Innate Immunity Flashcards

1
Q

What is the immune system?

A

A collection of cells and chemicals that work together to protect us from disease

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2
Q

Where are leukocytes produced?

A

Red Bone Marrow

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3
Q

What types of immunity does Innate immunity involve

A

Humoral and cellular immunity

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4
Q

What does innate humoral immunity involve?

A

Proteins dissolved in serum, plasma and tissue fluid

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5
Q

What proteins does innate humoral immunity involve?

A

Acute phase, complement proteins and antibodies

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6
Q

What is cellular immunity?

A

Cells which have mechanisms to identify and kill foreign organisms
Cellular immunity occurs inside infected cells and is mediated by T lymphocytes. The pathogen’s antigens are expressed on the cell surface or on an antigen-presenting cell
slower

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7
Q

What has to happen for innate immune response to start?

A

Pathogens must breach physical barriers

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8
Q

What immune cells are involved in innate response?

A

Phagocytes (neutrophils and macrophages) and natural killer cells

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9
Q

What ways can a pathogen enter the body?

A

Respiratory tract, skin, eyes, gastrointestinal tract, genitourinary tract

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10
Q

What physical barriers does the body have to prevent pathogen entry?

A

Wax, hair, tears (lysozymes), mucus, membranes, specialist epithelial cells, air movement

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11
Q

What physical barriers are there to pathogens outside of the body

A
  1. Air flow
  2. Antimicrobial Enzymes e.g lysozymes in tears
  3. Low pH (skin has sebum that contains fatty acids)
  4. Defensins- antimicrobial peptides that destroy the cell membrane
  5. Normal microbiota/flora of skin outcompete pathogens- reduce space nutrients for pathogen entering
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12
Q

What physical barriers are there once pathogen has entered body tissue?

A
  1. Epithelial cells tight junctions- restrict microorganisms moving deep into tissue
  2. Goblet cells- secrete mucus that is sticky and traps bacteria
  3. Ciliated cells - cilia waft to push and flush out pathogens
  4. Immune cells in the tissue- phagocytes phagocytose pathogens
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13
Q

What happens if the barriers are breached?

A

Cells are damaged and exposed to the environment

A bump/cut can initiate inflammatory response even without presence of pathogen

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14
Q

What is inflammation?

A

Body’s response to damage to protect itself
Located to the site of damage and involves the immune response
Has a series of stages and is resolved and tissue returns to normal

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15
Q

Stages of inflammation?

A
  1. innate immune cells e.g basophils, eosinophils and platelets release histamine and cytokines
  2. Histamine binds to histamine receptors
  3. Histamine causes vasodilation of blood vessels resulting in localised heat and redness
  4. Increased temperature prevents pathogen colonising and reproducing
  5. Histamine causes blood vessels to become more leaky= exudation of fluid from blood into tissue
  6. Causes swelling (odema) and pain
  7. Cytokines attract phagocytes to infection site
  8. Phagocytes kill pathogen by phagocytosis
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16
Q

Signs of Inflammation

A
Rubor= Redness
Calor= Heat
Tumor= Swelling
Dolor= Pain
Functio Laesa= Loss of function
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17
Q

Receptor-Ligand Interactions

A
  1. Receptor binds to ligand
  2. Causes a conformational change in receptor
  3. Causing signal to change gene expression
    Immune system works by turning ligand-receptor interactions on/off
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18
Q

What happens when no microbes are present?

A
  1. Damaged cells are released into fragments
  2. Fragments contain Damage Associated Molecular Patterns (DAMPs)
  3. DAMPs bind to receptors
  4. Cytokines released
  5. Inflammation Triggered
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19
Q

Examples of DAMPs

A

DNA, RNA, proteins in nucleus

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20
Q

What happens when microbes enter the wound?

A
  1. Microbes enter body
  2. Microbes release chemicals that body sees as ‘foreign’
  3. Some microbes are pathogenic and can grow within the tissue causing more damage to cells.
  4. Some pathogenic microbes can enter cells living inside of them.
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21
Q

What immune response deals with Extracellular pathogens?

A

Humoral Immunity

By soluble factors: Antibodies, acute phase proteins, (e.g C reactive protein) and complement

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22
Q

What immune response deals with intracellular pathogens?

A

Cell mediated immunity

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23
Q

What are Acute Phase Proteins?

A

Proteins that change their serum concentration by >25% in response to inflammatory cytokines
They can have pro/anti or both inflammatory effects

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24
Q

Where are acute phase proteins released from?

A

Liver

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25
What do Acute Phase Proteins bind to?
Bind to pathogens and destroy them
26
3 examples of Acute Phase Proteins released from the liver
1. C-reactive protein 2. Fibrinogen 3. Mannose-binding lectin
27
What does C-reactive protein do?
1. promotes binding of complement= enhancing phagocytosis by macrophages It is an acute marker of inflammation Levels increase dramatically during inflammation
28
What is the complement system?
Made up of a large number of distinct plasma proteins (C1-C9) that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection Activated when C1q binds to antibody attached to antigen (IgG bound to antigen)
29
3 outcomes of the complement pathway?
1. Opsonisation/Phagocytosis 2. Chemotaxis 3. Membrane Attack Complex
30
What is chemotaxis?
C3a and C5a recruit phagocytes to infection site and promote inflammation C3A and C5a can increase permeability of blood vessels and activate mast cells
31
What are some chemotactic factors?
1. Products of injured tissue 2. Factors from blood e.g C5a 3. Histamine released from mast cells and neutrophils 4. Bacterial products
32
What factor forms membrane attack complex?
C3b combines with C3 convertase= C5 convertase C5 cleaved into C5a and C5b C5b recruits C6,C7 then recruits C8 Causes polymerisation of C9 in membrane Poly C9 protein in cell membrane = C5b6,7,8-9= Membrane attack complex
33
3 pathways of the complement system
Classical Pathway Lectin Pathway Alternative Pathway
34
Which of the pathways are antibody dependent?
Classical pathway | Needs an antibody/antigen complex to trigger it
35
What antibodies are involved in the complement pathway?
IgM and IgG
36
How is the membrane attack complex formed?
When complement enzymes cleave C5
37
What are C1-C9 proteins cleaved into?
a and b fragments
38
a fragment
smaller, inactive
39
b fragment
larger, active
40
What does C3a help in?
Inflamamtion
41
Membrane attack complex
Influx of Ca2+ into cell | causing osmotic lysis
42
Which 2 pathways are antibody-independent?
Lectin Pathway and Alternative Pathway
43
What initiates the lectin pathway?
Pathogen membrane containing Mannose
44
Components pf the alternative pathway
Factor B, Factor D, properdin protein
45
Innate Lymphoid Cell
Don't express antigen-specific receptors | Release cytokines
46
How do innate immune cells find and detect pathogens?
1. Damaged cells release DAMPs 2. DAMPs bind to receptors on immune cells (mainly macrophages and dendritic cells) 3. this activates transcription pathways to kill pathogen 4. PAMPs also bind to immune cells to make them aware of infection
47
What do DAMPs and PAMPs bind to?
Pattern Recognition Receptors
48
Where are PRRs found?
Surface of macrophages and dendritic cells
49
Examples of common PAMPs
1. Spike Coat Proteins on DNA/RNA viruses 2. LPS 3. LTA 4. Flagellin
50
Where is LPS found?
Outer membrane of Gram negative bacteria
51
Where is LTA found?
Cell wall of gram positive bacteria
52
Types of Pattern Recognition Receptors
1. External PRRs 2. internal PRRs 3. Phagocytic Receptors
53
Name of external PRRs
Toll like receptors
54
Name of Internal PRRs
NOD-RIG like receptors and endosomal receptors
55
Where are internal PRRs found?
Cytoplasm of immune cells
56
How may toll like receptors are there
9
57
Homodimer TLRs
TLR 4 | TLR 5
58
Heterodimer TLR
TLR 2 binds to TLR 1/6
59
Which TLRS are external?
TLRS 1,2,4,5,6
60
Which TLRs are inside immune cell?
TLRs 3,7,8,9 (all homodimer)
61
What does TLR 3 bind to?
Double stranded RNA
62
What does TLR 7 bind to?
Single Stranded RNA
63
What does TLR 8 bind to?
Single Stranded RNA
64
What does TLR 9 bind to?
CpG DNA
65
What cells is TLR 2&1/6 found on?
``` Monocytes Dendritic cells Mast cells Eosinophils Basophils ```
66
What cells is TLR 5 found on?
Intestinal epithelium cells
67
What cells is TLR 4 found on?
Macrophages Dendritic cells Eosinophils Mast cells
68
What are cytokines?
Chemical mediators of cell to cell communication
69
What are pro-inflammatory cytokines?
Signal cells there is danger | Activate immune cells and induce inflammation
70
Examples of pro-inflammatory cytokines
Tumour necrosis factor (TNFα) IL-6 IL-1 beta
71
What are anti-inflammatory cytokines?
Signal cells that there is no danger | Turn off inflammation
72
Examples of anti-inflammatory cytokines
IL-10 | Transforming Growth Factor beta (TGFβ)
73
IL-6
Earliest cytokine released by damaged cell | Causes release of acute phase proteins from liver
74
What releases cytokines?
Macrophages
75
What do cytokines do?
1. Cytokines released by macrophages signal hypothalamus to increase temperature= fever 2. Signal bone marrow to increase WBC production 3. Cause blood vessel walls to become leakier
76
Process with PRRs
PAMPs/DAMPs bind to PRRs Causes immune cells to release cytokines/chemokines Chemokines attract WBC to site of infection Pathogen binds to PRR Pathogen is engulfed and phagocytosed by macrophage/neutrophil
77
How do macrophages kill the pathogen?
1. pathogen is recognised by PRR 2. Macrophages are activated 3. Phagocytosis is induced 4. The pathogen is internalised in a phagosome by pseudopodia- The actin filaments in the cytoplasm push the cell membrane 5. Phagosome fuses with a lysosome containing antimicrobial peptides, enzymes and reactive oxygen species= phagolysosome 6. Activated macrophages make pro-inflammatory cytokines which attract and activate other immune cells 7. The pathogen is killed by oxidative burst and digested by enzymes
78
How do the immune cells find the pathogen?
Chemokines are made by macrophages | Immune cells will move to the area of the highest chemokine concentration
79
What do neutrophils do when they arrive?
1. Phagocytosis 2. Netosis 3. Killed by apoptosis when they are exhausted as they are v short lived
80
What is netosis?
Neutrophils create extracellular nets= meshwork of DNA, sugar and proteins that trap microbes
81
What happens if pathogen isn't cleared?
Pro-inflammatory cytokines are still released Causing systemic infection/inflammation Damaged blood vessels release bradykinins- continues to increase vascular permeability Results in chronic inflammation
82
What do bradykinins do?
Increase vascular permeability of damaged blood vessels Stimulates nerves Causing pain
83
What diseases can chronic inflammation lead to?
Rheumatoid arthritis | Multiple sclerosis
84
Example of an intracellular pathogen
Mycobacterium Tuberculosis
85
Why cant humoral response get rid of intracellular pathogens?
Humoral response wouldn't be able to access pathogen inside the cell
86
How do cells recognise intracellular pathogens?
1. DAMPs released by damaged cells by the pathogen are recognised by intracellular PRRs 2. PAMPs released from cell activate innate immune cells 3. Infected cells can flag themselves to show immune system they are infected
87
Most common intracellular pathogen
Viruses
88
How are Natural Killer cells and Adaptive immune cells activated?
By cytokines
89
What happens once DAMPs and PAMPs bind to intracellular Endosomal Toll-Like receptor?
Interferons are released
90
What do interferons do?
1. Interferes with viral replication 2. Enhances killing power of NK and cytotoxic cells 3. Enhances phagocytosis by macrophages 4. Stimulates production of antibodies 5. Slows cell division and tumour growth
91
What else do Interferons bind to?
Surface of uninfected cells
92
What do interferons cause uninfected cells to do?
1. Prevent viral replication by introducing transcription pathways 2. Cause uninfected cells to change their surface to prevent pathogen entery
93
Function of interferons
Increase viral defences and reduce viral replication in nearby uninfected cells
94
What are the anti-viral mechanisms of interferons?
Type 1 interferons= IFNa and β bind to IFNa receptor | These activate genes that degrades viral RNA and halts protein synthesis needed to make viral capsules
95
What do type 1 interferons also activate?
Natural killer cells
96
Interferon a and b
Feedback loop between these 2 - if IFN-B is produced first - It binds to receptors - Causes amplification of IFNa to be made - (IFNβ increases production of IFNα amplifying the response)
97
What do Natural Killer Cells do?
Kill virally infected and cancer cells by apoptosis
98
How do NK cells kill cells?
1. NK cells activate Interferon Gamma (IFNγ) and Interferon a (IFNa) 2. These interferons activate other immune cells 3. NK cells release perforin and granzyme
99
What does perforin do?
Punctures holes in cell wall
100
What does granzyme do?
Degrades pathogen= apoptosis
101
How do NK cells know which cells to kill when none of them are foreign?
A normal healthy cell is normally covered in inhibitory ligands But in cancer and virally infected cells these are degraded Cancer and virally infected cells up regulate activating ligands So these cells are coated in activating ligands
102
What does antimicrobial lysozyme do?
Digest bacterial cell wall
103
What does antimicrobial peptide defensin do?
Lyse bacterial cell wall
104
Does innate immunity provide long term immunological memory?
No
105
Once physical barriers are broken what are the 2 stages of innate immunity?
1. Antimicrobial enzymes, peptides, complement system | 2. Recognition of PAMPs by immune cells- acute phase proteins, inflammation
106
3 stages of response to initial infection
1. Innate immunity 2. Induced innate immunity 3. Adaptive immune response
107
Some anatomic barriers?
Phagocytes (macrophages) below epithelia- engulf and digest pathogen Antimicrobial enzymes/peptides
108
Route of entry of pathogen into body
GI tract Respiratory tract and mouth Urogenital tract external surface- wounds and abrasions/insect bites
109
Pathogenesis meaning
Means by which pathogen causes disease and host response
110
Why can't staphylococcus and streptococcus bacteria be killed by phagocytes?
They have protective polysaccharide capsule that prevents phagocyte entering for phagocytosis This activates the complement pathway
111
Mycobacteria characteristics
Facultative intracellular pathogens Can replicate inside/outside of cell Arabinogalactan
112
Why wouldn't innate immunity be helpful in removing toxins?
Highly specific antibody is needed to neutralise toxins | So adaptive immunity is required
113
Example of an endotoxin
LPS in outer membrane of gram negative bacteria
114
What do endotoxins trigger phagocytes to do?
Release cytokines
115
How does adaptive immunity differ from innate immunity?
AA targets structures specific to a particular strain or variants of a pathogen AA provides immunological memory
116
How does extracellular bacteria cause disease?
Release exotoxins
117
What do mucosal epithelium secrete?
Mucus (mucins=glycoproteins)
118
How does mucus help?
Mucus coats MO Prevents MO adhering to epithelium in respiratory tract MO flushed out by beating cilia once trapped by mucus
119
Why is peristalsis important?
keeps food and infectious agents moving through the body | if no peristalsis= accumulation of pathogenic bacteria in gut lumen
120
What is microbiota/commensal bacteria?
Non-pathogenic bacteria in the body
121
What does commensal bacteria do?
Competes with pathogenic MO for nutrients and attachment to epithelia surfaces
122
How does commensal bacteria compete with pathogenic MO?
Produce antimicrobial peptides (bacteriocins) Produce antimicrobial substances e.g lactic acid Strengthen barrier functions of epithelia which stimulates epithelia cells to make AM peptides
123
How does lysozyme kill bacteria cell wall?
Breaks chemical bond in peptidoglycan More effective in gram positive than gram negative bacteria as cell wall in gram positive is exposed in gram negative= cell wall covered by outer membrane LPS
124
How do defensins cause lysis of bacteria cell wall?
Insert ots hydrophobic region into membrane bilayer Create pores in cell wall= leaky = lysis
125
What does C5a in do complement system?
Stimulates respiratory burst in phagocytes Acts as chemoattractant for neutrophils and monocytes Promotes inflammation by increasing vascular permeability (bradykinin) Activates mast cells- release granules containing histamine and TNF-alpha= pro inflammation
126
What happens in induced innate response?
PPRs (TLRs) stimulate macrophages and dendritic cells by PAMPs
127
What do macrophages and dendritic cells secrete in induced innate immunity?
Cytokines and chemokines
128
What are chemokines?
Family of chemoattractant proteins | role in leukocyte migration
129
What do chemokines released by macrophages and dendritic cells do?
chemoattractants for leukocytes | recruits monocytes and neutrophils and otjer effector cells from blood to site of infection
130
What is the first immune cell to arrive at a site of infection?
Neutrophils
131
Which cells are recruited to site of infection after neutrophils?
Monocytes, immature dendritic cells
132
What do cell adhesion molecules do during an inflammatory response?
Control interactions between leukocytes and endothelial cells on blood vessels
133
During inflammation what cells cross the blood vessel wall and enter inflamed tissue?
Neutrophil
134
What do cytokines released by macrophages and dendritic cells activate?
acute phase proteins
135
What do acute phase proteins do?
Bind to pathogen Act as opsonins Activates classical pathway in complement system
136
Examples of acute phase proteins
C-reactive proteins serum amyloid proteins fibrinogen
137
What do pro-inflammatory cytokines(released by macrophages) cause?
Local effect- inflammation and repair | Systemic effect- fever, leukocytosis (accumulation of WBCs)
138
Local effects of pro-inflammatory cytokines?
Inflammation | Repair- activate fibroblasts to cause cell proliferation and collagen synthesis
139
Systemic effects of pro-inflammatory cytokines?
Fever (signal hypothalamus to increase body temp= prevent pathogen colonising) Leukocytosis- recruit neutrophils and monocytes to inflammation site (monocytes become macrophages when enter tissue) Neutrophil PRRs bind to PAMPs= phagocytosis
140
What happens during inflammation?
PAMPs of pathogen activate immune cells- macrophages and mast cells Mast cells release histamine (from their granules) Macrophages release pro-inflammatory cytokines
141
What are C3a and C5a?
Promote inflammation They are chemoattractants- attract immune cells Increase vascular permeability
142
What do dendritic cells/macrophages do once they have become activated APCs during inflammation?
Travel to lymph node (by chemokines) Dendritic/macrophage APC attracts naive B/T cells B cell= plasma cells= antibody T cell= T helper/cytotoxic
143
Chemotactic factors
``` C3a C5a Recruit neutrophils Increase vascular permeability Induce mast cells ```
144
In the complement cascade what acts as opsonins?
C4b, C1q, C3b
145
How is the complement cascade activated?
C1q binding to antibody(Ig M/IgG) (antibody-antigen complex)
146
What is the main component of membrane attack complex in complement cascade?
C9
147
What cytokine is produced once bacteria is cleared and tissue is clearing
IL-10 (anti-inflammatory)
148
What interferons activate NK cells?
Type1- alpha and beta