Week 1 Flashcards
(136 cards)
1
Q
What is an immune system?
A
Comprises group of cells, molecules, and organs that act together to defend the body against “foreign” invaders that may cause disease (e.g. bacteria, viruses, fungi)
2
Q
What is the overview of whats needed for the immune system to function?
A
The immune system MUST distinguish between self and non-self and “good” non-self from “bad” non-self
3
Q
What are an overview of the responses in the immune system?
A
RECOGNITION and RESPONSE (effector and memory)
INNATE and ADAPTIVE (or ACQUIRED) immunity
HUMORAL and CELLULAR responses
4
Q
What is an overview of innate immunity?
A
Rapid response
Low specificity
Limited diversity
No memory
5
Q
What are the physical parts of the innate immunity?
A
Physical and chemical barrier
Blood protein (cytokines, Complement (C’))
Cells (phagocytes, NK)
6
Q
What is an overview of adaptive immunity?
A
Slow response
High specificity
Large diversity
Memory
7
Q
What are the physical parts of the adaptive immunity?
A
Blood protein (cytokines, Antibodies)
Cells (Lymphocytes, APC)
8
Q
What is an overview of the cross talk between adaptive and innate?
A
Pathogen presentation –> Immature dendritic cell –> Mature dendritic cell –> Trigger adaptive B and T cells –> Trigger adaptive immune response
9
Q
What is an overview of Dendritic cells?
A
Professional antigen presenting cells
From Myeloid progenitor
10
Q
What is an overview of macrophages
A
Phagocytes and antigens presenting cells
From Myeloid progenitor
11
Q
What is an overview of neutrophil?
A
Kill bacteria
Phagocytosis/degranulation/NET
From Myeloid progenitor
12
Q
What is an overview of esoniphil?
A
Kill parasites
From Myeloid progenitor
13
Q
What is an overview of basophil?
A
Promote inflammation
Degranulation (histamine/heparin)
From Myeloid progenitor
14
Q
What is an overview of T helper cells?
A
Provide help to B cells
From Lymphoid progenitor
15
Q
What is an overview of cytotoxic t cells?
A
Kill infected cells via MHC1/ antigens/ TCR
From Lymphoid progenitor
16
Q
What is an overview of B cells?
A
Antibody production
From Lymphoid progenitor
17
Q
What is an overview of Innate lymphoid cell?
A
eg NK cell
From Lymphoid progenitor
18
Q
What are examples of non-lymphocyte cells?
A
neutrophils - motile, phagocytic, abundant
eosinophils - phagocytic, fight parasitic infections
basophils - release pharmacologically active substances
monocytes - become macrophages and dendritic cells
phagocytic - interferon g (from TH cells) potent activator
mast cells - granules contain histamine
dendritic cells - process and present Ag to TH cells MHC II
19
Q
Why are anitgen presenting cells needed?
A
Activation of both humoral and cell-mediated immune system requires cytokines produced by TH cells, which in turn require APCs.
20
Q
What cells are antigen presenting?
A
Macrophages
B lymphocytes
Dendritic cells
21
Q
What is the mechanism for antigen presentation?
A
Take up Ag by phagocytosis break into peptides display bound to MHC II interaction with TCR of TH cell co-stimulatory signal
22
Q
What is an overview of B cells?
A
Mature in bone marrow
Unique antigen-binding receptor membrane bound antibody molecule
23
Q
What happens when antigen encounters match antibody B cell?
A
Rapid division
Differentiation
Memory B cells
Plasma cells that secrete Ab
24
Q
What is an overview of T cells?
A
Mature in thymus (originate in bone marrow)
Unique antigen binding molecule
T cell receptor (TCR)
Recognises Ag bound to MHC molecules (major histocompatibility complex)
T cells = MHC restricted
25
What are subpopulations of T cells?
TH (T helper) and TC (T cytotoxic) subpopulations also Treg (regulatory)
26
What happnes with an encounter between antigen MHC and (THelper with antigen-MHCII, TC with antigen-MHCI)?
Rpid division
Differentiation
Memory T cells
Various effector T cells
27
What is an overview of T helper cells?
CD4
Recognises Ag with MHC II
Secretes cytokines (TH1 or TH2 response)
Activates B cells, TC cells, macrophages
28
What is an overview of T cytotoxic cells?
CD8
Recognises Ag with MHC I
Differentiates into Cytotoxic T lymphocyte (CTL)
Cell killing or cytotoxic activity
29
What is tolerance?
The apoptosis of T cells that would recognise the anigens presented on 'self' organs
30
What are primary organs of the immune system?
Microenvironment for development and maturation of lymphocytes
31
What are the secondary organs of the immune system?
Trap antigen, mature lymphocytes and antigen interact
32
What is an overview of bone marrow?
Primary organ
Primary site for B cell maturation
Stromal cells interact with maturing B cells and secrete cytokines required for development
B cells with self-reactive antibodies receptors eliminated
33
What is an overview of the thymus?
Primary organ
T cells originate in bone marrow but migrate to thymus to mature
Rapid proliferation and rapid death
antigenic diversity of TCR generated by random gene rearrangements whilst cells mature
Only cells whose TCR recognise MHC and foreign antigens survive, apoptosis removes the rest
34
What are examples of poor thymuses?
DiGeorge's syndrome
Nude mice
Ageing - decline in thymus function (atrophy in old people)
35
What is an overview of the lymphatic system?
Along with blood system, links primary and secondary lymphoid organs
plasma leaves capillaries
= interstitial fluid, lymph
Drains into network of lymphatic capillaries, vessels
returns to blood system via thoracic duct
36
How does the lymphatic system work?
similar to veins
Endothelial cell lining
Thin walls
Valves to stop back flow
Fluid flow by muscles squeezing, not heart
37
What is an overview of Lymph nodes?
Secondary organ
Clustered at junctions of lymphatic vessels
cortex - B cells, macrophages, dendritic cells
paracortex - T cells, dendritic cells
medulla - plasma cells secreting Abs
38
What is the function of lymph nodes?
Sites where immune responses are mounted to antigens in lymph
39
What is an overview of the spleen?
Filters blood – respond to systemic infections
Traps blood-borne antigens
Blood enters by splenic artery
Antigens trapped by dendritic cells which activate B and T cells
40
What is MALT?
Mucosal-Associated Lymphoid Tissue
41
What is an overview of MALT?
Mucous membranes lining digestive (Gut ALT), respiratory (Broncho ALT; Nasal ALT), urogenital tracts (?) are defended by lymphoid tissues known as MALT
42
What are M cells?
Sample the lumen to understand microbe content helps understand beneficial or pathogenic microbe
43
What happens with MALT immune resposnes
B cells plasma cells activated TH cells macrophages
IgA can be secreted by plasma cells and transported across epithelial cell layer lining intestine to lumen --> bind to pathogen to prevent invasion
44
What are the barriers for innate immunity?
anatomic barriers - skin, mucous membranes
physiologic barriers - temperature, low pH, chemical mediators (lysozyme, interferon, complement)
phagocytic/endocytic barriers - monocytes, neutrophils, macrophages
inflammatory barriers - influx of immune cells and molecules in response to perceived threat
45
What is an overview of skin innate immune function?
Mechanical barrier retards entry
Acidic environment (pH 3-5) inhibits growth of microbes
46
What is an overview of mucosal surfaces?
Epithelial barrier
Mucus traps foreign substances (immune exclusion)
Cilia propel foreign substances out of the body
47
What is an overview of temperature for immunity?
Normal body temperature and fever responses inhibit
growth of some pathogens (induced by pyrogens)
48
What is an overview of pH for immunity?
Acidity of stomach kills most invading microorganisms
49
What is an overview of chemical mediators for immunity?
Lysosyme
Interferons
Complement (C’)
50
What is an overview of cytokines?
Low molecular weight, soluble proteins that function as chemical Wmessengers (e.g.IL-1, IL-6, TNF-alpha, type 1 interferons (IFNs))
51
What is an overview of chemokines?
Chemokines are cytokines that enable the migration of cells from blood vessels into the tissues produced by many cells including monocytes, endothelial cells, fibroblasts, epithelial cells etc
52
What is an overview of antimicrobial peptides (AMPs)?
alpha- and beta-Defensins: produced by phagocytes, lymphocytes, epithelial cells of GI and GU tracts, cells of the tracheobronchial tree
53
What part of the immune system are complement proteins/
Soluble mediators of the innate immunity
54
What triggers the production of interferons?
When a virus infects a cell it induces the host to produce interferon mRNA which is translated into alpha and beta interferons
55
What happens to interferons produced by viral infected cells?
They bind to the plasma membrane or membrane cells on uninfected neighbouring cells, inducing the synthesis of antiviral proteins such as oligoadenylate synthetase and protein kinase
56
What happens when a virus infects a cell which has been warned by interferons?
Antiviral proteins (AVPs) degrade viral mRNA and inhibit protein synthesis interfering with viral replication
57
Outside of interfering how does interferons promote immunity?
Increase MHC class 1 expression
Increase antigen presentation
58
What is an overview of phagocytic/endocytic barriers?
Various cells internalise (endocytose/phagocytose) and break down foreign macromolecules
APCs antigen presentation by MHCII
59
What cells are in the phagocytic/endocytic barriers?
Specialised cells (blood monocytes, tissue macrophages, neutrophils, dendritic cells, [B cells])
Internalize, kill and digest whole microorganisms
60
What is an overview of macrophages?
Macrophages are stationed at strategic points where microbial invasion or accumulation of air-borne particles is likely to occur
Microglia are also macrophages just of brain
61
What is an overview of phagocytosis?
Ingest and digest exogenous antigens
Receptor mediated process
Chemotaxis, adherence, pseudopodia, phagosome, phagolysosome, exocytosis & MHC II presentation
62
What is interface?
Interface between innate and adaptive immune system
63
What are cells involved in the interface?
Dendritic Cells (and other APCs) operate at the interface between innate and adaptive Immunity
64
What are examples of how the dendritic cell directly responds to viruses?
Produce inflammatory cytokines leads to inflammation and potential shock
Produce interferons
65
What are examples of how the dendritic cell directly responds to viruses?
Differentiation of T cells to either Th1 or Th2
Th1 instructs cytotoxic T cells --> virus infected cells/ cancer/ bacteria
Th2 instructs B cells --> Attack by antibody release, can cause allergic reaction
66
What are granulocytes?
Granulocytes with membrane bound granules
Includes, neutrophil, basophil, eosinophil and mast cells
67
What are granules?
Membrane bound vesicles that contain chemical mediators and enzymes to promote their function
68
What are definsins?
Type of granule
defensins = 29-35 amino acids
3 stranded beta structure with S-S
69
What amount of defensins are needed to kill infectious agents?
1mM needed to kill infectious agents - defensins are thought to be mM in neutrophil 1° granules
70
What are the different types of defensins?
Alpha - HNP1-4 present in all neutrophils
Beta - HBD4 - Neutrophils, epithelium of testes, stomach, uterus, lung and kidney
71
How do defensins work?
Positively charged defensins attracted to negatively charged
72
What are examples of antimicrobial peptides, what produces then and their microbial target?
Cathelicidins, human and bovine targetting bacteria
Magainins, frogs and target bacteria and fungi
73
What are examples of oxygen-dependant molecules?
Reactive oxygen intermediates e.g. superoxide anions and hydroxyl radicals
Reactive nitrogen intermediates e.g. nitric acid and nutorgen dioxide
74
What produces reactive oxygen species?
Reactive oxygen species generated in phagolysosome by NADPH oxidase
75
What is NADPH oxidase?
multi-component enzyme that pre-exists in neutrophils and activated by signals from phagocytic receptors
76
What produces reactive nitrogen species?
NO produced in cytoplasm by inducible nitric oxide synthase (iNOS), then diffuses into phagosome
77
What are neutophil responses to bacteria?
Netosis
Degranulation
Phagocytosis
78
What is degranulation?
The releasing on toxic granule proteins which deactivates and kills pathogens
79
What are the two types of netosis?
Netosis (slow cell death)
Non-lytic netosis (rapid release from live cells)
80
What is an overview of slow cell death netosis?
Nuclear delobulation and disassembely of nuclear envelope, followed by cellular depolarisation and chromatin decondensation. Finally plasma membrane rupture and release of NETs
81
What is an overview of non-lytic netosis?
Degranulation and explusion of nuclear chromatin and extracellular assembly of NET
82
What do NK cells recognise?
Intracellular pathogens can induce the expression of stress-induced ligands (SILs) by infected cells
83
What on NK cells recognises SILs?
Recognition of these by NK cells through their receptor NKG2D initiates the killing process
84
What are PAMPs and MAMPs for the immune system?
Pathogen/microbe-associated molecular patterns (P/MAMPs) on the surface of microbes can be recognized by the innate immune system through toll-like receptors (TLRs) and other pattern recognition receptors (PRRs)
85
What is an overview of direct recognition by the innate immune system?
Direct recognition of surface molecules on pathogen by phagocyte surface receptors
86
What is an overview of indirect recognition by the innate immune system?
Indirect recognition through deposition of serum-derived
molecules onto pathogen surface and their subsequent
binding to phagocyte surface receptors (i.e. opsonisation)
87
What are examples of direct recognition receptors?
Scavenger receptors (LDL, negative charge)
Carbohydrate receptors (lectins)
Toll-like receptors
88
What are examples of indirect recognition receptors?
Collectins and ficolins (serum lectins)
Pentaxtrins (acute phase protein CRP)
Complement
89
What is an overview of Lipopolysaccharide receptor?
Targets lipopolysaccharide (gram-negative bacterial cell wall) which trigers a delievery to cell membrane
90
What is an overview of NOD family receptors?
Targets bacterial cell wall and induces innate responses
91
What is an overview of the expression of toll-like receptors?
Expressed in very low levels
Mainly on immune cells including DCs and Macrophages
Found either on cell membrane or endosome membrane
92
What is an overview of the function of toll-like receptors?
Function as either hetero or homodimers
Pairing affects specificity e.g. TLR1/2: bacterial parasites
TLR2/6: Gram positive bacteria and fungi
93
How does ligand locaton and function link?
TLRs that recognize extracellular ligands are on cell surface
TLRs that recognize intracellular ligands are on endosome
94
What are examples of bacterial recognising TLRs?
TLDR6 and TLDR2 Lipoproteins (also fungal Zymosan)
TLR4 LPS (also viral F protein)
TLR5 Flagellin
95
What are examples of virius recognising TLRs?
TLR9 - unmethylated CpG DNA
TLR3 - dsRNA
TLR7 - ssRNA
96
What is the mechanism for TLR signalling?
Binding of a TLR ligand to the TLR triggers a signaling cascade
97
What are the two major gene activators activated by TLR signalling?
NF-KB is a transcription factor that plays a key role in regulating the immune response to infection
MAPK regulate various cellular activities, such as gene expression, mitosis, differentiation, and cell survival/ apoptosis
98
What is MyD88?
MyD88 is an adapter protein in the signal transduction pathway mediated by interleukin-1 and Toll-like receptors
The TLR signaling pathway can be either MyD88 dependent or independent
99
Where are complement proteins produced?
Primarily produced in the liver, factor D in adipose tissue, C1 in gut epithelium and H-ficolin in epithelial duct cells.
(Other cells include monocytes/macrophages, fibroblasts, endothelial cells, leukocytes)
100
What are the seven functional categories of complements?
1 - Intitators - Ficolins
2 - Enzymatic mediators - Convertase such as C1r
3- Main section of molecule forms membrane attack proteins (forming pores)
4,5 - Small section of molecule forms opsonins to help phagocytosis and anaphylatoxins (inflammatory)
6 - Complement receptot proteins
7 - Regulatory complement proteins
101
What are the effects of complement activation?
Lysis
Oponisation
Activation of inflammatory response
Clearance of immune complexes
102
What is an overview of the activation of complement?
Classical pathway, lectin pathway and alternative pathway triggers C3 to C3b conversion resulting in the complement effects
103
What triggers the classical pathway for complement activation?
IgM and IgG activate series of serum glycoproteins
Lysis of bacterial cell by perforation of membranes
104
What is an overview of IgG?
most abundant Ig in serum ~80%
4 sub classes:
Differ in hinge region
Different biological activities
105
What are the subtypes IgG?
IgG1,3,4 cross placenta
IgG3 best complement activator
IgG1,3 mediate opsonisation
106
What is an overview of IgM?
~5-10% serum Ig monomeric IgM is membrane bound on B cells
IgM secreted as pentamer - held together by S-S additional Fc-linked polypeptide: J (joining) chain
1st class of Ig produced in primary response
Activates complement mucosal secretion
107
What does the C1 complex comprise of?
The C1 complex consists of C1q and two molecules each of C1r and C1s
108
How does C1 complex and Ig binding trigger complements?
The binding of the recognition subcomponent C1q to the Fc portion of immunoglobulins results in autoactivation of the serine protease C1r
109
What is the function of the C1r serine protease?
C1r then cleaves and activates C1s, which translates the activation of the C1 complex into complement activation through the cleavage of C4 and C2 to form a C4b2a enzyme complex
110
What is the function of the C4b2a enzyme complex?
C4b2a acts as a C3 convertase and cleaves C3, which results in products that bind to and cause the destruction of invading bacteria
111
What is the function of C4a?
Anaphylotoxin - derived from complement activation that is pro-inflammatory: causes smooth muscle contraction, capillary leakage, and even anaphylactic shock
112
What is an overview of Mannose-binding lectin?
Mannose-binding lectin (MBL) binds foreign surface and associated proteases (MASP1 + 2), generate activate C-1 like complex
113
What happens when a mannose-binding lectin binds to a bacterial cell surface?
MBL associated proteases (MASP1 + 2), generate activate C-1 like complex
They an bind and catalyse the cleavage of C4 and C2 to generate the C4b2a C3 convertase
Potential cleavage of C3 to C3b directly
114
What triggers the alternative pathway?
C3 splits spotaneously at slow and small amounts
115
What happens to the C3 thats splits in the alternative pathway?
C3b binds to factor B forming C3bB
C3bB is cleaved by factor D to form C3bBb which is a C3 convertase
116
What are pathogenic molecules which can speed up the alternative pathway?
Lipopolysaccharides from gram-negative bacteria
Teichoic acid from gram-positive cell walls
Fungal cell walls
Viruses and viral infected cells
117
What are nonpathogenic molecules which can speed up the alternative pathway?
Human IgG, IgA and IgE complexes
Cobra venom factor
Heterologous erythrocytes
Anionic polymers
118
What are examples of controls on the alternative pathways?
Host = high levels of sialic acid (inhibits C3 cleavage) pathogens = low levels of s.a.
C3bBb - short half life of 5 minutes, molecules such as properdin can stabalise
119
How are C5 convertase made in the classical and lectin pathways?
C4b2a converts C3 to C3b + C3a
C3b binds to C4b2a to form C5 convertase C4b2a3b
120
How are C5 convertase made in the alternative pathway?
C3bBb converts C3 to C3b + C3a
C3b binds to C3bBb to form C3bBb3b the c5 convertase
121
What happens with the C5 convertase?
C5 convertase converts C5 to C5b + C5a
C5b starts MAC
C5a diffuses away
122
What happens to the C5b complex?
C5b complexes with C6 and C7 to induce conformational change in C7, the exposing of hydrophobic binding side with high affinity for phospholipids
123
Where does the C5b67 membrane go?
The C5b67 complex inserts into lipid bilayer of cell membrane
124
What interaction happens with the C8 to c5b67?
C8 binds to C5b67 and it’s alpha- chain penetrates the lipid bilayer to cause leakage of intracellular K+, amino acids, ribonucleotides
125
What happens with the interaction of C9 with C5b678?
1-16 molecules of C9 bind to the C5b678 complex, polymerize and form a pore in the membrane
The final addition to the Membrane Attack Complex (MAC)
126
What are examples of innate immune cells that can bind to anaphylatoxins and their response?
Macrophages - chemotaxis, cytokine production and phagocytosis
Neutrophil - chemotaxis, oxidative burst, phagocytosis and degranulation
Basophil - degranulation
Eosinophil - degranulation and chemotaxis
Mast cell - degranulation and chemotaxis
127
How can the anaphylatoxins C3a and C5a influence immunity?
C3a and C5a bind to G-protein-coupled receptors C3aR and C5aR; stimulates release of pro-inflammatory mediators
128
What are methods to regulate complement activity?
C1INH
Decay Accelerating Factors (DAF)
Factor I
129
What is an overview of C1INH?
Serpin (serine protease inhibitor) forms complex with C1r2s2 dissociates from C1q, preventing cleavage of C2C4 proteins therefore C3 convertase
Also inhibits MASP2
130
What is an decay accelerating factors?
Breakdown of C3 convertase complex (DAF found on host cells not microbial cells) C2a (classical pathway and Bb (alternative pathway diffuse away
131
What are overview of factors which inhibit of complement activity?
Factor I degrades residual membrane bound C3b or C4b
(requires cofactors only found on host cells)
(Factor H and C4BP bound by eukaryotic membrane – sialic acid and heparin – not found on microbial invaders)
132
What are examples of molecules which regulate complement activity if it has started to form?
Protectin
Vitronectin
Serum carboxypeptidases
133
What is an overview of protectin?
A host cell surface protein that binds any C5b678 complexes that maybe deposited on host cells and prevents their insertion into the host cell membrane.
Also block addition of C9
134
What is an overview of Vitronectin?
Vitronectin a soluble component binds any soluble C5b67 complexes released from microbial cells
135
What is an overview of Serum carboxypeptidases?
Serum carboxypeptidases inactivate anaphylatoxins by cleavage of C-terminal arginine residues (des ARG = “without arginine”)
136
