Week 6 Clarke - Immunology I & II Flashcards
(100 cards)
1
Q
What are the principals of recognition?
A
How to identify self versus non-self:
- antigen recognition molecules
- complement
- antibodies
- PAMP (Pathogen Associated Molecular Patterns)
- DAMP (Damage Associated Molecular Patterns)
- TLR (toll-like receptor)
- MHC Class I/II
- T-cell/B-cell receptor
- specific binding
- affinity
- avidity
- Positive selection
- Negative selection
2
Q
What is avidity?
A
- Specific binding
- Cooperative interactions
- The SUM of many tiny binding sites yield very high binding strength.
- ex. monomeric IgM binds weakly to antigen, however pentmeric IgM binding can be strong
3
Q
What is affinity?
A
- An attraction or force between particles that causes them to combine, as the attraction between an antigen and an antibody.
(higher affinity → smaller Kd)
4
Q
What is an exogenous agent?
A
An antigen (recognized) that has immunogen properties (induces immunity).
5
Q
What is the Secondary Response?
A
The “trained” response.
- system that is already trained to react
- still short lag period when immune response cells are being delivered to infection
- greater antibody concentration, smaller peak
- high IgG levels (due to memory cells)
- lower IgM levels
6
Q
Why is there a lag time in the primary response?
A
Lag period = 5 days
- Time it takes to recognize antigen, allow antigen presenting cells to educate and activate T-cells, produce antibodies, and deliver immune response cells to site of infection
- Also need to screen B-cells and memory cells for antigen recognition and deliver them to site of infection if already trained to fight particular infection
7
Q
What are PAMPs?
A
Pathogen Associated Molecular Patterns
- Molecular moieties that are absolutely required for pathogen survival
- outside alert signal
- e.g.: endotoxin, flaggelin, peptidoglycan, terminal mannose
- initiates inflammation
- recognition by innate immune system
- recognition system has co-evolved with the appearance of the PAMP
8
Q
What are DAMPs?
A
Damage Associated Molecular Patterns
- Occult and obscured from the defense mechanisms (hidden)
- Danger/Damage signal
- Recognized by the innate immune system
- E.g.: Proteins (heat shock proteins), Non-proteins (uric acid crystals, ATP, DNA, Heparin sulfate, Hyaluronan fragments)
9
Q
What are TOLL Like Receptors?
A
- recognize non-self from extracellular sources
- about 12 types
10
Q
What are the *** Immunological Zones?
A
- Skin (Entry)
- Interstitial
- Mucosal
11
Q
What are the three lines of defense?
A
- Epithelium
- barriers
- Mesoderm
- cellular responses
- flushing
- lyses
- trapping
- Endoderm
- cellular responses
- flushing
12
Q
What cells respond to pathogens (parasites, protozoans, helminthes, fungal, viral) that pass through the Skin Immunological Zone?
A
- Langerhan’s cells
- Mast cells
- Neutrophils
- Macrophage
- Eosinophils
13
Q
What cells respond to pathogens (viruses/bacteria) that pass through the Interstitial Immunological Zone?
A
- Macrophage
- CD4+ Helper T-cell
- Cytotoxic T-cell
- Natural Killer Cell
14
Q
What cells respond to pathogens (bacteria/viruses) that pass through the Mucosal Immunological Zone?
A
- Macrophage
- Dendritic cell
- gamma-delta T-cell
- B1 cells
15
Q
What is the difference between natural and artificial immunization?
A
- Natural
- Passive (maternal)
- Active (infection)
- Artificial
- Passive (antibody transfer)
- Active (immunization)
16
Q
Summarize Innate immunity.
A
- Provides sensors for pathogens (TLR’s)
- Rapid response
- Genetically hardwired
- Limited repertoire
- Principle agent = Complement
17
Q
Summarize Adaptive Immunity
A
- Provides high affinity receptors for antigen, production of high affinity requires anticipatory receptors that can be modified (class switching and somatic hypermutation)
- Genetic recombination
- Protracted response - lag time
- Immense repertoire
- Principle agent: Antibody
18
Q
Dendritic Cell
A
- Leukocyte derived (pDC, plasmacytoid)
- Myeloid derived (mDC)
- Process Ag from MHC Class II display
- Identifies non-self using receptors for PAMPs
*
19
Q
Macrophage
A
- Leukocyte derived (pDC, plasmacytoid)
- Myeloid derived (mDC)
- Differentiated from monocytes
- Involved in phagocytosis and activation of bactericidal mechanisms
- Antigen presentation
- Found in many tissues
- Cannot re-enter blood
20
Q
Monocyte
A
- Leukocyte derived (pDC, plasmacytoid)
- Myeloid derived (mDC)
- non-granular
- found only in the blood/circulation
21
Q
Mast Cell
A
- Release of granules containing histamine and active agents
- Large, irregular shaped
- Large granules: histamine, heparin, TNF-alpha
- responsible for causing vascular dilation
- found in skin, lung alveoli, GI mucosa, nasal mucosa
- questionable derivation
22
Q
Eosinophil
A
- Killing of antibody-coated parasites
- Allergies and helminthic parasites
- Large and low abundance
- Peroxidase, basic proteins, leukotrienes
- Generally in bone marrow and connective tissues
- bilobed
- Fc-epsillon
- Phagocytosis
- Attaches to target for extracellular degranulation
23
Q
Neutrophil
A
- Phagocytosis and activation of bactericidal mechanisms
- Fundamental defense (would be dead w/o)
- Multi-lobed
- 50%-70% of leukocytes
- 60% of bone marrow activity
- Fc and Complement Receptors
- Phagocytosis
- Lytic secretions
- Lysoszyme
- Oxidases
- Defensins
- Pus
24
Q
Natural Killer Cell
A
- Lymphoid derived
- No antigen receptor
- Screen for the absence of MHC Class I
- if no MHC Class I → kills cell
- Induces apoptosis in target cells
- releases lytic granules that kill some virus-infected cells
- Works in partnership with cytotoxic T-cells
25
What are Cytokines?
* Small glycoprotein that is a soluble mediator
* Commonly operate in sequential patterns, cascading
* Synthesized on demand
* Autocrine/Paracrine (short-range acting)
* No discrete organ, ubiquitously found
26
What are the steps of Recognition of Non-self?
1. Proteins and peptides are scavenged by myeloid dendritic cells
2. Proteins are processed to small peptides
3. Myeloid dendritic cell expresses antigen in MHC Class II
4. PAMP directs the surface expression of the Antigen-MHC class II
5. T-cells screen myeloid dendritic cell for antigen (T-cells express surface receptors that weakly recognize pepties)
6. A match results in T-cell activation
27
What is MHC Class I?
Major Histocompatibillity Complex I
* Present in all nucleated cells (except RBCs)
* Antigen display is of self-proteins
* "designates self"
* Antigen is generally synthesized intracellularly and expressed on the cell surface to alert the immune system
* ex. active immunization
28
What is MHC Class II?
Major Histocompatibillity Complex Class II
* Antigen display is of extracellular proteins
* antigen was acquired at the site of inflammation, but displayed in a secondary immune organ
* present antigen to T-cell (how lymphocytes are educated)
* Present in dendritic cells, macrophages, and B-cells
29
How do B-cells and T-cells recognize antigens?
* B-cells
* use cell surface immunoglobulin
* T-cells
* use a fragment of the immunoglobulin at the cell surface
30
What are some important structural characteristics of immunoglobulins (antibodies)?
* Antigen binding domains
* 2 types of light chains form variable ends
* beta-barrels give rigid properties to variable ends
* 2 hinge regions allow for flexible antigen binding
* Fc
* homodimer heavy chain consistent with AA → crystallizes
31
What two structural motifs refer to the Fc region of immunoglobulins (antibodies)?
* Isotype
* Variation dependent on heavy chain identity
* 5 types of heavy chains (IgG, IgD, IgE, IgA, IgM)
* Allotype
* Allelic variation of the isotype outside of the antigen binding region
32
What structural motif refers to the antigen binding region of immunoglobulins (antibodies)?
* Idiotype
* variation within the variable domain
* **idiotype specifies antigen binding**
33
\*\*\*What are the three antibody functions?
1. **Neutralization** (antibodies bind to and degrade bacterial toxins)
2. **Opsonization** ("sauce" that coats bacteria)
3. **Complement activation** (starts cascade to pop holes in target or lyse bacteria, and ingest)
34
What are the five segments of a T-cell Receptor?
1. Variable region (V) (idiotype- binds to antigen)
2. Constant region (C)
3. Stalk segment
4. Transmembrane region
5. Cytoplasmic tail
\*\*Has alpha chain and beta chain (allotype depends on type of antibody)
35
\*\*In order to direct an adaptive immune response, what do T-cells recognize?
MHC Class II molecules
36
In order to identify intracellular pathogens, what do Cytotoxic T-cells (CD8+) recognize?
MHC Class I molecules
37
What kind of cells do Natural Killer cells kill?
Cells not expressing MHC Class I molecule
(without it → you dead)
38
What do T-helper (CD4+) cells do?
* Direct immune response:
* Cell mediated immunity
* Humoral immunity
* inflammation
39
What is the early response to pathogens?
(Hint: 3 steps)
Pathogen entry leads to innate response of flush (fluid extravasation), clot (trap particles), then remove (Neutrophils and Macrophages).
40
How do Mast Cells coordinate the inflammatory response?
(Hint: 3 mechanisms)
* Direct interations:
* Recognition by toll-like receptor (TLR)
* CSCL8 recruits leukocytes to the inflammatory site.
* Fc-receptor-mediated activation
* CSCL8 recruits leukocytes to the inflammatory site
* C-receptor-mediated activation
41
What is released in all three Mast Cell mechanisms?
* IL-1, TNF, IL-6
* stimulates acute phase response
* GM-CSF
* stimulates leukocyte production
42
Why are Mast Cells referred to as "sentinels"?
Function to both respond directly to pathogens and send signals to other tissues to modulate immune response.
43
What is Neutrophil Extravasation?
* Mast cells and macrophages stimulate neutrophil entry by excreting CXCL8 (recruits)
* Neutrophil receives the CXCL8 message to pass through capillary wall.
* Neutrophils continuously contact the endothelia lining (Marginalization), at sites of inflammation the region expresses additional adhesion molecules (integrins).
* The Neutrophil will follow the chemokine gradient to target the inflammatory site.
44
What are the four steps in neutrophil extravasation?
1. **Rolling adhesion** (sugar group tethers neutrophil to selectin)
2. **Tight binding** (ICAM grabs onto CXCL8R)
3. **Diapedesis** (squeezes through endothelial wall of capillary into tissue)
4. **Migration** (to site of infection)
45
What molecules aid in neutrophil extravasation?
* Various adhesion molecules involved with extravasation.
* Each serves as tissue specific address,
* i.e. MAdCAM-1 recruits at mucosal regions
* VCAM-1 recruits at peripheral vascular beds
46
What five inflammatory cytokines do activated macrophages secrete?
* IL-1beta
* Activates vascular endothelium & lymphocytes
* TNF-alpha
* Activates vascular endothelium
* Increases vascular permeability → inreased entry of IgG, complement
* IL-6
* Lymphocyte activation
* CXCL8
* recruits neutrophils
* IL-12
* Activates NK cells & TH1 cells
47
What three inflammatory cytokines secreted by activated macrophages have systemic effects?
* IL-1beta
* fever
* production of IL-6
* TNF-alpha
* Fever
* shock
* IL-6
* Fever
* induces acute phase protein production
48
What occurs in cytokine control of inflammation in the liver due to IL-1beta, IL-6, and TNF-alpha?
* Liver
* Acute-phase proteins
* C-reactive protein
* mannose-binding lectin
* Activation of complement opsonization
49
What occurs in cytokine control of inflammation in the _bone marrow epithelium_ due to IL-1beta, IL-6, and TNF-alpha?
* Bone marrow epithelium
* Neutrophil mobilization, leads to
* Phagocytosis
50
What occurs in cytokine control of inflammation in the _hypothalamus_ due to IL-1beta, IL-6, and TNF-alpha?
* Hypothalamus
* Increased body temperature, leads to
* Decreased viral and bacterial replication
* Increased antigen processing
* Increased specific immune response
51
What occurs in cytokine control of inflammation in the _fat/muscle_ due to IL-1beta, IL-6, and TNF-alpha?
* Fat/Muscle
* Protein and energy mobilization to allow increased body temperature, leads to:
* Decreased viral and bacterial replication
* Increased antigen processing
* Increased specific immune response
52
What occurs in cytokine control of inflammation in the _dentritic cells_ due to IL-1beta, IL-6, and TNF-alpha?
* Dendritic cells
* TNF-alpha stimulates migration to lymph nodes and maturation, leads to:
* Initiation of adaptive immune response
53
What is the acute phase response?
* Bacteria induce macrophages to produce IL-6
* IL-6 acts on hepatocytes to induce synthesis of acute-phase proteins
* C-reactive protein binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement
* Mannose-binding lectin binds mannose residues on bacterial surfaces, acting as an opsonin, and also activating complement
54
What three things happen in the inflammatory response?
* Vasodilation
* increased blood flow
* Increased vascular permeability
* plasma infusion
* Emigration of neutrophils
* neutrophil extravasation
55
What is positive selection?
Antigen receptor activation.
56
What is Negative Selection?
Removal of cells recognizing self tissue.
57
What are the three primary lymphoid organs?
1. Bone marrow
2. Thymus
3. Fetal Liver
58
What things live in the bone marrow?
* Site of hematopoiesis
* Lymphoid progenitor cells
* Mature B cells (B2 cells)
59
What things live in the thymus?
* Mature B cells
* CD4+ cells (Helper T-cells)
* CD8+ cells (Cytotoxic T-cells)
* CD25+CD4+ T-cells (Regulatory T-cells)
\*\*Over 97% of cells produced by the thymus are killed off by negative selection.
60
What things live in the fetal liver?
* "Specialized Immune Cells"
* Mast Cells (mesenchymal tissue)
* Astrocytes (Blood Brain Barrier)
61
What are the Secondary Lymphoid Organs?
1. Lymph Node
2. Peyer's patch
3. Spleen
4. Vermiform Appendix
5. Tonsils
62
What occurs in the secondary immune organs?
* Lymphocyte education!
* naive T-cells and mature B-cells are matched to antigen
* Site of Germinal Center
* T-cells → effector cells
* B-cells → plasma cells
63
How does a dendritic cell report inflammation?
* immature DC roams through the tissues constantly sampling material and packing/repacking MHC class II
* PAMP stimulates a change → becomes mature
* 1) new chemotactic pattern to seek the lymph node
* 2) DC change shape (round to stellate)
* 3) Express high amounts of MHC class II for T cells to sample
* 4) Express _co-stimulatory molecules_ (CD80/CD86).
64
What is the only cell capable of activating a naïve T-cell?
* A mature DC is the only cell capable of activating a Naïve T cell:
* high MHC class II expression and
* high expression of co-stimulatory molecules (CD80/CD86).
* DC also provides a signal to control early
* T-cell development (IL-12 directs development of TH1)
65
What does a T-cell produce when it becomes activated?
IL-2
66
\*\*\*What is necessary for complete T-cell activation?
Co-stimulation!
* T-cell receptor engages antigen presented by MHC II
* Co-receptor restricts the matching of T-cell Receptor to MHC type
* MHC I to CD8+
* MHC II to CD4+
* Co-stimmulation (CD28) is required to activate the naÏve T-cell, so you don't inadvertantly turn on T-cell
* will only occur if antigen presenting cell came from site of inflammation
67
What three signals do APCs deliver to naïve T-cells?
1. Activation (CD4)
2. Activation/Survival (CD28)
3. Differentiation (cytokines IL-6,IL-12,TGF-beta)
68
How do you shut off active T-cell?
CTLA!
| (a.k.a. CTLA-4)
69
What T-cells target virus-infected cells?
CD8+ (Cytotoxic T-cells)
70
What T-cells provide help to B-cells for antibody production, espcially IgE?
TH2 cells (CD4+)
71
What type of T-cells shut down immune response or suppress T-cell responses?
CD4 Regulatory T-cells (various types)
72
What type of T-cells enhance neutrophil response?
TH17 cells (CD4+)
73
What type of T-cells activate infected macrophages and provide help to B-cells for antibody assistance with complement?
TH1 cells (CD4+)
74
How do T-cells gain entry into the lymph node?
**High Enothelial Venule (HEV)**
Naïve T-cells express a selectin (CD62L) that permits entry through a special region (HEV) that post capillary beds in the lymph node. The T-cell extravasates into the node then seeks out paracortical area.
75
What do addressins do?
They can direct cells to different targets or residences.
(retinoic acid plays a role in directing)
76
What are some of the common places T-cells park?
* 41% in Kidney
* 30% each:
* Lung
* Liver
* Gut
* 20% in Peripheral Blood
* 11% in Spleen
* 7% in Bone Marrow
77
What are the two functions of B-cells?
* Produce antibodies
* Secretory & surface antibodies
* Secrete cytokines (memory B-cells)
78
Where do B-cells come from and where do they go?
* Mature B-cells emerge from the bone marrow
* Visit secondary immune organs
* Screen for antigens on the surface of follicular dendritic cells
* Once matched with an antigen, B-cells differentiate into Plasma Cells in Germinal Centers of lymph node
* Plasma cells emerge and return to the bone marrow
79
What do resting Mature B-cells (B-2 type) express?
* IgM and IgD
* once exposed to antigen the IgD is lost
* IgM is the product of gene recombination
* No further changes in the antigen binding domain will occur due to gene recombination
* However, Isotype switching (IgG, IgA, IgE) does occur due to additional recombinations
* Further changes to the antigen binding region are due to somatic hypermutation.
80
What cell helps direct isotype switching and affinity maturation in B-cells?
Helper T-cells
| (ah, they're so nice!)
81
What is B-cell selection controlled by?
availability of antigen bound to the surface of the Follicular dendritic cell
82
B cells go through a continuous change in antigen receptor binding affinity due to what?
Somatic hypermutation
83
How long do B-cells remain in the Germinal Center?
As long as their surface Ig’s continue to bind antigen on the FDC.
(The T cells only remain in the region as along as the B cells are present and presenting appropriate antigen on their MHC class II.)
84
B-cells screening for antigen recognition is sometimes referred to as "Mass chaotic movement", why?
Low affinity B cells interact with the FDC, they proceed through affinity maturation and either drop off and die when they produce non-productive changes.
B-cells that complete the education process become memory B cells (surface Ig) or Plasma Cells (no surface Ig, high volume secretion of Ig).
85
\*\*\*What protein in granules of cytotoxic T-cells is responsible for activating caspaces leading to apoptosis?
Granzymes
86
In proliferating B cells (centrocytes), differentiation cytokine IFN-gamma leads to plasma cells that produce what antibodies?
IgG2a or IgG3
87
In proliferating B cells (centrocytes), differentiation cytokine TGF-beta leads to plasma cells that produce what antibodies?
IgA or IgG2b
88
In proliferating B cells (centrocytes), differentiation cytokine IL-4 leads to plasma cells that produce what antibodies?
IgE or IgG1
89
In proliferating B cells (centrocytes), differentiation cytokines IL-2, IL-4, and IL-5 lead to plasma cells that produce what antibodies?
IgM
90
Proliferating B cells are referred to as what?
Centrocytes
91
Activated B-cells are referred to as what?
Centroblast
92
What is the role of Th1?
IFNγ
Promotes macrophage activity
Promotes macrophage mediated inflammation
Drive production of Ig2a and Ig3
93
What is the role of Th2?
IL-4
Humoral activity (antibodies)
Drives the production of IgG1, IgG2b, IgA and IgE
Allergy
94
What is the role of Th17?
IL-17
Inflammation
recruit Neutrophils
95
What is the role of Treg?
TGF-β/IL-12
Down regulates antigen specific T-cell activity
96
What does a Follicular Helper T-cell do?
Guide B-cell development
97
What does an Invariant Natural Killer T-cell do?
monitor and maintain control over commensal bacteria
98
What is the function of a B-1 Cell?
Produce IgM and IgG
99
The cell that controls the immune stategy (i.e. cell-mediated, humoral, or inflammatory) is what?
Mature Dentritic Cell
(binds and activates antigen,
drives toward particular strategy)
100
