Midterm 2 Flashcards
(203 cards)
1
Q
why does the first line of defence against a virus have to be at the cellular level in the host?
A
viruses are intracellular parasites
2
Q
what are the two types of defence mechanisms vertebrates have?
A
- host immune response: coordinated multicellular approach at organismal level
- intrinsic cellular response: rapid pathogen recognition, cell communication to control pathogen
3
Q
what are the 5 steps of the intrinsic cellular defence?
A
- detection of virus infection
- host cell response to infection
- interferons: structure and synthesis
- induction of antiviral activity
- viral defences against interferon response
4
Q
what makes it so a pathogen can be recognized?
A
- microbe associated molecular patterns (MAMPs)
- for a virus this can be viral glycoproteins, nucleic acids specific to dsRNA, ect.
5
Q
what part of the host recognizes MAMPs?
A
-Pattern recognition receptors/molecules (PRRs or PRMs)
6
Q
what cells have PRRs?
A
phagocytic cells (macrophages, dendritic cells, and polymorphonuclear leukocytes (type of white blood cell), epithelial cells in mucosa membranes)
7
Q
what is an endocytic PRR?
A
-surface of phagocyte, promote attachment of virus to phagocyte which leads to engulfment and destruction
8
Q
what is a signalling PRR?
A
- include TLR, NRL, RLR
- can be expressed internally or externally
- activates pro-inflammatory signal pathways when bound to cognate MAMP ligand
9
Q
what is a secreted PRR?
A
- secreted by epithelial cells, hepatocytes
- activates complement, opsonins
- accessory for MAMP recognition
10
Q
what are the three types of signalling PRRs?
A
- Toll-Like Receptors: can localize in cell surface or in lumen of intracellular vesicles
- important for activation of innate and adaptive immunity - Retinoic Acid-Inductible gene-I (RIG-I) like receptors: located in cytosol
- specializes in detection of viral nucleic acids and coordinate initial responses - Nod (nucleotide-binding oligomerization domain) like receptors: intracellular
- include detection of viral nucleic acids in cytoplasm
11
Q
what happens when a ligand binds to a TLR?
A
-triggers signal transduction pathways that result in the synthesis and secretion of pro-inflammatory cytokines and co-stimulatory molecules (ex. NF-kappa beta signalling and Map Kinase pathway)
12
Q
what do cell surface TLRs (2 and 4) recognize?
A
-virion glycoproteins
13
Q
what do endosomal TLRs (3, 7/8, and 9) recognize?
A
different forms of nucleic acids
14
Q
what is a phagosomes role in detecting a virus?
A
they trap the virus and deliver it to a endoscope that harbours TLR-7/8, and TLR-3
-autophagy
15
Q
what is autophagy?
A
- intracellular digestion
- highly conserved
- tags internal microbes for destruction by labelling with ubiquitin protein
- an autophagosome fuses with a lysosome to degrade contained virus
16
Q
when a PRR of any type detects a viral component what always happens?
A
-they activate a defence response that involves activation of genes encoding for production of cytokines and interferons (amount others)
17
Q
what is Nuclear factor kappa beta for?
A
-its a transcriptional activator that’s needed for expression of cytokine genes and some interferon genes
18
Q
what are interferon regulatory factors 3 and 7 (IRF3 and IRF7) for?
A
-transcriptional activators needed for expression of interferon genes
19
Q
signal transduction pathway by binding of viral ligand to TLR if interaction occurs with MyD88:
A
- ligand binds to TLR and interacts with adaptor molecule MyD88
- MyD88 activates kinase IKK to phosphorylate I kappa B alpha (can also phosphorylate IRF3,7)
- the phosphorylated IκBα releases NFκB which moves to the nucleus to induce transcription of cytokine genes
20
Q
signal transduction cascade caused by binding go viral ligand to TRP if interaction occurs with TRIF:
A
- ligand binds to TLR and interacts with adaptor molecules TRIF
- TRIF activates kinase TBK-1 which phosphorylates IRF3 and IRF7
- the IRF3 and 7 move to the nucleus and induce transcription of type 1 interferon genes
21
Q
what is MyD88?
A
Myeloid differentiation primary response gene 88
22
Q
what is TRIF?
A
TIR-domain-containing adapter-inducing interferon-beta
23
Q
which TLRs bind to MyD88?
A
- TLR-2
- TLR-7/8
- TLR-9
- TLR-4
24
Q
which TLRs bind to TRIF?
A
- TLR-3
- TLR-4
25
what proteins are includes in RLRs?
- RIG-I (retinoic acid inducible gene I)
- MDA5 (melanoma differentiation-associated protein 5)
- LPG2 (laboratory of genetics and physiology 2)
26
what features of the virus does RIG-I recognize?
5'-triphosphate RNA and short dsRNA
| paramyxoviridae, orthomyxoviridae, rhabdovirisae and flaviviridae
27
what features of the virus does MDA5 recognize?
-long dsRNA that gets generated during the course of the infection
(picornaviridae)
28
what virus is detected by both RIG-I and MDA5?
-west nile virus
29
signal transduction pathway of RIG-I and MDA5:
1. RIG-I and MDA5 bind to viral RNA and interact with IPS-1 protein (IFN-Beta promoter stimulator-1)
2. IPS-1 activates the kinase IKK-i and TBK-1
- TBK-1 phosphorylates IRF-3 and IRF-7 which travel to nucleus and activate transcription of INF genes
- IKK-i phosphorylates IkBa which removes it from NF-kb/IkB grouping and NF-kB can now travel to nucleus and activate transcription of cytokine genes
30
what happens when IPS-1 associates with the mitochondrial membrane by binding?
gets involved in activation of apoptotic pathway
31
what do NRLs do?
- sense bacterial protein, viral ssRNA, and DAMPs of host(damage associated molecular patterns)
- participate in regulation of inflammatory, autophagy and apoptotic responses
32
what do NRLs activate?
- inflammasome by caspase-1
| - NF-kB and MAPK signalling pathway
33
what does the NLRP3 nod-like receptor (and AIM2) do?
- activates formation of inflammasome by caspase-1 (cleaves pro-IL-1 into active IL-1 (requires participation of adaptor protein that contains a CARD (ex. protein ASC) to activate it))
- active IK-1B mediates inflammatory response and is involved in cell proliferation, differentiation and apoptosis
34
how are NLRs activated by DAMPs?
by binding cathepsin, ROS, and stress molecules
35
how do TLRs and NLRs work cooperation together when binding to a MAMP?
they activate two different response mechanisms that cooperate and produce a potent inflammatory cytokine(IK-1)
- MAMP binding to TLR causes a signal transduction cascade that produces TF NFkBthat up regulates cytokine IL-1 gene which produces pro-IK-1 (needs activation)
- MAMP binding to NLR activates proteolytic enzyme capsase which cleaves pro-IK-1 activating it into IK-1
36
what does PKR stand for and do?
- protein knase R
| - senses viral dsRNA and inhibits translation by inactivating translation initiation factor eIF2a
37
what does OAS stand for and do?
- 2'-5' oligoadenylate
| - activates RNase L that degrades all cellular RNA
38
what does DDX3 do?
- RNA helicase family
- involved in mRNA metabolism
- may be involved in induction of interferon
39
list all the things that that sense viral RNA:
- RIG-1 and MDA5 (cytoplasmic RNA helices always present in host)
- some TLRs
- some NRLs
- PKR, OAS, and DDX3 (all in cytosol)
40
list the PRRs that recognize cytoplasmic dsDNA:
- DAI: induces production of interferon
- AIM2: activates caspase-1-activating inflammasome
- cGAS: activates expression of IFN I
- IFI16: activates production of cytokines and IFN I
41
what is the cell death pathway called proptosis dependant on?
caspase-1 and pro-inflammatory cytokines
42
after host cell responds to viral infection and cytokines are produced what do they stimulate?
- interferons: major part of host defence against most viruses
- pro-inflammaotry cytokines: active immune cells in circulatory system
- chemokines: recruit other immune cells to site of infection
- anti-inflammatory cytokines: suppress pro-inflammatory cytokines
43
what is the extrinsic pathway?
-binding of a molecule like TNFa to receptors on the cell surface
44
what is the intrinsic pathway?
-activated by internal stress like DNA damage or viral DNA replication
45
extrinsic pathway for apoptosis:
1. TNfa binds to cell receptor
2. adaptor proteins form a DISC (death inducing signalling complex)
3. procaspase-8 is activated to caspase 8 which leads to activation of other caspases 3/7 and auxiliary proteins that promote cell death
46
intrinsic pathway to apoptosis:
1. the viral infection (DNA damage, viral DNA rep.) activates protein p53 which induces production of Bax protein
2. Bax proteins bind to mitochondrial membrane
3. mitochondrial membrane becomes leaky and cytochrome c leaks out
4. cyt c activates caspase-9
5. caspase-9 activates caspase 3/7 which leads to apoptosis
47
other than intrinsic and extrinsic, how could a cell go through apoptosis?
activation of the RLR, MDA5
- it interacts with IPS-1 which binds to mitochondria membrane that results in leaking of cyt c
- TLR-3 and RGIG-1 also may be involved in apoptosis
48
what are interferons?
- get secreted from virus infected cells and protect nearby cells against the viral infection
- first line of host defence
- discovered in 1957 by Isaac and J. Lindenmann
49
what is viral interference?
-infection with one virus that interferes with infection of another virus
50
explain the interferon system
1 virus infects a cell
2. viral dsRNA goes into nucleus of the cell
3. cell recognizes virus and transcriptional activate of interferon genes begin
4. interferons are synthesized
5. interferons are secreted
6. interferons bind to outside of nearby cell (to receptors)
7. transcriptional activation of antiviral genes begins
8. antiviral proteins are synthesized
51
why is therapeutic use of cloned interferons limited?
- unpleasant side effects
| - short-lived antiviral effects
52
what can induce interferon production?
- RNA viruses
- dsRNA molecules
- LPS
- metabolic inhibitors of protein synthesis
53
why are slow infections more likely to invoke interferon response that fast virulent infections?
-virulent infections affect host transcription
54
4 key characteristics of interferons:
1. pretty unspecific
2. produced by almost any cell
3. protective effect is only useful on cells of same species
4. one of the first antiviral defences
55
when a cell interacts with an interferon, what is that hosts general responses?
- inhibit virus rep. (INF treated)
- inhibit growth of target cell
- activate macrophages, NK cells, and Tc cells
- induce MHCI and MHCII antigens and Fc receptors
- induce fever
- induce antiviral state in target cells
56
what are the three classes of interferons?
Type I: antiviral response
- IFN-a (leukocytes fibroblast. macrophages, epithelial cells)
- INF-B (fibroblasts and epithelial cells)
Type II: antiviral response
- IFN-lamba (leukocytes, fibroblast, macrophages, epithelial cells)
- gets induced by mitogens, antigens, interleukin-2
Type III: modulates immune response
- IFN-gamma (T cells, macrophages, NK cells)
- stimulates dev and actions of immune effector cells
57
what is the structure and synthesis of interferon a?
- name: leukocyte interferon
- type: I
- receptors: IFNAR1 and INFAR2c
- length: 165 aa
- number of genes: 13
- principal producer cells: leukocytes, fibroblasts, macrophages, epithelial cells
- induced by: virus, dsRNA
- activity: antiviral action
58
what is the structure and synthesis of interferon B?
name: fibroblast interferon
- type: I
- receptors: IFNAR1 and INFSR2c
- length: 165 aa
- number of genes: 1
- principal producer cells: fibroblasts, epithelial cells
- induced by: viruses, dsRNA
- activity: antiviral infection
59
what is the structure and synthesis of interferon lamda?
name: interleukins 28A, 28B, 29
- type: III
- receptors: IL28Ra and IL10RB
- length: 196-200 aa
- number of genes: 3
- principal producer cells: leukocytes, fibroblasts, macrophages, epithelial cells
- inducing agent: virus, dsRNA
- activity: antiviral action
60
what is the structure and synthesis of interferon gamma?
name: immune interferon
- type: II
- receptors: IFNGR1 and IFNGR2
- length: 146 aa
- number of genes: 1
- principal producers cells: T lymphocytes, macrophages, NK cells
- induced by: mitogens, antigens, interleukin-2
- activity: immune stimulation
61
what effects does IFN gamma have on the immune system?
-activates macrophages and induces Class II major histocompatibility complex (MHCII)
stimulates antigen processing and presentation by:
-enhancing MHCI expression
-promoting dev of CD8+ cytotoxic T cells
-modifies activities of components of proteosomes enhancing immunogenicity of viral proteins
62
how is interferon production induced by RIG-1?
- RIG-1/dsRNA formation which recruits MAVS (IPS-1) which activates kinases
- initiates cascade leading to activation of TFs IRF-3 and IRF-7
- activated IRF-3 and 7 induce expression of type I IFN
- produced interferon is released to neighbouring cells
63
when a cell recieves an interferon what happens to it?
goes into antiviral state
| -JAK-STATs signal transduction cascade is activated
64
what happens when the JAK-STAT pathway is activated by an interferon?
cascade leads to expression of interferon stimulated genes
65
what occurs when a cell goes into an antiviral state?
- antiviral effector molecules are induced and synthesized
- cells express new membrane associated surface proteins
- alternation of glycosylation patterns
- 2'5' OligoA synthetase and dsRNA dependent protein kinase (PKR) are produced
66
what antiviral activities are induced by interferons?
1. Myxovirus proteins interferes with transcription of influenza and other RNA viruses
2. 2'5'-oligoA synthetase activates by binding to dsRNA and activates ribonuclease L that degrades viral and cellular mRNAs
3. PKR is activated by dsRNA then phosphorylates a variety of cell proteins (inactivation of a factor involved in protein synthesis)
67
what does 2',5' oligoA synthase need to make 2,5 oligo A (adenylic acid oligomers)?
ATP
68
what does Oligo A activate?
- pro-enzyme Ribonuclease L
- RNase L cleaves viral and host RNA (mRNA and rRNA)
- the process induces apoptosis
69
how does the protein kinase system work?
- PKR is dsRNA dependant
- phosphorylates factor eIF2 which inactivates it in turn, blocking viral and cellular protein synthesis which kills virus and host cell
70
what are the negatives about interferons?
1. INF is negative growth regulator what induced apoptosis (cell dies)
- sometimes does reverse though
2. induced inflammation and high fever for host
71
what are the ways viruses have developed to evade interferon response?
1. inhibit PKR activity
2. inhibit production and activity of interferon
3. interfere with signalling pathways
72
what do plants and invertebrates do instead of producing interferons?
-use RNA interference to fight against viral infection
73
what are the possible entry points for viruses?
- G.I. tract
- conjunctiva
- capillary (arthropod)
- skin (injury)
- urogenital tract
- respiratory tract
74
what is the definition of the immune system?
-group of organs, cells, and tissues designed to recogonize and deal with foreign elements
75
what is immunity?
hosts ability to resist infection and disease
76
what is immunology?
study of the immune system and its responses
77
what are the two types of immunity?
1. innate: natural/non-specific host defences
- immediate and always on stand by
- natural ability to avoid infections
(ex. reaction to trauma, first response)
2. specific: acquired/adaptive host defence
- slower to respond, specific target orientated
- can develop memory
-the systems work together and are closely interconnected
78
what are the organs, proteins, and cells involved in the innate immune system?
1. physical barrier: epithelial cells (skin (inhospitable and tough to penetrate) and mucous membrane (bathed in antimicrobial properties)), cleansing mechanisms
2. specialized cells: phagocytes (macrophages and neutrophils) and NK cells
3. proteins: complement, cytokines, chemokines
79
what is the effectiveness of our innate response affected by?
- nutrition
- age
- physiological status
- hygiene
- living conditions
80
how can epithelial cells be flushed in order to not allow viruses inside the hosts body?
- saliva
- swallowing
- urination, defecation
- sweating
- coughing
- sneezing
- tearing
- peristaltic movements
81
what are the general characteristics of epithelial cells?
- line external and internal body surfaces that are exposed to external environment
- properties depend on location
- polarized (basal and apical surfaces)
- attached to basal lamina
- cover regions of loose connective tissue (fibroblasts and ECM components)
82
what components are found in the connective tissue?
- fibroblasts
- collagen
- laminin
- fibronectin
- glucosamaminoglicans (chondroitin sulfate, hyaluronan, heparin sulfate)
83
what are the types of epithelia?
- lumen of intestine (some areas in R tract)
- skin, cornea, interior mucosa exposed to abrasions
- dermis and some glandular organs
84
features of the epidermis:
- avascular layer of stratified squamous epithelium
- made of diff strata, outermost is dead cells
- form a keratinized protective layer on surface that sheds (desquamation)
- cells divide in base layer, then die as they are pushed outward
- epidermis cells replace monthly
85
what are keratinocytes?
- 90% of epidermis
- keratin fibers for networks make epithelial cells mechanically resilient
- major constituent in hard and nails
- some stains of papillomavirus live in skin keratinocytes
86
what cells are the host for some HPVs?
skin squamous stratified epidermis
87
features of the dermis:
- epidermis joins dermis at the dermal-epidermal junction
- irregular dense fibrous connective tissue
- contains collagenous and elastic fibres, together with fibroblasts, mast cells, and macrophages
- supplied with blood vessels
- structures: sweat glands, sebaceous glands, hair follicles
88
what is SALT?
- Skin Associated Lymphoid Tissue
- a specialized dense system that traps any microbes that have crossed epidermis
- provides connection to adaptive immune systems made of langerhans cells and intraepidermal lyphocitrs
89
what are langerhan cells?
type of dendritic cell the phagocytes antigens
- upon phagocytosis it turns into a interdigitating dendritic cell
- presents antigen to T cell (activating them) by travelling to nearest lymph node
90
what is a intraepidermal lymphocyte?
-type of T cells
91
what is the mucous membranes features?
- thin layer of epithelial cells that cover internal surfaces
- absorptive or secretory functions
- tightly packed and attached to each other by tight junctions and desmosomes (difficult to penetrate)
- sheds and traps microbes
- bathed by mucus or other secretions that contain antimicrobial compounds of host
- protected by mucosal associated lymphoid tissue (MALT)
92
how does the mucosa defend against viruses?
- get replaced regularly
- goblet cells that secrete mucin are bather by secretions containing antimicrobial compounds (mucus, saliva, tears)
- uses peristaltic movements , rapid flood of liquid and ciliate cells to move secretions along surface
- MALT (depends on tissue)
93
what is to mucociliary escalator?
-ciliate columnar cells that propel mucus with trapped microbes out of the area (happens in throat so microbes don't get to the lungs)
94
what is MALT?
- Mucousa-Associated Lymphoid Tissue
- founds in small intestine, colon, tonsil, respiratory and urogenital tract
- areas under mucosa containing small elements of adaptive immune system (T and B cells)
- macrophages present antigen to lymphocytes T and B and rapid localized specialized response is acheived
95
what mechanisms does MALT use for protection?
- macrophages trap and process microbes
- present microbial antigen to T lymphocyte which stimulates associate B cells to differentiate and become plasma cells that produce specific slgA
96
in the small intestine, what are MALT called?
- Peyer's patches (have additional type of cell called M cells located between mucosal epithelial cells that trap microbes)
- start disappearing as a person ages (you have the most when your young)
97
what do the M cells do as a Part of GALT that protects the intestine?
- captures antigens and passes them down to macrophages which in turn process the antigen and later interact with proper local T and B cells
- the active B cells secrete sIgA which is released into mucus
98
what antimicrobials are in body fluids?
- lysozyme
- lactoferrin
- lactoperoxidase
- cationic peptides (defensins)
99
if an individual has been exposed to a virus what will they have?
-secretory immunoglobulin A (slgA) that has specific reactions to particular viruses (ex. could bind to and neutralize viruses)
100
what are the features of cationic peptides called defensins?
- small peptides that are open ended, rich in arginine and cysteine, and disulphide linked
- secreted in repose to pathogens
- found in neutrophils, respiratory epithelial cells, and GI tract (Paneth cells)
- can sometimes block virus entry to host, prevent attachment
- presense stimulates activity of other cells of the immune system
- two types: alpha and beta
101
what do alpha defensins do?
- bind to virus causing them to clump which prevents them from reaching their host receptor
- produces by epithelial cells and neutrophils
102
what do beta defensives do?
- can interact with enveloped virus and disrupt their envelope
- expressed by epithelial cells
103
what are the features of the complement?
- belong to acute phase protein group
| - made of several proteins in blood plasma C1 to C9,B and H
104
what is the job of the complete in general?
- attract and active phagocytes
- help phagocytosis by opsonization
- form Membrane Attack Complex (MAC) that kills gram negative bacteria and our own cells when bound by antibodies or abnormal
- mediates inflammation
105
what are the 3 pathways a complement can be activated by?
- classical
- alternative
- MB-lectin
106
how is the complement activated by the alternative pathway?
complement protein C3 is circulating in the blood
- C3 protein spontaneously breaks up into 2 fragments
- fragment C3b lands on membrane of any cell of the body (silica acid of our cells attracts serum protein H which combines with C3b to make C3b-H target for degradation by serum protein I (protection mechanism for our cells so they don't die))
- bacteria or virus without silica acid doesn't attract protein H so C3b isn't degraded
- activation is complete
107
what happens once the complement has been activated for the alternative, MB-lectin, and classical pathway?
- protein D in blood cleaves protein B which produces a fragment Bb
- the bound C3b interacts with Bb to form C3 convertase
- C3 convertase recruits more C3 and it breaks into C3b and C3a
- large amounts of C3a (which is a anaphylotoxin) is released which initiates inflammation
- C3bBb is joined by another C3b fragment to form C3bBbC3b which changes proteolytic target from C3 to C5 (now called C5 convertase
- C5 convertase breaks C5 into C5a and C5b
- C5a is released and acts as chemoattractant to phagocytes
- C5b binds to surface of target cell and recruits complement proteins C6-C9 to form MAC
108
how is the classical pathway activated?
- a bacteria, infected cell, or virus, is bound by an antibody
- bound antibody attracts C1 protein from complement
- C1 cleaves C4 and C4 which forms C3 convertase (C2a and C4b)
- C4 and C2 produce a fragment a and b
- C2b and C4a are chemoattractants
- continues the same as the alternative pathway from here (formation of MAC
109
how is the MB-Lectin Pathway activated?
- a lectin protein called Mannose Binding Protein (MBP) binds to mannose on bacteria, some viruses, antigen/antibody complex
- the MBP interacts with and activates Mannose-binding lectin-Associated Serine Protease (MASP)
- the activated MASP cleaves complement proteins C2 and C4
- C2a and C4b form C3 convertase
- when C3 convertase recruits C3, rest of process is similar to the other two pathways
110
what are the roles of the complement?
1. opsonization: C3b bound to cell or virus facilitates phagocytosis
2. chemoattractant: fragments C5a, C4a, and C2b attract phagocytes
3. vasodilation/anaphylactoxins: fragments C3a, C4a, C5a contributes to inflammatory response (increase permeability of blood capillaries and trigger degranulation of mast cells)
4. formation of transmembrane channel leading to cell lysis (MAC formation)
111
what are cytokines?
-proteins or glycoproteins released by cells that act as intercellular mediators or signalling molecules
112
what induces cytokine production?
- nonspecific stimuli (infection)
- inflammation
- T cell-antigen interactions
113
what is the role of cytokines?
- regulate innate resistance mechanisms
- regulate adaptive immunity
- stimulate hematopoiesis
- inhibit proliferation
- chemotaxi
- apoptosis
- differientiation
- proliferation
- metabolic activity
114
what are important examples of cytokines?
monotones, lymphokines, interleukins, colony stimulating factors (CSFs)
115
what are the pro-inflammatory cytokines?
tumor necrosis factor-a, interleukin-1, interleukin-8, chemokines, interferon-g
- all appear early in infection and stimulate monocytes and granulocytes to leave the blood by IL-1 and and TNFa stimulating endothelial cells to produce selections to slow down PMNs
- also induce respiratory burst in macrophages and productions of IL-12, lymphotoxin and TNF
- Interleukin-6 and Interleukin-18
116
what type of interferon is this class focused on and what are the two classes?
- type I
- IFNa and IFNB
- gets produced by cells under viral attack
- secreted to be picked up by near cells
117
what stimulates acute phase protein production?
1. macrophage activated by a pathogen
2. cytokine is released
3. liver is stimulated
4. acute phase proteins are produced (C-reactive protein, mannan0binding lectin, surfactant proteins A and D)
- these can bind pathogens surfaces and act as opsonins
- may be pro- or antiinflammatory
118
what organs, tissues, and cells belong to the immune system?
```
ORGANS/TISSUES
-bone marrow
-circulatory and lymphatic systems
-blood
-lymph
-monocyte-macrophage system
CELLS
-most white blood cells
```
119
types of cells involved in immune system:
1. auxiliary: platelets, megakarynocytes, mast cells, basophils
2. phagocytes: neutrophils, eosinophils, monocytes, macrophages, dendritic cells
3. lymphocytes: T cells, B cells, plasma cells
others: granulocytes, leukocytes (WBC)
120
where do white blood cells arise from?
-pluripotent stem cells
121
what do monocytes and macrophages do?
- phagocytic cells that connect innate and specific immune systems
- monocytes circulate through the blood and reach target tissues to differentiate into macrophages (fixed residents of particular tissue)
122
what are the three types of lymphocytes?
natural killer
- T cells (cell mediate immunity)
- B cells (antibody production-humeral)
123
what are granulocytes?
-leukocytes contain lots of lysosomes (granules)
124
what tissues contain resident macrophages?
- liver (kupffer cells)
- brain
- spleen
- lung
- kidney
- lymph nodes
- blood
- joint synovial liquid
125
what is the mononuclear phagocyte system?
overall distribution of residential macrophages on different areas of the body
-resident macrophages protect areas from microbial invasion
126
what do dendritic cells look like?
-cells with neutron-like appendages
127
where can dendritic cells be found?
blood, skin (Largerhans), mucous membranes of nose, lungs, and intestines
128
what do dendritic cells do to antigens?
- makes contact with them, phagocytose them, and process the antigen displaying it on their surfaces (antigen presentation)
- best APC
129
what do neutrophils do? explain their transmigration.
- short lives
- circulate in blood
- kill microbes
- are the first to arrive at the site of an injury
- can leave blood vessels and move into the tissue (transmigration) by diapedesis or extravasation
130
what do basophils do?
- release histamines, prostaglandins, serotonin
| - involved in allergies
131
what is a mast cells and what does it do?
- located under skin and mucosa membranes
- releases granules (histamines) when activated as well as various hormonal mediators into interstitium
- when the chemicals are released, vasodilation occurs which makes blood vessels leaky
- this can be stimulated by injury or when foreign material is detected
- important in allergies
132
what is opsonization?
- antibodies and/or complement proteins bind a a microbe
| - phagocytes have receptors that can bind to opsonizing agents and facilitate phagocytosis
133
what is a opsonin dependant target recognition of phagocytes?
-microbe is coated by antibodies or C3b from complement
134
what is a opsonin independent target recognition of phagocytes?
-recognizes MAMP like lipopolysaccharides (LPS), mannose, and other material found in bacteria, viruses, etc. but not in host
135
what do pattern recognition receptors (PRR) do?
- receptors on phagocyte surface that are designed to recognize set of typical microbial molecules (recognizes MAMPs)
- used in opsonin-independent target recognition
136
how does intracellular digestion occur?
- when a microbe is bound its internalized and take not a lysosome which fuses with a phagosome
- respiratory burst reactions occur producing toxic oxygen which kills the invading microbe
137
what happens after intracellular digestion?
- neutrophils release microbial fragments by exocytosis
- macrophages and dendritic cells process peptides from microbe and eventually present them to the outside in special surface receptor called MHCII
- antigen presentation which activates Th cells
138
when do neutrophils use exocytosis?
- to expel microbial fragments after they've been digested
| - the phagolysosome units with the cell membrane and microbial fragments get released
139
how does antigen presentation occur?
- fragments from phagolysosome are moved to ER and the peptide fragment components combine with glycoproteins (MHCII) to become part of the cell membrane
- happens with macrophages and dendritic cells
140
why is antigen presenting important?
-activates Th cells which connects adaptive immune elements
141
other than antigen presenting what do macrophages do?
its the second most potent secretory cell in the body and secretes:
- enzymes capable of degrading ECM proteins (collagenase and elastase)
- products involved in host defence
- regulatory molecules
- granulocyte-macrophage colony stimulating factor, IL-3
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what is the definition of an antigen?
-a protein that elicits an immune response
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what is an antigen determinant or epitope?
- a specific portion of a protein that's recognized by appropriate antigen presenting cells
- may have none, one or several epitopes
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what are the types of epitopes?
1. sequential: primary structure aa sequence
2. conformational: appear after proper folding, affected by denaturation
3. surface: on external part of protein, detectable by humoral system
4. buried: internally located in folding protein, detectable after denaturation
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what are all of the antigen presenting cells (APC)?
- B cells
- epithelial cells
- dendritic cells
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what is antigen processing?
breakdown of antigenic molecules, selection of epitope, binding of selected epitope to surface MHC II proteins
-this occurs because when an antigen is presented by a macrophage its 1000x more immunogenic and recruits Th cells
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what do natural killer cells do?
- they are non-phagocytic granular lymphocytes
- role in innate immunity
- kill malignant cells and cells infected with pathogens by releasing granzymes (cytotoxic enzymes)
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how do neutrophils recognize target cells?
1. by binding to antibodies which coat infected or malignant cells (antibody-dependant cell-mediated cytotoxicity (ADCC)
2. or recognize and kill cells that have lost their class I major histocompatibility antigen due to presence of virus or cancer (if a cell doesnt have a MHC I it will be killed)
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how do NK cells kill virus infected cells?
-NK cell releases cytotoxic perforin and granzyme B which activates apoptosis
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what can activate a NK cell?
Cytokines:
| IL-1, IL-12, IL-15, and/or IFNs
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what stops an NK from killing a cell?
-it the NKs inhibitory receptor binds to MHC on cell
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how does the vascular endothelium work to fight antigens?
- endothelium that lines blood vessels has TNFa and IL-1 that induce expression of adhesion molecules which initiates leukocyte rolling and adherence extravasion (cells can get out of blood vessels)
- chemokines reach the PMN and activate it to produce integrins which leads to adhesion of PMN to blood vessel wall (marginalization)
- selectins slow to PMNs that pass through the blood vessel wall (diapedesis)
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how is kallikrein activated?
-its an extracellular enzyme that is activated by presence of antimicrobial chemicals released by macrophages and acute phase proteins that are released by the liver
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what does activated kallikrein do?
- gets cleaved to produce bradykinin which acts upon nerve cells, endothelial cells and mast cells (histamine release)
- bradykinin causes blood vessels to leak which leads to inflammation
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what is chronic inflammation?
- formation of new connective tissues
- causes permanent tissue damage
- at inflammation site there is dense infiltration of lymphocytes and macrophages called granuloma
- inflamed area is walled off
- happens when phagocytic cells can't destroy a pathogen
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what are the characteristics of adaptive immunity?
- discrimination between self and non self: produces specific responses towards antigen stimuli
- diversity: generates large diversity of molecules (antibodies that recognized trillions of foreign substances
- specificity: can be directed at a specific pathogen among trillions
- memory: response to a second exposure to a pathogen is so fast that there is no noticeable pathogenesis
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what are the two types of adaptive immunity?
- humoral: antibody-mediated, based on antibody production by plasma cells, the antibody activity is used to neutralize the pathogen
- cellular: cell-mediated, based on action of cytotoxic T lymphocytes, Tc goes into surveillance mode to detect and kill infected cells
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how do the innate and adaptive immune system interact?
- antigen presenting cells from innate must show antigen to T-lymphocytes to engage adaptive response
- elements of adaptive response are involved in enhancing some of the innate responses (antibody coating cell so NK can kill it, antibodies bound to cell to activate complement, antibodies bound to antigen to facilitate phagocytosis)
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what does immunogenic mean?
elicits an immune response
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what makes a vaccine work?
they engage the adaptive immune response elements and production of memory cells so that cells can remember the target and know how to fight it off
161
when can an immune response be bad?
- autoimmune diseases
| - allergies
162
how can the Antibody to antigen interaction be exploited for research?
ELISA (ex pregnancy tests)
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what are the main cells of the adaptive immune system and where do they originate from?
T and B cells
- B cells are from bone marrow and mature there
- T cells are from bone marrow but move to thymus to mature
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what are the sets of cells that are specifically designed to work against particular viruses?
- Th, Tc, and B sets
- each set is screened to avoid self reactivity
- each set matches a specific epitope of the antigen
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what happens when autoimmune diseases occur?
a set of Th, Tc, and B cells are self reactive to cells in the body so the immune systems attacks its own cells
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what is antigen valence?
-the number of epitopes that determine the number of antibodies that can attach to an antigen at one time
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what are antibodies produced by?
-plasma cells (activated and differentiated B cells)
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what is the structure of an antibody?
- multimeric
- two different types of protein subunits
- two identical copies of light and heavy chains
- heavy and light chains are bound covalently by disulphide bonds
- Fab fragment is where the antigen binds (there are two pockets made of variable regions of heavy and light chains that provide the antigen binding sites)
- Fc fragment is constant and crystallizes, sticks out of the cell so the complement can recognize it (important for opsonization, binds and interacts with complement, has phagocyte receptor , used to classify antibody types)
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how are Tc cells different from NK cells even though they resemble each other?
- Tc don't kill any cell that looks wrong, they are more specific and only kill infected cells that have specific virus
- leaves memory cells too
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what are IgE antibodies?
- related to allergies
| - attach to individual molecule to expose the surfaces of basophils and mast cells
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what are IgG antibodies?
- account for 80% of all antibodies
| - responsible for resistance against many viruses and bacteria
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what are IgD antibodies?
-individual molecules on surface of B cells that can bind to antigens in extracellular fluid
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what are IgM antibodies?
- first valid of antibodies secreted after antigen is encountered
- IgM concentration declines as IgG prod accelerates
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what are IgA antibodies?
- found mostly in glandular secretions like mucus, tears, saliva, and semen
- attack pathogens before they gain access to internal tissues
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what are the functions of antibodies?
1 opsonization
2. neitralization (involves presenting antigen to bind to our cells)
3. complement activation
4. Agglutination (clumping)
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what is antibody affinity?
the strength with which antibodies bind to antigens at a given antigen-binding site
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what three things contribute to the generation of antibody diversity?
1. rearrangement of antibody gene segments
2. generation of different codons during antibody gene splicing
3. somatic mutations
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what is an antibody titer?
- a measure of serum antibody concentration
| - reciprocal of highest dilution of antiserum that gives positive reaction
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when does the primary antibody response begin?
several days to weeks lag after initial exposure
- B cells must differentiate into plasma cells and then the antibodies are secreted
- first IgM is secreted then IgG
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what happens during a secondary antibody response?
- B cells are heightened
- memory response
- has a shorter lag
- more rapid log phase
- longer persistence
- higher IgG tiger and production of antibodies with higher affinity for antigen
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what is the clonal selection theory?
- the body forms large diverse B cell pool that can bind large range of antigenic epitopes
- the self reactive cells are eliminated (clonal deletions)
- encounter with antigen stimulates only those B cells that recognize and bind antigen
- stimulated B cells proliferate to produce B cell clones that all have same antigen specificity
- B cell clone differentiates to form two cell populations (plasma cells and memory B cells)
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what are the primary lymphoid organs that harbor B and T cells?
- bone marrow: where all cell of the immune system are generated
- thymus: where T cells mature
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what are the secondary lymphoid organs that harbor B and T cells?
- spleen: filter the lymph before returned to blood (also MALT)
- lymph nodes: T and B cells reside and where antigen presentation takes place
- lymphatic system: transports microbes to the lymph nodes also where cells differentiate into plasma cells
- gut
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what are the two sub-populations of T cells?
- Th (CD4 surface marker): cell to which the antigen is presented by the macrophage or dendritic cell, stimulates proliferation of T and B cells
- Tc (CD8 surface marker): circulate in blood and lymph searching for infected cells to kill, provide cell mediated immunity, produce cytokines
185
what are TS cells?
- dampen activity of B and T cells and temper the immune response as levels of antigen fall
- also important in controlling autoimmunity
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what are naive Th cells called before they've been activated and differentiated?
Th0 cells
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what type of cells do Th0 cells differentiate into once they've been activated?
-Th1 cells: activates the cytotoxic T cells by producing a specific set a cytokines, involved in cellular immunity, responsible for delayed hypersensitivity racoons and macrophage activation
-Th2 cells: activate B cells to proliferate and develop into plasma cells, involved in humoral immunity, defat against helminth parasites
Th17: recruits neutrophils
-Treg
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how are Tc cells activated?
- Tc interactions with Th1 and pie presented the antigen by a APC (proliferation and differitation will occur producing memory cells, Tc cells and regulatory TCLs)
- alternatively they can be activated when they interact with a APC with antigen in its MHVI
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what are the two pathways a Tc could kill and infected cell?
- perforin pathway
| - CD95 pathway
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how does our immune system detect our own cells?
-we have personal ID system (are cells are presented by the MHCI)
191
what are MCHI and MHCII ?
- MHCI: found on almost all types of nucleated cells, present personal ID if they aren't infected by a virus
- MHCII: found only on antigen presenting cells (macrophages, dendritic cells, B cells)
192
if an antigens epitope is presented by MHCI what detects it?
Tc or NK cells
193
if an antigen epitope is presented by MHCII what detects it?
Th cells
194
how do MCHI and MHCII participate in immune response?
- MHCI: surveillance cells like Tc and NK are always checking it, infected cells or cancerous cells have abnormal promotions showing on MHCI which activates NK or Tc into action
- MHCII:antigen is presented and showed to Th cells
195
what do proteasomes do?
- degrade intracellular proteins (important for cell cycle control, cell stress responses, intracellular signalling, and MHCI antigen processing)
- protein to be degraded is tagged with ubiquitin by three enzymes
- the tagged protein is recognized by 26S proteosome
- the proteins enters the proteasome and is cleaved into smaller peptides which re released into cytoplasm
- ubiquitin is released and recycled
- this is used when a cell presets a sample of cell proteins in MHCI to help immune surveillance system know which proteins are normal and which aren't
196
what are the two signals needed for Th cells to activate?
1. presentation of antigen at MCHII to the T-cell receptor
2. interaction between APCs own B7 (CD80) proteins and the T cell CD28 receptor
- allows the adaptive immune cells to become involved in the defence strategy
197
what are the receptors on B cells that activates them?
- immunoglobulin receptors
| - they associated with B-cell receptors which tell what kind of antibody the B cell will produce
198
what are the two steps of T-dependant B-cell activation?
- B cell receptor interacts with antigen
- B cell then interacts with corresponding activated Th2 cell which stimulates release of cytokines tHAT ACTIVATE THE B CELL
- activated B cell trigger proliferation into plasma cells
- T-dependant activation is best because it stimulates production of memory cells
- cells involved in this activation are macrophages and other APC, Th cells, and B cells specific for antigen
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what are the steps of T-independant B cell activation?
- polymeric antigens with large number of identical epitopes that induce B cell activation along with interaction of TLR with MAMPs
- antibodies produced how low affinity for antigen
- less effective than T -dependant (no memory cells formed)
200
what do superantigens do?
- bind externally with MHCII (by forcing an interaction) of APC
- able to interact unspecifically to T cell receptors to stimulate about 30% of T cells of immune system (causes T cells to overexpress and release too much cytokines
- results in cytokine storm that causes shock responsethat turns into failure of multiple host organs
201
what happens in normal antigen processing?
- normally 1 of every 10 00 T cells are stimulated
1. APC normally digests protein antigen and displayed one peptide on MHCII
2. antigen peptide in MHCII eventually decide by a specific Th cell
3. Th cell activated produces cytokines (IK_2) that stimulates T cell proliferation and interaction with B cells with concomitant antibody production
202
what happens in super antigen processing?
1/100nT cells stimulated
1. whole antigen binds to MHCII without being processed
2. any APC- Th cell pari interactions, many T cell stimulated at once
3. mass production of IL-2 by stimulated Th cells which results in fever, nausea, vomiting, malaise
4. stimulation of other cytokines production will lead to shock
203
what are examples of super antigens?
- mouse mammary tumor virus
- rabies
- ebola?
