Immunology test 3 Flashcards
1
Q
Peripheral or secondary lymphoid organs (spleen, lymph nodes)
A
What activates Naive T cells when they recognize antigen?
2
Q
MHC, mature dendritic cell
A
What must naive T cells encounter to become activated?
3
Q
Professional APCs
A
Capture antigen in periphery and transport it to local lymph nodes
Has processed antigen on surface in association w/ MHC
4
Q
They are activated by naive T cells and dendritic cells are drawn to the T cell zone of the lymph node by chemokines
A
What is the role of the CCR7 chemokine receptor?
5
Q
- Antigen in association w/ MHC which provides specificity to the response
- Costimulation from the APC ensures only APCs can activate T cells
- Cytokines produced by the APC, the T cell or surrounding cells-drives proliferation and differentiation of T cells w/ specific effector functions
A
3 signals required for the activation of naive T cells
6
Q
Endogenously synthesized proteins
A
Where are MHC I presented antigens derived from?
7
Q
Exogenously synthesized proteins
A
Where are MHC class II antigens derived from?
8
Q
Adhesion molecules on the T cell - integrins
A
What stabilizes the T cell APC interaction?
9
Q
Naive T cells
A
Require activation by professional APCs
Strategically located to capture and transport antigen to lymph node
Express high levels of MHC and costimulatory molecules
10
Q
Effector cells
A
Can respond to antigens presented by a wider variety of APCs
Less dependent on costimulation and require less antigen to be activated
11
Q
Prime naive T cells
A
Macrophages and B cells also act as APCs and are efficient at activating effector and memory cells but do not?
12
Q
- Secretion of cytokines
- Proliferation
- Differentiation into effector cells
- Differentiation into memory cells
- Decline of T cell responses
A
5 functional responses of T lymphocytes
13
Q
IL-2
A
Made by naive T cells
This is a T cell survival growth factor
14
Q
Clonal expansion
A
Outgrowth of antigen experienced T and B cells is called?
15
Q
Eliminate antigen, activate other immune cells
A
What do effector cells do?
16
Q
TH1 help CD8 T cells, stimulate IgG2a isotype switching B cells, activate macrophages and aid ini responses against intracellular pathogens
TH2 cells, stimulate IgG1 isotype switching and aid in responses to extracellular pathogens
A
What do CD4 effector cells do?
17
Q
CD8 effector cells
A
Termed cytolytic T lymphocytes and kill cells expressing foreign antigens in association w/ MHC I
18
Q
IL 15
A
Appears to be important in maintaining CD8+ T cell memory
19
Q
Deprived of survival stimuli and they die by apoptosis
A
What happens to activated effector lymphocytes after they eliminate the antigen?
20
Q
Homeostasis
A
Apoptosis of the majority of the activated effector T cells allows the immune system to return to?
21
Q
- Antigen association w/ MHC- provides specificity to the response
- Costimulation from the APC
- Cytokines- produced by the APC, the T cell or surrounding cells, drive proliferation and differentiation of T cells w/ specific effector functions
A
3 signals required for the activation of naive T cells
22
Q
Surface of the activated APC
A
What cells express CD28, B7-1 (CD80), and B7-2 (CD86)?
23
Q
Stimulate T cells
A
Costimulators function together with antigen and the MHC to?
24
Q
Cross presentation of antigens to CD8 cells
A
How are cells infected w/ microbes ingested by dendritic cells and presented in association w/ class I MHC to CD8 cells?
25
Cytokines
| Signal 3
How can CD4+ T cells act directly on the CD8+ T cell?
26
By using CD4+ cells
How can APCs stimulate the expression of costimulatory molecules by the APC?
27
To ensure that T cell responses are initiated at the correct time and place
Why is the expression of costimulatory molecules tightly regulated?
28
Have to have CD28 or B7
How can you get T cell response and differentiation?
29
Leads to DC expression of B7 and secretion of cytokines. Activated DCs stimulate T cell proliferation and differentiation
Causes upregulation of B7 and now the APC can prime other Naive T cells
What is the role of CD40 in T cell activation?
30
CD40L: T cells
CD40: APC
Which cells express CD40 and which express CD40L?
31
Competes for B7 on the APC. Thereby preventing CD28 mediated costimulation.
Alternatively, CTLA-4 may block the signalling of the TCR and or CD28
Function of CTLA-4
32
Costimulatory blockade
Ab or recombinant proteins that block the interaction of costimulatory molecules w/ their cognate receptors on T or B cells
Ex: Fusion protein of CTLA-4 and an Ig molecules that blocks the interaction of B7 on the APC w/ CD28 on the T cell
33
IL 2
Stim the survival and proliferation of antigen activated T cells
Required for survival and function of regulatory T cells
T cell initially expresses a low-affinity receptor
34
Allows the cell to respond more effectively to IL 2
What does CD25 do?
35
IL-2
Stimulates the survival and proliferation of antigen activated T cells
Autocrine growth factor**
Required for survival and function of regulatory T cells thereby controlling responses against self antigens
36
Clonal expansion
proliferate rapidly to produce sufficient #s of effector cells to control the infection
37
Contraction
| or Homeostasis
When activated effector cells have successfully controlled the infection your body needs to get rid of most of them to make room for cells responding to the next infection
38
IFNy, macrophage activation IgG production, intracellular microbes
Signature cytokine, immune rxn, and area of host defense involved for TH-1
39
IL-4 IL-5 IL-13, Mast cell eosinophil activation IGE production alternative macrophage activation, helminthic parasites
Signature cytokine, immune rxn, and area of host defense involved for TH2
40
IL-17A IL-17F IL-22, neutrophilic monocytic inflammation, extracellular bacteria fungi
Signature cytokine, immune rxn, and area of host defense involved TH17
41
Induction
Influenced by cytokines produced early during the response by innate immune cells
42
Commitment
Cytokines cause changes in the expression of lineage specific transcription factors by the T cells. The transcription factors cause changes in gene expression and chromatin structure that commit the cell to a specific T helper lineage
43
Amplification
Cytokines expressed by the now activated T cell promote the development of other T cells of the same subset and repress the development of a different subset
44
Induction, Commitment, Amplification
Development stages of Th-1, Th-2, and Th-17
45
IL-12: Dendritic cells
| IFNy: NK cells
What is IL-12 produced by?
| What is IFNy produced by?
46
STAT1, STAT4, and Tbet
What polarizes the T cell into a TH1 cell?
47
Secretes IFNy which amplifies the response and inhibits the development of TH2 and TH17 cells
WHat does TH1 do?
48
Activated T cells, mast cells, eosinophils in response to helminth infections
What is IL 4 produced by?
49
TH2
What does the upregulation of the transcription factors STAT 6 and GATA 3 polarize the T cell into?
50
IL4
What does the TH1 cell secrete which amplifies the response and inhibits the development of TH1 and TH17
51
Produce cytokines that stimulate CTL differentiation or enhance the ability of APCs to stimulate CTL differentiation
2 ways the CD4 cells can prime CD8 cells?
52
express anti-apoptotic proteins
How do memory cells survive the contraction phase?
53
CD4 and Class II MHCs
How does the immune system respond to microbes that live in the phagosomes of macrophages?
54
CD8 and MHC I
How does the immune system respond to microbes which do not live in phagosomes?
55
Induction phase
Naive CD4 T cells and CD8 T cells are primed by professional antigen presenting cells in peripheral lymphoid organs. The T lymphocytes proliferate and differentiate and effector cells enter the circulation
56
Migration phase
Effector T cells and other leukocytes migrate thru blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues
57
Effector phase
Effector T cells recognize the antigen in the tissues and respond by secreting cytokines that activate phagocytes to eradicate the infection. T cell derived cytokines also stimulate inflammation
58
Cytokines
Migration of leukocytes to sites of infection is stimulated by? which induce the expression of adhesion molecules on the surface of endothelial cells and the chemotaxis of leukocytes
59
CD4 T cell recognizes antigen in tissue
CD4 T cell and macrophage mutually activate each other
Down regulation of response: death or suppression of T cells
What are the roles of CD4+ T cells and costimulatory molecules during cell mediated immune response?
60
Need: if the bug lives in a phagosome inside of a macrophage. Have to activate macrophage to destroy the bug.
Don't need: if the bug is in the cytoplasm (need CD8)
When do you need CD4 T cells and when do you not need them?
61
IFNy
What is produced by TH-1 type CD4+ and Cd8 T cells?
62
Dependent on IFNy
T cell mediated macrophage activation
63
T lymphocytes, but not by serum
How can immunity from a viable bacteria be transferred in mice?
64
Reactive O2 intermediates, NO, Lysosomal enzymes, may also be released into adjacent tissue to kill extracellular microbes and may damage normal tissue.
How do activated macrophages kill phagocytosed microbes?
65
Secrete TNF, IL-1, and chemokines
| Short lived lipid mediators of inflammation
How do activated macrophages stimulate acute inflammation?
66
Remove dead tissue, secrete growth factors such as fibroblasts, collagen synthesis transforming growth factor B, angiogenesis fibroblast growth factor
How do macrophages facilitate repair?
67
Fibrosis
Hallmark of chronic delayed type hypersensitivity reactions
| Tissue injury followed by replacement w/ connective tissue
68
Necrosis
Type of inflammation that is a chronic delayed-type hypersensitivity reaction against persistent microbial and other antigens
69
Clusters of activated macrophages often will surround particulate sources of antigen producing nodules of inflammatory tissue called granulomas
What happens if activated macrophages cannot eradicate the infection?
70
Transcription factors
T-bet associated w/ IL-12 and Th1 amplifies Th1 response
GATA-3: IL-4 and Th2 cells, critical for Th2 differentiation
What are T-bet and GATA 3?
71
IFNy
Can inhibit the *proliferation of TH-2 cells polarizing helper cell responses to TH-1
72
IL-4, IL-10
___ inhibits the activation of TH1 cells and ___inhibits their proliferation polarizing T helper cell responses towards TH-2
73
Th-1
Differentiation pathway is the response to microbes that infect or activate macrophages and or NK cells
74
Th-2
Differentiation pathway occurs in response to helminth and allergens which cause chronic T cell stimulation w/o a significant innate immune response or macrophage activation
75
IL-12 stimulates the differentiation of CD4 helper cells to TH1 effectors which produce IFNy. IFNy then activates macrophages to kill phagocytosed microbes and to secrete more IL-12
What is the role of IFNy and IL-12 in cell mediated immunity?
76
CD4+ helper T cells to TH1 effectors
What kind of T helper cells do IL-12 and IFNy cause production of?
77
Secrete IL-4,IL-5, and IL-13. Ab production, mast cell degranulation, intestinal mucus secretion and peristalsis, eosinophil activation, alternative macrophage activation
Effector functions of TH2 cells
78
Neutrophil responses, secretion of antimicrobial peptides, enhancebarrier functions in mucosal tissues
IL 17 stimulates?
79
IL-4 and IL-13
IgE production and eosinophil mediated rxns stimulated by?
80
Alternative macrophage activation
IL-4 and IL-13 activate macrophages to express enzymes that promote collegan synthesis and fibrosis
81
IL4 and IL13
Stimulate the production of IgE
82
IL5
Activates eosinophils
83
Eosinophils
Express an Fc receptor specific for IgE and will bind the opsonized worm and release their granules which can destroy even the tough integument of the worm
84
1. Antigen recognition and immune synapse formation
2. Granule exocytosis
3. Detachment of CTL
4. Target cell death
Steps in CTL mediated lysis of target cells
85
Perforin and granzymes
| Fas ligand
2 main mechanisms CTL kills target cells
86
Perofrin
Exocytosed in CTL granules polymerizes in the target cell plasma membrane *forming pores*
87
Granzymes
Exocytosed in CTL granules, enter target cells through the perforin pores, and induce target cell apoptosis
88
Fas ligand
Expressed on activated CTLs, engages Fas on the surface of target cells and induces apoptosis
89
Central memory T cells
Express CCR7 and L selectin so they can come home to lymph nodes
Express only limited effector functions
When exposed to antigen they rapidly proliferate and their progeny express effector functions
90
Effector memory t cells
Home to peripheral tissues (not lymph nodes)
Immediately express effector functions upon re exposure to antigen
They do not proliferate much after antigen exposure
91
Effector memory T cells
Provide an immediate response to reinfection
92
Central memory T cells
Provide a means of expanding the memory T cell pool after reinfection
93
Strong innate response= CD4 help may not be necessary
Weak innate response/not infected= CD4 may be crucial
CD4 enhances the ability of the APC to stimulate CTL differentiation by secreting cytokines that activate the APC
What are the roles of costimulation and helper T cells in the differentiation of CD8 t lymphocytes?
94
Macrophage activation and killing of ingested microbes via cytokine secretion
What is the effector function of TH1 cells?
95
Migrate thru blood vessels in peripheral tissues by binding to endothelial cells that have been activated
Cytokines induce the expression of adhesion molecules on the surface of endothelial cells
How do leukocytes find the site of infection?
96
Secretes cytokines in the tissue and respond by secreting cytokines that activate phagocytes to eradicate the infection. Also stim inflammation
What happens once a T cell has found the infection?
97
Return to circulation, thru lymphatic vessels
What happens to T cells which do not find their cognate antigen at the site of infection?
98
```
Activates them to kill phagocytosed microbes
Acts on B cells to promote Ab class switching
```
Promotes differentiation of Th-1 CD4 cells and inhibits Th-2 and TH-17 CD4 T cell development
Stimulates expression of proteins involved in MHC I and MHC II antigen presentation
What role does IFNy play in macrophage activation?
99
Kill microbes in phagolysosomes
What role does producing reactive oxygen intermediates like NO and lysozyme have in cell mediated immunity?
100
TNF, IL-1 chemokines: leukocyte recruitment, inflammation
| IL-12: TH1 differentiation, IFNy production
What role do TNF, IL-1, chemokines, and IL-12 have in cell mediated immunity?
101
Increased T cell activation (amplification of T cell response)
What role does increased expression of B7 costimulators, MHC molecules have on cell mediated immunity?
102
Remove dead tissue
| Secreting growth factors (fibroblasts, collagen synthesis, angiogenesis-fibroblast growth factor)
How do macrophages facilitate tissue repair?
103
Continual production of cytokines and growth factors which progressively modify the local tissue environment.
Tissue injury is followed by replacement w/ connective tissue
Macrophages undergo physiological and morphological changes in response to chronic cytokine signals
Take on the appearance of skin epithelial cells
Fusion of activated macrophages to form multinucleate giant cells
What happens if activated macrophages can't eradicate the infection?
104
Granuloma
Area of activated macrophages and lymphocytes. May have a central area of necrosis. This type of inflammation is a chronic delayed-type hypersensitivity rxn against persistent microbial and other antigens
Cluster of activated macrophages often surround particulate sources of antigen producing nodules of inflammatory tissue called ?
105
TH-2 differentiation pathway. Chronic T cell stimulation w/o a significant innate immune response or macrophage activation
How does the immune system respond to helminth infections?
106
APCs stimulated by IFNy or CD40-CD40L secretes IL-12 which then stimulates the differentiation of CD4+ helper T cells to TH1 effectors, which produce IFNy. IFNy then activates macrophages to kill phagocytosed microbes and to secrete more IL-12
What role does CD40-CD40L and IFNy play in macrophage activation?
107
1. Recognition phase: antigen binds to naive IgM or IgD resting mature B cell
2. Proliferation phase: clonal expansion
3. Differentiation phase: Become plasma cells or memory cells
3 phases of the humoral immune response
108
T cell dependent or thymus dependent antigens
```
Heavy chain class switching and affinity maturation is common
Require CD4 T lymphocytes that recognize the same antigen
```
Almost always protein antigens
109
T cell independent antigens
Ab responses can be made in the absence of CD4 T cell help
110
Secondary lymphoid organs (spleen, lymph nodes, mucosal lymphoid tissues)
Where are humoral immune responses initiated?
111
Dependent: CD4 must recognize the same antigen, protein antigen
Independent: Ab can be made in absence of CD4. Polysaccharides, lipids, nucleic acids
What antigens are T cell dependent/not T cell dependent?
112
Spleen: Blood borne
Lymph nodes: Skin/epithelial surfaces
Mucosal lymphoid tissue: Inhaled/ingested antigens
Where does the spleen/draining peripheral lymph nodes/mucosal lymphoid tissue collect antigens from?
113
Primary: stimulates naive B cells and makes memory B cells.
Secondary: Stimulates memory B cells. Faster proliferation and differentiation, production of greater quantities of specific Ab than are produced in the primary response
How are primary and secondary immune responses different?
114
Follicular B cells
T cell dependent response
| Naive cells continuously recirculate and can get T cell help when they respond to protein antigens
115
Germinal center
When the follicular B cells get help from the CD4 T cells the now activated B cells form a ?
116
Class switching
Somatic hypermutation
High affinity Ab responses develop
Long lived memory cells develop
117
Marginal zone B cells
Found in the marginal zone of spleen and respond to non protein multivalent antigens
T cell independent response*
Cannot class switch cuz no help from CD4 so they undergo affinity maturation or become memory B cells. The response is mostly low affinity IgM
118
B-1 cells
Behave just like marginal zone B cells and elicit T independent responses but these cells live at mucosal sites
119
Binding of antigen to membrane immunoglobulin molecules which are the antigen receptors* of mature B cells
What event initiates the activation of antigen specific B cells?
120
1. Binding of antigen= clustering of receptors and this initiates a signal transduction cascade that starts the cellular activation process
2. INternalizes the antigen into endosomal vesicles* where it is broken down into peptides which can be displayed on the surface in association w/ MHC II (protein antigens)
What 2 purposes does the antigen receptor serve?
121
IgM and IgD
What are the antigen receptors on the surface of Naive B cells?
122
Phosphorylation in Iga and IgB
What happens to ITAMs when antigen binds and crosslinks the receptor?
123
Contain ITAMs in their cytoplasmic tails that mediate signaling functions
Called the B cell receptor complex
What is the function of Iga and IgB?
124
zeta chain in T cells
What do Iga and IgB serve the same function as in T cells?
125
CD3 binds to the antigen
How is the CCR2 complex activated?
126
PAMPs
If present during the infection can also trigger TLRs in the responding B cell
127
^ Survival/proliferation
^ B7 expression
^ expression of cytokine receptors
^ expression of CCR7 and migration from follicle to T cell areas
4 things antigen mediated crosslinking of the BCR causes?
128
1. Antigen induced crosslinking of membrane Ig
2. Clustering of the Iga and IgB molecules
3. Tyrosine phosphorylation of the ITAMs in the cytoplasmic tails
4. This leads to docking of Syk subsequent tryosine phosphorylation events
5. Activation of several transcription factors
5 major steps of signal transduction by the BCR complex?
129
Classical pathway
Activation of the complement system by binding to antigen complexed Ab molecules
Can be acitvated by preexisting Ab or those produced early in a response
130
Alternative and lectin pathways
Activation of the complement system by binding directly to soem microbial surface (in absence of Ab) or to a carb
Can be activated during innate immune response
131
Provides additional signals
What does complement do in B cell activation?
132
C3d is required as a second signal for B cell activation so a B cell response will only occur when microbes and antigens that activate complement are encountered.
This also amplifies the response because the B cell will produce more Ab which will activate complement and lead to more B cell activation
How does complement activation play a regulatory role in the development of Ab response?
133
Leads to phosphorylation of ITAMs in Iga and IgB
How does crosslinking of several antigen receptors help the B cell to transduce the extracellular signal into an intracellular biochemical event?
134
Stimulate B cell clonal expansion, isotype switching, affinity maturation, and differentiation into memory cells
What do helper T cells help B cells do?
135
Early: Extrafollicular locus
Late: Germinal center
Where do early and late events in T cell dependent B cell activation occur?
136
Germinal center
```
Within a lymph node, where mature B lymphocytes proliferate, differentiate, mutate Ab, and class switch during a normal infection response
* Contained w/ in the follicle and includes a basal dark zone and an adjacent light zone
```
137
B cell antigen presentation to activated helper T cells
Activation of B cells by cytokines and CD40 ligation; initiation of germinal center rxn
Extrafollicular B cell activation; isotype switching; limited somatic mutations, short lived plasma cells
Germinal center formation, isotype switching, affinity maturation, long lived plasma cells, memory cells
What is the mechanism of helper T cell mediated B cell activation?
138
Increase the ability of the B cell to activate T cells.
What do B7 do?
139
Initiates B cell proliferation and differentiation
What is the role of CD40 and CD40L?
140
Stimulate B cell responses
What do cytokines do once bound to cytokine receptors?
141
Plasma cell
Secrete Ab for years after the antigen is eliminated providing immediate protection upon reinfection
Differentiated into by an Ab secreting cell in the lymph node
142
Bone marrow
where do plasma cells reside?
143
1. BCR recognizes Hapten protein
2. B cell internalizes antigen and degrades it into peptides
3. B cell then presents a carrier epitope in association w/ MHC II and triggers a carrier specific CD4 T cell
What does the BCR do before the T cell can help it?
144
CD40 and cytokines
Ab synthesis and secretion is stimulated by?
| Activate transcription factors that enhance Ig transcription
145
Cytokines
May affect RNA processing to increase the amount of transcripts encoding secreted forms of Ig
Stim Ab production
146
Red pulp of spleen/ medulla of lymph node
Where are Ab secreting cells primarily found?
147
IgM, IgG, IgE, IgA
What are the 4 Ig subclasses?
148
IgM
What Ig participates in complement activation?
149
IgG
What Ig is an Fc receptor dependent phagocyte responder, complement activation, and neonatal immunity?
150
IgE
What Ig is immunity against helminths, mast cell degranulation?
151
IgA
What Ig is mucosal immunity?
152
Switch recombination
The rearranged VDJ gene segment Downstream C region gene and the intervening sequences are lost
153
Mantle zone
Parent follicle within which the germinal center has formed
154
IgG2a
What isotype does IFNy stimulate?
155
Some IgE and IgG1
What isotype does IL-4 stimulate?
156
IgA
What isotype does TGFB and IL-5 stimulate?
157
No cytokine signal
What cytokine stimulates isotype switching in IgM?
158
So they do not form during T cell independent Ab responses
Why does germinal center formation require T cell participation?
159
Activated B cells at the edge of a primary follicle migrate into the follicle and proliferate
How is the dark zone formed?
160
Differentiate into Ab-secreting or memory B cells
What happens to B cells w/ the highest affinity Ig receptors?
161
Somatic hypermutation
Increases the affinity of Ab for antigen
162
Display antigen and those B cells which bind the antigen w/ the highest affinity are selected to survive
What role do follicular dendritic cells play in the process of affinity maturation?
163
CDR regions
Where are mutations during the primary and secondary responses confined to?
164
Ab feedback
Downregulation of Ab production by secreted IgG
165
Binds ITIM
| On the antigen specific B cell helps inhibit continued B cell activation
What is Fcy RII receptor and what does it bind?
166
Inhibitory motif on the cytoplasmic tail of the Fc-y II receptor
When it is phosphorylated it forms a docking site for SHIP which has a phosphatase* that hydrolyzes the 5' phophate of PIP3 and terminates the signalling pathway that leads to B cell activation
What is ITIM and how does it terminate the B cell response to antigen?
167
IgM: Binds complement and Ab potentiates the Buell response
IgG: Downregulate the response by Ab feedback
How does the circulating level of secreted IgM and IgG modulate the Ab response?
168
Polysaccharides and glycolipids and nucleic acids
What 3 types of compounds can induce antibody responses in the absence of helper T cells?
169
They getno help from CD4+ T cells so they cannot class switch efficiently or undergoaffinity maturation or become memory B cells
Why are T cell independent Ab responses generally IgM and of low affinity?
170
IgM
Activation of the classical pathway of complement
| Antigen receptor of naive B lymphocytes
171
IgA
Mucosal immunity: secretion of this into the lumens of the GI and respiratory tracts
172
IgE
Ab-dependent cell-mediated cytotoxicity involving eosinophils
Mast cell degranulation (immediate hypersensitivity rxns)
173
IgD
Antigen receptor of naive B lymphocytes
174
- Ab blocks binding of microbe and infection of cell
- Ab blocks infection of adjacent cell
- Ab blocks binding of toxin to cellular receptor
How do Ab neutralize microbes and toxins? (3 ways)
175
Fc receptors
Ab of certain IgG subclasses bind to microbes and are then recognized by ___ on phagocytes
Signals from these promote phagocytosis of the opsonized microbes and activate the phagocytes to destroy these microbes
176
Killing of Ab-coated cell (IgG, Fcy receptor on NK cells)
| Killing of helminth (IgE, Fce receptor on eosinophils)
What are the 2 major types of Ab dependent cell mediated cytotoxicity reaction?
177
Zymogen
Protein who gains proteolytic activity after being cleaved by another protease
178
1. Classical
2. Alternative
3. Lectin
3 complement pathways
179
Classical pathway
Activated by certain Ab isotypes (IgG, IgM) which are bound to antigen
180
Alternative pathway
Activated on microbial cell surfaces in the absence of Ab
181
Lectin pathway
Activated by a plasma lectin that binds to mannose receptors on the surface of microbes
182
1. Binding of C3 to C3b
2. Formation of C3 convertase
3. Cleavage of C3
4. Covalent binding of C3b to microbial surface
What are the early steps in the alternative complement activation pathway?
183
Absence of Ab
What triggers the alternative pathway?
184
1. IgG binds to C1
2. Formation of C3 convertase
3. Cleavage of C3
4. Covalent binding of C3b to microbial surface
What are the early steps in activation by the classical complement pathway?
185
Ab isotypes bound to antigen
WHat triggers the classical pathway?
186
C4bC2b
What functions as the C3 convertase for the classical pathway?
187
C4b2aC3B
What functions as the C5 convertase of the classical pathway?
188
C1 must bind to 2+ Fc portions to initiate the complement cascade
The Fc portions of soluble IgM are not accessible to C1
Soluble IgG only has one Fc region
Why does soluble IgM and IgG not activate complement?
189
Creates pores in the membrane and induces cell lysis
What is MAC?
190
1. C5 convertases cleaves C5 and generates C5b
2. C5b becomes bound to the convertase
3. C6 and C7 bind sequentially
4. The C5,C6, and C7 complex is inserted into the lipid bilayer of the plasma membrane
5. This leads to stable insertion of C8
6. C9 molecules then polymerize around the complex to form MAC
How is MAC formed?
191
1. Regulation of C1 activity by C1 inhibitor preventing C1 from becoming proteolytically active
2. Inhibition of the formation of the C3 convertase
3. Proteolytic cleavage of C3b leaving an inactive form of C3b on the surface of the microbe
4. Direct inhibition of MAC
What are the four major ways complement can be regulated?
192
1. Phagocytosis of microbes
2. Recruitment and activation/inflammation of leukocytes by C5a, C3a, destruction of microbes by leukocytes
3. Osmotic lysis of microbe by MAC
3 major functions of complement
193
Binds to poly-Ig receptor at the base of an epithelial cell. This is actively transported thru the epithelial cell and the bound IgA is released into the lumen by proteolytic cleavage = Transcytosis
How is IgA transported through epithelial cells?
194
Tolerance
Unresponsiveness to an antigen that is induced by previous exposure to that antigen
195
Tolerogen
Antigens that result in tolerance
196
Immunogen
Antigen that result in immunity
197
Depends on how the naive cell first encounters the antigen
How can the same antigen be both tolerogenic and immunogenic?
198
We end up w/ autoimmune disease
What happens when self/non self discrimination fails?
199
Central tolerance
Involves immature lymphocytes
Occurs in generative organs
Example: Negative selection of T cells in the thymus getting rid of the bad cells during development b4 they can cause damage in the periphery
200
Peripheral tolerance
Involves mature lymphocytes
Occurs in peripheral tissues
Need to turn off or kill escaped self reactive T cells
Induced when a mature lyphocyte recognizes antigen in such a way that the cells receive either an inactivating signal (anergy*) or an apoptosis signal
201
1. Apoptotic cell death
2. Anergy
3. Suppression of lymphocyte activation by regulatory lymphocytes
= peripheral tolerance
What factors promote tolerance?
202
Anergy
Functional inactivation w/o cell death
203
Clonal ignorance
Some antigens are completely ignored by the immune system so when a lymphocyte encounters this antigen it fails to respond in any detectable way but it remains viable and functional
204
Anergy: inactivated
Clonal: viable and functional
Difference b/t anergy and clonal ignorance
205
thymus
| dies/becomes a regulatory cell
Where does recognition of self antigen occur? What happens to the T cell?
206
Stimulation: B7 engages a costimulatory molecule and T cell becomes activated= proliferation and differentiation
Anergy: TCR engages but B7 is either not engaged or interacts w/ an inhibitory molecule (CTLA4) T cell becomes anergized= Unresponsive T cell
What role does B7 play in T cell stimulation and anergy?
207
Inhibitory receptor for B7 molecules
| *Delivers an inhibitory signal to the T cell*
What is the function of CTLA4?
208
Uncontrolled lymphocyte activation
Fatal multi-organ lymphocytic infiltrates
Blocking CTLA-4 enhances autoimmune diseases
T cells lacking CTLA-4 are resistant to the induction of anergy
What happens to CTLA-4 deficient mice?
209
Naive T cells express lots of CD28 which favors activation and proliferation. Antigen experienced T cells don't express much CD28 so CTLA4 can turn the T cell response off and return the boyd to homeostasis.
If CTLA-4 is always going to turn off the T cell, how do we ever manage to make a T cell response in the first place?
210
Contact dependent inhibition
Mechanism of suppression is not presently known but it requires direct contact b/t the T cell and the regulatory T cell or b/t the regulatory T cell and the APC
211
Contact independent inhibition
Does not require direct contact b/t the regulatory T cell and the target T cell
Probably works thru immunosuppressive cytokines that can act at a distance
212
IL-10
Inhibits APC function and macrophage activation
213
TGF-B
Inhibits T cell proliferation and also macrophage activation
214
Do: ^ anti-apoptotic proteins
| Don't: Upregulate pro apoptotic proteins or Fas and FasL
What happens if T cells do/do not receive costimulation?
215
Passive cell death
Death by neglect
When activated T cells dont get survival signals
Elimination of antigen and other signals
Release of mitochondrial cytochrome C, activation of caspase-9
216
Activation induced cell death
When activated T cells receive too much stimulation
Fas is the death receptor and FasL is the signal to die
Persistance of antigen repeated stimulation
Activation of caspase 8
217
Fas is the death receptor and FasL is the signal to die
What is Fas and FasL?
218
Recognize self. When immature B cells recognize the antigen in the bone marrow, the B cells may be deleted by apoptosis, may change the specificity of their antigen receptors, or the cells may leave the bone marrow w/ greatly reduced levels of receptor expression
Describe the cardinal features of central tolerance in B cells
219
Receptor editing
B cells changing the specificity of their antigen receptors is called what?
220
When MATURE B cells encounter self antigen in the absence of T cell help, the B cells are excluded from lymphoid follicles, and they become incapable of responding to antigen recognition
1. Block in antigen receptor induced signals (anergy)
2. Exclusion of B cells from lymphoid follicles
Describe peripheral B cell tolerance
221
Central: high avidity recognition of antigen in thymus
Peripheral: Antigen presentation by APCs lacking costimulators repeated stimulation by self antigen
How do regulatory T cells induce tolerance?
222
Normal immune response
Maintained via apoptosis, some responses may be terminated by active regulatory mechanisms (CTLA-4 or death receptors), memory cells are the only surviving T cells
What is homeostasis and how is it maintained under normal circumstances?
223
1. Receptor mediated endocytosis of antigen, peptide fragments are presented in association w/ class II MHC
2. Antigen processing and presentation. Antigen binding to the B cell also stimulates expression of the costimulatory molecules B7 which increases the ability of the B cell to activate the T cell
3. Helper T cells recognize the MHC peptide complexes and costimulators and are activated to then stimulate B cell responses
What are the 3 steps in B cell antigen presentation to helper T cells?
224
Affinity maturation
is the process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response
225
Isotype switching
changes a B cell's production of antibody from one class to another,
226
Germinal rxn center
Dark zone: B cells proliferate
Light zone: B cells migrate here and the ones w/ the highest affinity Ig receptors are selected to survive and they differentiate into memory B cells
What are the late events in helper T cell dependent Ab production and where do they occur?
227
IgG
Ab isotype that opsonizes phagocytosis by macrophages and neutrophils
Activation of the classical pathway of complement
Ab-dependent cell mediated cytotoxicity mediated by NK cells and macrophages
Neonatal immunity: transfer of maternal Ab across the placenta and gut
Feedback inhibition of B cell activation
