelial
- also on B and T cells
- 10 in humans (not TLR 11-13) and 12 in mice (not TLR10)
18
Q
TLR-4
A
recognizes LPS
19
Q
TLR-3
A
recognize double stranded RNA
expressed in the endosome
20
Q
TLR structure
A
- leucine-rich repeat motifs in extracellular domain
- cysteine-rich flanking motif
- TIR domain inside the membrane, transduces the signal
21
Q
TLR signal transduction
A
- TLR engagement by bacterial or viral molecules
- recruitment of adapter proteins MyD88 and TRIF
- activation of transcription factors and cytokine production
a. cytokine production leads to acute inflammation and stimulation of adaptive immunity
b. production of type 1 interferon leads to antiviral state
22
Q
all TLRs can recruit MyD88 except…
A
TLR3; TLR3 recruits TRIF and triggers production of type 1 interferon, IFNa/B
23
Q
Inflammasome
A
- Complex of molecules that activates inflammatory processes and provides host defense
- 14 types
24
Q
disease involvement of inflammasome multiprotein complex
A
- periodontitis-dental calculus
- gout-urate crystals
- atherosclerosis-cholesterol crystals
- obesity-associated T2D-free fatty acids and lipids
- Alzheimer’s disease-B-amyloid
- auto inflammatory syndromes
25
NLRP3 inflammasome assembly and function
- oligomerization of several molecules of NLRP3 (sensor), adaptor and inactive caspase-1
- inflammasome assembly leads to caspase-1 activation and results in cleavage of pro-IL1 (inflammatory cytokine) and secretion of IL-1, leading to acute inflammation
26
what initiates NLRP3 assembly?
- microbial products
- substances indicating cell damage and death
- endogenous substances in excess in tissues
- inorganic particles
27
What are the components of the innate immune system?
Epithelial barriers, phagocytes, NK, and mast cells
*physical barrier first to be encountered, then cells of innate immunity, and then adaptive immune system
28
functions of epithelia in immunity
- physical barrier
- chemical barrier: secretes peptide antibiotics
- cellular barrier: intraepithelial lymphocyte
29
physical barrier to infection
Different things produced in different areas
- keratin (skin)
- mucus (GI and respiratory and genitourinary tract)
- saliva (oral cavity)
- tight junctions of epithelial cells
30
antimicrobial peptides
- killing of microbes by locally produced antibiotics, defenses, calthelicidins
- calthelicidin: are cleaved into 2 peptides to become activated (neutrophil, epithelial cells)
- defensin: 29-33 AA peptide (epithelial cells, granules from neutrophil, NK, CTL, Crypticidins (paneth cells)
- disrupt outer membranes of bacteria and some viruses
31
intraepithelial lymphocytes
- are lymphocytes with limited diversity
- killing of microbes and infected cells by intraepithelial lymphocytes
- gamma-delta T cells: TCR with little diversity recognize PAMPs
- B-1 cells produce natural antibodies with limited diversity specific for bacterial carbohydrate
32
neutrophil characteristics
- polymorphonuclear
- 1x10^11 per day and short lived (6 hrs in blood) - thus a lot of them needed
- contain 2 types of granules: specific and azurophilic
33
Specific granules of neutrophils
enzyme (lysozyme, collagenase, elastase)
34
Azurophilic granules of neutrophils
microbial substances (defensins, cathelicidins) and lysosome containing enzymes (acid hydrolase, elastase, myeloperoxidase)
35
neutrophil activation and function
Sequential steps:
1. active recruitment: chemotaxis by following gradient of chemokine
2. microbe recognition and phagocytosis (ingest microbe)
3. destruction
Neutrophils mediate the earliest phase of inflammatory responses
36
mononuclear phagocytes characteristics
- 10x less abundant in blood than neutrophils
- long-lived (major difference with neutrophil)
- monocytes differentiate into macrophages in tissues
37
macrophage characteristics
- sequential steps: active recruitment, microbe recognition, phagocytosis (ingest microbe), and destruction
- come from bone marrow, called monocyte in the blood, called macrophage when in the tissue
- mediate the later stages of the innate immune response, 1 or 2 days after infection
- are dominant effector cells of the innate immune response: rapid response, persist at inflammation sites, not terminally differentiated and can undergo cell division
38
tissue-resident macrophages
Specialized tissue-resident macrophages divide/differentiate in tissue
- brain: microglial cell
- liver: Kuppfer cell
- lung: alveolar macrophage
39
function and activation of classical or M1 macrophages
- trigger inflammation
- kill microbes
- important effector cells in adaptive immunity
40
classical or M1 macrophage activation
- activated by TLR, cytokine binding, complement
- produce pro-inflammatory cytokine for enhanced adaptive immunity
- initiate phagocyte oxidase to produce reactive oxygen species (ROS) and iNOS to produce nitric oxide both to kill microbes. Also phagocytosis of microbe into phagosome to kill microbes.
41
dendritic cell characteristics (5)
- derived from bone marrow myeloid precursors
- constitute 2-5% of the mononuclear cells in the blood
- widely distributed in lymphoid tissues, mucosal epithelium, and organ parenchyma
- possess dendrites and phagocytic capabilites (but goal is not to phagocyte to kill, goal is to digest and present antigen to T cells in lymph nodes)
- different types of DC: classical and plasmacytoid
42
classical dendritic cells
- link innate and adaptive immune responses
- capture and display microbial antigens to naive T lymphocytes
- tune T cell response by secreting cytokines
- orchestrate the T cell response
43
Plasmacytoid dendritic cells
- play an important role in defense against virus
- bind dsRNA via TLR3 in endosmose
- produce type I interferon (IFNa/B-antiviral activities)
44
natural killer cells
- constitute 5-20% of the mononuclear cells in the blood and spleen
- neither T or B cells
- do not express somatically rearranged clonal distributed antigen receptors
- kill target cells without a need for additional activation (but can be further activated by cytokines)
- killers of the innate immune response (cytotoxic cells killer of adaptive immune response)
45
stimulates NK cell development and maturation
IL-15
46
NK cells killing function is enhanced by...
IL-12 and IFNa/B
47
inhibition of natural killer cell activation
- inhibitory receptor engagement: signals from inhibitory receptors block signals from activating receptors and determine NK cell activation
- NK cells have two receptors: activating and inhibitory (binds to self class I MHC-self peptide complex)
- if inhibitory receptor is bound, NK cell is not activated, thus no cell killing occurs
48
Explain how the expression of ligands for NK cell receptors impacts the balance between the activating and inhibitory receptors
- healthy nucleated cells express class I MHC molecules (ligand for inhibitory receptor)
- expression of class I MHC molecules is decreased in tumor cells and some virus-infected cells
- MIC-A and MIC-B is produced by stressed cells (infected, cancerous, damaged) and bind to the activating receptor
- activating receptor takes precedence
49
Class I MHC molecules
A collection of cell surface proteins encoded by a family of genes called the major histocompatibility complex. Class I MHC molecules are found on nearly all nucleated cells.
50
natural killer cell function
- NK cells are non-phagocytic cells that kill virus-infected cells via perforin/granzyme
- eliminate the reservoir of infection by preventing the virus from using host machinery to survive
- NK cells produce IFNgamma (inflammatory molecules) which activates macrophages and leads to killing of phagocytosed microbes
51
mast cells, basophils, eosinophils
- myeloid precursors
- mast cells mature in tissue such as skin and lungs and are found near blood vessels in tissues
- basophils and eosinophils are found in blood
52
function of mast cells, basophils, eosinophils
- Upon activation, they release proteolytic enzymes and substances that contribute to inflammation: histamine, prostaglandins, heparin, leukotrienes, TNFa
- important in helping to protect against helminth and bacterial infection (receptors for IgG and IgE) and involved in allergy
53
role of innate immune responses in stimulation of adaptive immunity
- lymphocyte activation requires two signals
- innate immunity molecules provide second signals (microbial antigen is first signal): IL-6 and C3d for B lymphocytes; costimulatory molecules (B7) for T lymphocytes: leads to lymphocyte proliferation and differentiation
54
cytokines (IL-12 and IL-6) produced by ___ direct differentiation of T cells
dendritic cells -> leads to T cell survival, proliferation, and differentiation
55
3 signals
1st signal: antigen recognition by T-cell receptor
2nd signal: interaction of B7 with CD28 on T-cells
3rd signal: cytokine that dendritic cells are making
a. IL-12 tells T-cells to make IFNgamma to become hyper T-cells
b. IL-6 tells naive T-cells to make IL-17
*cytokine produced by dendritic cells direct the differentiation of the T-cells
56
What is the most important function of the innate immunity at early time-points (days) following a bacterial infection?
Controlling the levels of bacterial infection until the adaptive immunity is activated is the main function of the innate immunity.
57
_______ immunity is essential for effective host defense at the early stage of infection
Innate
58
_______ immunity is essential for microbe clearance
adaptive
59
In regards to innate immunity, (extracellular/intracellular) microorganism are accessible to soluble molecules & phagocyte
Extracellular
60
In regards to innate immunity, (extracellular/intracellular) microorganism require killing or activation of infected cells
Intracellular
61
In regards to innate immunity, what is the defense mechanism of interstitial spaces, blood and lymph
Complement, Macrophages, Neutrophils
62
In regards to innate immunity, what is the defense mechanism of epithelial surfaces
Antimicrobial peptides
63
In regards to innate immunity, what is the defense mechanism of intracellular cytoplasmic microorganisms?
NK cells
64
In regards to innate immunity, what is the defense mechanism of intracellular vesicular microorganisms?
Activated macrophages
65
In which type of immunity can identical toll-like receptors be found?
Innate
-For structures shared by classes of microbes (pathogen-associated molecular patterns) or damaged cells (damage-associated molecular patterns)
66
In which type of immunity can distinct antibody molecules be found?
Adaptive
-For structural detail of microbial molecules (antigens); may recognize nonmicrobial antigens
67
PRR encoded in germline posses ______ ______
limited diversity
68
What type of receptors can be found in innate immunity? What is their distribution?
Encoded in germline; limited diversity (pattern recognition receptors --> PRR)
Nonclonal: identical receptors on all cells of the same lineage
69
What type of receptors can be found in adaptive immunity? What is their distribution?
Encoded by genes produced by somatic recombination of gene segments; greater diversity
Clonal: clones of lymphocytes with distinct specificities express different receptors
70
Does innate immunity have discrimination of normal self and nonself?
Yes; healthy host cells are not recognized, or they may express molecules that prevent innate immune reactions
71
Does adaptive immunity have discrimination of normal self and nonself?
Yes; based on selection against self-reactive lymphocytes; may be imperfect (giving rise to autoimmunity)
72
Molecules expressed and/or produced solely by microbes
PAMPs (Pathogen Associated Molecular Patterns)
-Are recognized by PRR (pattern recognition receptors) expressed by immune cells
73
PRR expression and ligands are redundant. Where are they localized at?
Plasma and endosomal membrane, and in the cytosol
-Recognize similar types of ligand
74
Where are Toll-Like Receptors expressed?
On cells that are components of the innate immune system
**TLR-4 recognizes LPS
**TLR-3 recognizes double-stranded RNA
(TLRs recognize PAMPs)
75
Recruitment of adaptor proteins, _____ and _____ leds to activation of transcription factors and cytokine production
MyD88 and TRIF
76
TLR3 recruits TRIF and triggers ________ production
IFNalpha/beta
77
Increased expression of cytokines, adhesion molecules, and costimulators leads to....
-Acute inflammation
-Stimulation of adaptive immunity
78
Production of type 1 interferon (IFN alpha, beta) leads to what type of state?
An antiviral state
79
NLRP3 inflammasome assembly is initiated by sensing what molecules?
-Microbial products
-Substances indicating cell damage and death
-Endogenous substances in excess in tissues
-Inorganic particles
80
List a physical barrier of epithelia
Saliva (oral cavity)
81
List a chemical barrier of epithelia
Kill microbes by disrupting outer membranes of bacteria and some virus
82
List some key characteristics of neutrophils
-Most abundant 1x10^11/day
-Short lived --> 6 hours in blood (dies if it doesn't encounter anything
-No lysosome
-Mediate the earliest phase of inflammatory response (1st to be recruited if there's an infection)
83
List some key characteristics of mononuclear phagocytes
-10x less abundant in blood than neutrophils
-Long-lived
-Monocytes differentiate into macrophages in tissues
84
List some key characteristics of macrophages
-Mediate the later stages of the innate immune response, 1 or 2 days after infection
-Divide and persist at inflammation site
85
What is the function and activation of classical or M1 macrophages?
-Trigger inflammation
-Kill microbes
86
List a key characteristic of dendritic cells (DC)
Posses dendrites and phagocytic capabilities
87
List characteristics of Classical DC
-Links innate and adaptive immune responses
-Captures and displays microbial antigens to naive T lymphocytes
-Tunes T cell response by secreting cytokines
88
List a key characteristic of Plasmacytoid DC
Produces type I interferon (IFNalpha/beta) that possess antiviral activities
89
List key characteristics of NK cells
-Do not express somatically rearranged clonally distributed antigen receptors
-Are not phagocytes
-Kill virus-infected cells via perforin/granzyme
90
What happens if the inhibitory receptor is engaged?
Signals from the inhibitory receptors block signals from activating receptors (NK cells not activated; no cell killing)
91
What happens if the inhibitory receptors is not engaged?
Lack of inhibitory receptor engagement triggers activation (NK cell activated, killing of infected cell)
92
Mast cell, basophil and eosinophil function
-Upon activation, release proteolytic enzymes and substances that contribute to inflammation.
ex: histamine, prostaglandins, heparin,
leukotrines, TNFalpha
-Protect against helminth
93
Lymphocyte activation requires two signals. Describe these signals
Signal 1 = antigen binding to antigen receptor
Signal 2 = molecules provided by innate cells
94
Describe the signals provided by innate cells to T cells
-Second signal for lymphocyte T activation
-Differentiation signal or third signal
