Final Exam Immunology Flashcards
1
Q
eosinophil
A
kills antibody coated parasites through release of toxic granule contents
- combats multicellular parasites or heminths
- 1-6% of WBC
- Granules contain toxic enzymes and histamine
- Granules stain brightly with dye; Eosin - acid loving
2
Q
basophil
A
- Controls immune response to parasites
- least common granulocute (0.01%-3%)
- Granules contain histamine, proteoglycans (heparin and chondroitin)
- IL4 - central to many allergic reactions
- Express IgE
3
Q
Mast cells
A
- Expulsion of parasites from the body by release of granules containing histamine + other active agents
- Major mediator of type I hypersensitivity
- Express IgE
- Granules contain histamine and heparin
4
Q
Macrophage
A
Phagocytosis and killing of microorganisms
5
Q
Dendritic cells
A
activates T cells to initiate the adaptive immune system
6
Q
Macrophages and dendritic cells
A
- Both phagocytic
- Macrophages: bactericidial activity
- Dendritic: No bactericidial activity
7
Q
“professional antigen presenting cells”
A
dendritic cells
8
Q
Neutrophils
A
- phagocytosis and killing of microorganisms
- PMN (polymorphonuclear cells)
- 40-70% of leukocytes
- short life span: 24hr half life
-
Migrate from blood to sites of infections
1. phagocytosis
2. Granules loaded with degradative enzymes
3. Produce reactive oxygen and nitrogen radicals
9
Q
Three major funcitons of neutrophils
A
- Migrate from blood to site of infection
- Phagocytosis followed by intracellular degranulation
- Produce reactive oxygen radicals through respiratory burst - NADPH-oxidase
10
Q
diapedesis
A
leukocyte extravasation - movement of leukocytes out of the circulatory system and toward sites of inflammation or infection
11
Q
Neutrophil Migration
A
Neutrophils rapidly moves through vessels and it has receptors (selectin and integrin) that allow the neutrophil to bind and interact with several ligands on the surface of endothelium.
- During an inflammation/infection, these sites of receptors become more sticky and chemokines are released.
- Neutrophils slow down and the receptors are binding to the vessel with higher affinity.
- Integrins recieve signal from chemokines
Selectin ligand on neutrophil binds to selectin on the vessel surface, slowing it down, then the integrin binds to integrin ligands in the vessels and the cell performs diapedisis.
12
Q
LFA-1 + ICAM1
A
low affinity integrin LFA1, binds to ICAM1, when a chemokine receptor and chemokine have interacted.
13
Q
Bacteria killing process
A
- receptor binding
- engulfment
- phagocytosis
The real killing is when granules fuse with phagosome
14
Q
Killing of microbes process
A
- microbes bind to phagocyte receptors
- phagocyte membrane zips up around membrane
- microbe ingestedin phagosome
- fusion of phagosome with lysosome
Killing of microbes by ROS, NO, and lysosomal enzymes in phagolysosomes.
15
Q
enzymes
A
degrade bacterial components
16
Q
defensins
A
poke holes in bacterial membranes
17
Q
lactoferrin
A
sequester iron away from bacteria
18
Q
Respiratory burst
A
- When NADPH oxidase is activated, and production of bactericidal compounds begin
- Superoxide + Hydrogen peroxide
- ## HOCl - hypochlorous acid
19
Q
Neutrophil death: two fates
A
Macrophage ingestion
Exits the body as Pus
20
Q
DIseases with Neutrophil dysfunction
A
CGD
Chediak Higashi
LAD
21
Q
CGD
A
NADPH oxidase defects
No respirator burst , greatly reduced bacterial killing
22
Q
Chediak Higashi syndrome
A
phagocytosis and granule defects
unable to engulf and kill bacteria
23
Q
LAD deficiency
A
deficiency in adhesion molecules, migration into tissue is minimal
Very high # of neutriphils in blood, but they cannot migrate to site of infection. Infection goes unchecked
24
Q
the complement system is a grouo of _ found in serum involved in:
A
zymogens
- Control of inflammation - Recruitment of phagocytes
- Enhanced pathogen uptake and clearance - Opsonization
- Lyttick attack of cell membranes (killing bacteria)
25
Classical Pathway
Antigen: Antibody complex
- Initiated by **antibody** or C reactive protein (**CRP**) binding to pathogen surface
- C1 (C1q, C1r, C1s)
- C1 binding + CRP (phosphocholine) on pathogen surface
26
Perfect ligand for C1q in the classical pathway
IgM
27
MBL pathway
- Initiated by MBL binding to **mannose** and **fucose** residues on pathogen surface
- Initiating complex --> MASP1 and MASP2 and MBL
Ligand recognition molecules from classical and MBL are structurally similar
28
Classical pathway mechanism
- C1 binds to IgM
- C2 and C4 bind forming **C2aC4b**
- C3 binds to C2aC4b
- C3a leaves, **C3b** stays on pathogen surface
Cr1 = phagocytosis
C5-9 = lysis of pathogen
29
MBL initiation and after
- Activated MASP2 cleaves C4 to C5a and C4b. Some C4b binds covalently to the microbial surface
- Activated MASP2 also cleaves C2 to C2a and C2b
- C2a binds to surface C4b forming the classical C3b convertase C4b2a
- **C4b2a binds C3** and cleaves it to C3a and C3b. **C3b** binds covalently to microbial surface
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30
how is the alternative pathway activated?
Spontaneously. Without the help of a ligand-binding molecule
31
Spontaneous activation of C3 in plasma
C3 spontaneously hydrolyzed
1. C3b attach to the bacterial membrane and liberation of **C3a** which acts as a chemoaatractant (**anaphylatoxin**) to phagocytes)
32
example of anaphylatoxin
C3a
33
C3 convertase classical
C4b2a
34
Alternative C3 convertase
C3bBb
35
How complement activation induces phagocyte recruitment
1. anaphylatoxins (C3a, C5a) act on blood vessels to increase vascular permability
2. Increased permeability - increased leakage from blood vessels and extravasation of complement and other plasma proteins to the site of infeciton
36
opsinization basics
I. complement activation leads to deposition of C3b on the bacterial cell surface
- **CR1 on macrophage binds C3b on bacterium**
- Endocytosis of the bacterium by macrophage
- Macrophage membranes fuse, creating a membrane bounded vesicle, the phagosome
- Lysosomes fuse with phagosomes, forming a phagolysosome
37
C3 cleavage
C3a - recruits phagocyte s
C3b - tags bacterium for destruction (opsonization or membrane attack)
38
lyttick membrane attack
C5-C9
39
C1 inhibitor
Binds to activated C1r, C1s, removing them from C1q and to activated MASP2, removing it from MBL
40
Factor H
binds C3b, displacing Bb for cofactor I
41
Factor I
Serine protease that cleaves C3b and C4b
42
CD59 (protectin)
**Prevents formation of membrane attack complex**
binds to C5b678, preventing recruitmen of C9 from the pore
43
Acute phase response
**IL6** goes into liver, producing **CRP** (C reactive protein).
CRP is a common clinical readout of infection or inflammation
CRP binds phosphocholine on bacterial surfaces
MBL binds carbohydrates on bacterial surfaces
44
C1,C2,C4 deficiency
Immune complex disease
45
C3 deficiency
Susceptibility to Capsulated bacteria
46
C5-C9 deficiency
Susceptibilty to Neisseria
47
Facor I deficiency
Similar to C3 (susceptbility to capsulated bacteria)
48
Which complement components are associated with which functions?
C3a, C5a = recruitment
C3b = opsonization
C5b,6,7,8,9 = membrane attack
49
immediate innate response
0-4 hrs
Very minor tissue damage is repaired
50
Induced innate immune response
4hrs - 4 days
minor tissue damage is soon repaired
51
Adaptive immune response
4 days +
Major tissue damage is gradullay repaired
52
Gram +
peptidoglycan, lipotheichoic acid
53
gram -
Lipopolysachharide
54
PAMP
hypomethylated CpG DNA
55
Microbes contain genetically conserved patterns called
PAMPS - pathogen associated molecular patterns
56
PAMPS are recognized by
**PRR** (pattern recognition receptors) of the **innate** immune system: Macrophages, NK cells, neutrophils, DC
57
Types of PRRs
TLRs and Cytosolic receptors
58
Uptake receptors
Facilitate uptake of particles
- complement receptors
- scavenger
- mannose
59
Signaling recepotrs
recognize bacterial PAMPs and inducde activation of the cell through signaling cascades leading to changes in gene expression
TLR
NOD like
RIG-I-like
60
TLR structure
**Amino end** - pathogen recognition domain outside of the cell
**carboxyl end**: **TIR** domain on cytosolic side of cell
61
TLR structure
**Amino end** - pathogen recognition domain outside of the cell
**carboxyl end**: **TIR** domain on cytosolic side of cell
62
TLR2 + TLR6
Lipoteichoic acid
Gram positive bacteria
63
TLR4
Lipopolysachharide
Gram - Bacteria
64
TLR7
ss viral RNA
RNA virus
65
TLR8
ss viral RNA
RNA
66
TLR9
Unmethylated CpG rich DNA
Bacteria + DNA virus
67
TLR3
DS viral RNA
RNA VIRUS
68
TLR5
Flagellin
Bacteria
69
which TLR are on plasma membrane
TLR2+6
TLR4
TLR5
70
Which TLR are on endosomes
- TLR3,7,8,9
71
TLR4 needs help from other molecules to access
**LPS**
- Complex of **TLR4, MD2, Cd14 and LPS** assembled on surface
- **MyD88** binds TLR4
- Leads to release of **NFkB** which enters the nucleaus
- NFkB activates transcription of genes for inflammatory cytokines, which are synthesized in the cytoplasm and secreted via ER
72
TLR4 SIGNALING by the TRIF and MyD88 cascade
Synthesis and secretion of TNF-alpha and other inflammatory cytokines
73
NOD like receptors recognize
**bacterial cell wall**
74
inflammasomes recognize
**pathogens** as well as **intracellular** damage or injury
75
RIG I , MDA5 recognize
**Viral** nucleic acids
76
activation of NfkB results in
gene transcription
77
proinflammatory cytokines
IL6
IL1
TNF
IL12
IFNy
78
**IL1/IL6/TNF-alpha**
**Liver**
- activation of complement
- Acute phase proteins
**BM endothelium**
- phagocytosis
- Neutrophil mobilization
**Hypothalamus**
- decreased viral and bacterial replication
- Increased body temperature
**Fat, muscle**
- Decreased viral and bacterial replication
- Protein and energy mobilization to generate increased body temperature
79
immature DC
- Tissue resting
- Highly endocytic
- Low expression
- poor stimulators of T cells
80
Mature DC after exposure to inflammatory stimuli, PAMPS
- Homes to lymph node
- endocytosis shuts down
- High level coexpression
- Highly stimulatory for T cells
81
antiviral acts in both
autocrine and paracrine
82
MDA5 + RIG-I
cytoplasmic pattern recognition receptors
83
Type I interferons are very helpful for
Viral infections
84
Antiviral immune response
- Type I interferons! (alpha and beta)
- work in both autocrine and paracrine manner
85
after viral infection...
TLRs or cytoplasmic receptors can acativate transcription factors
- **IRF --> move to nucleus and activate IFN alpha and beta**
86
anti viral state by type I interferons
- inhibition of viral protein synthesis
- degradation of viral RNA
- inhibition of viral gene expression and virion assembly
87
RIG I facilitates activation of
**IRF3 and NFkB**
IRF3 - type I interferon
NfkB - inflammatory cytokines
88
TLRs that have strong type I interferon response
TLR7 and TLR3
89
only TLR that doesnt associate with MyD88
TLR3, it associates with TRIF
90
interferon responses from virus infected cells
- increase expression of ligands for receptors on **NK** cells
- Activate **NK** cells to kill virus infected cells
91
NK cells (lymphocytes)
A **balance of activation and inhibition** determines the fate of target cells
**INNATE** immune system
Type I interferon drives the proliferation of NK cells
Type I interferon drives the differenctation of NK cells into cytotoxic effector cells
92
Important functions of NK cells
1. killing of infected or damaged cells
- activating (killing) /inhibitory receptor (no killing)
- whichever one has stronger signal determines the fate of the cell
2. production opf cytokines to activate macrophages
- NK produce IFNy to stimulate activation of macrophages and their killing
93
KIRs
killer cell immunoglobin like receptors
Can be activating or inhibitory, depending on their tail
94
Inhibitory receptors (KIR) have
**long** cytoplasmic tails
95
activating receptors (KIR) have
**short**, cytoplasmic tails which interact with **adapter** molecules to facilitate signaling
96
NK cell delivery of toxic molecules (synapses)
Formation of NK killing "synapse" thrpigh tight association with NK cell
- **perforin**: poreforming molecule, much in common with C9 complement cascade
- **granzymes**: delivered through the pore, activate an apoptotic cascade, activate caspases
DNA cleavage, nulcear fragmentation, membrane blebbing
Apoptosis of target cell
97
rebuck skin window
measures migration of leukocytes to sites of inflammation/injury
98
CD18 deficiency
integrin beta 2
99
LAD
subject to recurrent bacterial infections
- PMN + minocytes unable to emigrate to tissues that are infected and are trapped in crirculation
- very high WBC count
100
Factor I deficiency
inhibits C3 convertase
Leads to C3 depletion
101
CH50 assay
Not testing MAC on bacteria, but engineering the attack of red blood cells as a measure of complement activity
Red blood cells are being lysed
**Tests Patients Serum**
RBC must be present (deosnt matter the source)
Antibody against RBC - bind to RBC
CH50 = 0
- C5-C9 = membrane attack complex. A deficiency in these leads to **susceptibility to Neisseria**. Because doctor suspected she had a deficiency in one of the MAC molecules.
102
innate immunity expl.
distinguish host from infectious agents bu recognizing **conserved motifs**
- activated within min to hrs of exposure
- **not significanlty increased by previous exposure**
103
adaptive immunity expl.
cells with exquisitely specific receptors for a potentially **unlimited number of targets**
- effective only after several days
- possess immunological **memory**, enhanced responsiveness upon reencounter of same pathogen.
104
What is antigen processing?
series of intracellular events in which antigen presenting cells make antigens available to **T cells**
Involves **uptake** of antigens, their degradation to peptides, binding of the peptides to MHC class. Ior MHC class II and **transport** to the cell surface
Presentation of MHC peptide complex on the cell surface for the stimulation of T cells
105
What are antigen presenting cells?
- Dendritic Cells
- Macrophages
- B cells
106
CD8 T cells bind
A3 of MHC class I
107
CD4 T cells bind
Beta2 of MHC class II
108
**Endocytic** antigen processing
**exogenous** or **MHC class II**
109
**Cytosolic** antigen processing
**endogenous** or **MHC class I**
110
Endocytic antigen processing
- Antigen is taken up from the ECS into intracellular vesicles
- In early endosomes of neutral pH, endosomal proteases are inactive
- Acidification of vesicles activates proteases to degrade antigen into peptide fragments
- Vesicles containing peptides fuse with vesicles containing MHC class II molecules
111
Invariant chain
blocks binding of peptides to MHC Class **II** in the ER
in vesicles, invariant chain is cleaved, leaving the **CLIP** fragment bound.
112
CLIP blocks
binding of peptides. toMHC class II in vesicles
**HLA-DM** facilitates release of CLIP, allowing peptides to bind
113
KEY players of MHC class II pathway
- **MHC class II** - presents antigens
- **Invariant chain** - Directs class II away from typical secretory pathway to endocytic pathways and blocks peptide loading in the ER
- **HLA-DM** - acts as a chaperone or catalyst to facilitate exhange of clip with antigenic peptides
- **pH** - low pH and degradative environment facilitate denaturation of antigenic proteins
- **Proteases** - Cathepsins and other degradative enzymes chew up antigens into peptides
114
KEY players of **cytosolic** (MHC class I) pathway
- **MHC class I** - presents antiugenic peptides to T cells
- **Proteasome**: multicatalytic enzyme complex that degrades proteins into peptides
- **TAP**: transporter that shuttles peptides from cytosol to ER
- **Calnexin, tapasin, Erp57**: stabilize MHC class. Iand facilitate association with TAP to enable peptide loading (peptide loading complex)
115
Class I heavy chain is stabilized by
clanexin, until b2 microglobulin binds
Peptide loading complex formed
A peptide delivered by **TAP** binds to the CLass I heavy chain, forming the mature MHC class I molecule
Then the class I molecule ddissociates from. thepeptide loading complex
116
peptides produced in the cytosol are transported into the
ER
117
Cytosolic pathogens
- degraded in: Cytosol
- Peptides bind to MHC class I
- Presented to **CD8** T cells
- effect on APC: Cell death
118
Extracellular pathogens and toxins/Intravesicular pathogens
Endocytic vesicles (low PH)
MHC class II
CD4 T cells
- Activation to lill intravesicular bacteria. and parasites
- Activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins
119
End result of antigen processing
display of MHC peptide complex for **TCR** recognition
120
MHC - Major histocombatability Complex
- Present peptides derived from pathogens to T cells
- HLA in humans
- MHC I and II
121
MHC class I structure
1 transmembrane region
CD8 binds to Alpha3
Peptide binding cleft: Alpha 1 and Alpha 2
122
MHC class II structure
Peptide binding cleft: A1 + B1
2 transmembrane regions
CD4 binds to Beta2
123
MHC class II structure
Peptide binding cleft: A1 + B1
2 transmembrane regions
CD4 binds to Beta2
124
Pwptide binding cleft MHC I
Alpha 1 + Alpha 2
Strict binding site: 8-10 aa in length
125
Peptide binding cleft MHC class II
Alpha 1 + beta 1
**Flexible** binding site - 10-24+aa in length
126
Where is the variability in MHC class I ?
Alpha 1 and alpha 2
127
Where is the variability in MHC class II?
Beta. 1
128
MHC is both
polymorphic and polygenic
129
genetic polymorphism
variants or alternative forms of a gene present in a population at a stable frequency
130
haplotype
allele
haplotype - the collective set of MHC alleles present in an inidivudal chromosome
alllele: one type of variant
131
MHC class I isotypes
HLA-A
HLA-B
HLA-C
Highly polymorphic
132
MHC class II isotypes
HLA-DP
HLA-DQ
HLA-DR
133
MHC I expression
Expressed by all cells
Can be upregulated by **type I interferon (IFNa or IFNb)**
134
MHC class II expression
Expressed by antigen presenting cells. (**Macorpahges, DC, B cells**) can be upregulated by **IFN-y** + **CIITA**
135
MHC genes are expressed
co-dominantely
136
Immunoproteasome
**Induced by INF-y**
Exhange of **beta** subunits: improves generation of peptides that bind to **MHC class I**
**Different cap**s: speed export of peptides
137
Results of innate immune response
complement - induces inflammation
**Produce inflammatory cytokines (IL1,6 and TNFalpha)**
138
Inflammation awakens adaptive immunity through **DC**
Communicates between **Innate and adaptive systems**
DC at sites of infection become triggered to "**mature**" in response to **PAMPS** or inflmmation
DC migrates through lymphatics to draining lymph nodes, interacting with many B and T cells
139
Immature DC
- **Tissue resident**, resting
- **Highly endocytic** , phagocytic
- **Low level expression **of molecules
- **Poor stimulators of T cells**
140
Mature DC
Homes to **lymph node**
**Endocytosis shut down**
**High** level expression of costimulatory molecules
**Highly stimulatory for T cells**
141
Primary lymphoid organs
Thymus
Bone Marrow
sites at which leukocytes undergo hematopoiesis (**development and differention**) and/or selection. Houses **naive leukocytes**
142
secondary lymphoid organs
spleen, lymph nodes etc. Sites at which naive , activated, and memory cells are housed
143
T cell receptor
Alpha and beta chain
Variable + constant regions + transmembrane region
Antigen binding site consists of both alpha and beta chains
144
B cell receptor
Surface (transmembrane region) or antibody (plasma , no transmembrane region)
Heavy and light chain
Antigen binding site: **1 HC 1 LC**
Variable region: **1 HC, 1LC**
**Constant region**: Heavy chain
Transmembrane region: only for Surface B cells
145
Life stages of B and T cells
1. Generating receptor
2. Selection
3. Activation
4. Differentation
146
generating receptor
Rearrangement
147
selection
making sure the receptor does not react with self
148
activation
providing all of the signals needed to cause clonal expansion
149
differentation
signals recieved during activation dictate the differentiation of the cell and its specific function
150
Gene rearrangement in somatic cells generate potential
for great diversity
151
B cells recognition of antigen :
"see" naive antigen through BCR
152
T cells antigen recognition
see antigenic peptides (digested or processed pieces of antigens) presented by MHC molecules
153
B and T cells see things very differently
Epitopes recognized by T cells are often buried, and the antigen must be broken down into peptide fragments and the epitope peptide binds to MHC molecule. The T cell receptor binds to a complex of MHC molecule and epitope peptide
BCR and antibodies recognize native protein antigens
154
What. areantibodies good for?
Bacterial toxins - get **neutralized** = toxins unable to bind to receptors because the antibody binds it.
Bacteria in ECS - get **opsonized** tagged with C3b for destruction
155
What does it take for a T cell to recognize antigens?
DC cells take up pathogens for degradation.
1. pathogen is taken apart inside the DC
2. Pathogen proteins are unfolded and cut into small pieces
3. Peptides bind to MHC and go to cell surface
4. TCR bind to peptide:MHC complex on DC surface
156
Basic structure of an immunoglobin
- Two heavy chains and two light chains
- Disulfide bonds
- Contains discrete antigen binding regions in the **N** terminus from both the heavy and light chains
157
Fab region
comsists of both heavy and light chains
158
Fc region
consists of only heavy chains
159
antigens bind to what region on antibody
variable region of heavy and light chains
159
antigens bind to what region on antibody
variable region of heavy and light chains
160
Fab name meaning
fragment antigen binding
161
Fc name
fragment crystallizable
162
Membrane bound BCR associates with
signaling molecules Ig-alpha and Ig-beta
163
antitgen bontact by antibody is mediated through
Hypervariable loops of the heavy and light chains **CDR**
- antigen is contacted by six hypervariable loops, 3 in the light chan and 3 in the heavy chain
- Most of the diversity between antibodies is in these regions
164
The most diversity is in _ of CDR
CDR3
The highest number of Ab;Ag contacts are usually within the CDR3 region
165
5 major classes of human antibodies
IgG
IgM
IgD
IgA
IgE
166
monomeric IgM
antibody + J chain, whereas pentameric IgM is just five antibodies together.
167
Dimeric IgA is held together by
J chain
168
Valency and avidity
Monovalent interactions has a low avidity
pentameric IgM is polyvalent and has very high avidity of interaction
169
IgA specific function
transport across mucosa, neutralization
170
IgD specialized function
antigen receptor on naive B cells, sensitized basophils
171
IgE
immediate hypersensitivity, sensitizes mast cells
172
IgG
neutralization, opsonization, complement activation and neonatal immunity (crosses placenta)
173
IgM
antigen receptor on naive B cells, complement activation
174
antibody diversity is due to
Combinatorial diversity - multiple germ line segments
Junctional Diversity
Somatic hypermutaiton
175
VDJ
heavy chain
176
VJ
light chain
177
Heavy chain recombination
D-J
V-DJ
VDJ
178
light chain recombination
V-J
VJ
179
opsonin
any molecule that enhances phagocytosis by tagging it for binding to a cell surface receptor
- complement proteins that bind complement receptors
- antibodies that bind Fc receptors on phagocytic cells
180
opsonization
the process by which bacteria are altered by opsonins so as to become more readily and more efficiently engulfed by phagocytes
181
two types of light chains
Kappa and lambda
182
Recombination process
DETAILED
1. Heavy chain undergoes Rearrangement. D-J
2. Then V is added to become VDJ
3. After heavy chain, light chain rearrangement occurs. The only thing that occurs is V-J.
183
Sequence of events during VDJ recombination
Synapsis
Cleavage
Hairpin
Joining
184
VDJ synapsis
two selected coding segments and their adjacent RSSs are brought together by chromosomal looping
185
VDJ cleavage
RAG1/2 complexes generate double stranded breaks in DNA, forming hairpin loops
186
VDJ hairpin processing
Artemis opens hairpins at coding ends
187
VDJ joining
non-homologous end joining
Ku70, Ku80, DNA ligase
188
Generation of a functional BCR
Early Pro B cell
- Heavy chain rearrangement: D-J
Late Pro B cell
- Heavy chain rearrangement V-DJ
Pre B cell
- Light chain rearrangement
- Rearrange K on 1st chrom
- Rearrange K on 2nd
- Rearrange L on 1st
- Rearrange L on 2nd
189
Junctional diversity
Occurs at CDR3 - allowing greater variability than that encoded by gene segments
Diversity is increased by addition of nucleotides
Mediated by TdT
190
what is junctional diversity mediated by
TdT
191
antibody deficiency leads to
increased susceptibility to extracellular bacterial pathogens - Pyogenic infections
Strep. pneumoniae
Staph. aureus
Strep. Progenies
192
SCID
RAG Deficiency -->No B or T cells
193
CD40:CD40L
B cells need two signals for full activation by T dependent antigens
194
Hyper IgM
AID deficiency
Defect may be in MHC class II - No CD4 T cells to stimulate isotype switch
Only IgM isotype antibodies, reduced diversity of B cell response
195
X linked agammaglobulinemia (XLA)
defect in BTK
- B cells become arrested at the pre B cell stage
NO DETECTABLE B CELLS - No antibody
196
Big picture of B cell development
repertoire assembly
negative selection (BM)
positive selection (2ndary organs)
searching for infection
finding infection
attacking infection
197
What does the Pre-B cell receptor do?
VpreB + lambda5
Surrogate light chain!
induces allelic exclusion at other heavy chain locus.
Surrogate light chain takes place of rearranged light chain. Allows testing of heavy chain
198
alternative splicing to give both delta and mu chains
before activation
199
alternative splicing to secrete Ig
Isotype switching
Somatic hypermutation
after activation
200
Somatic hypermutation
Induced by AID
Results in point mutations most often within the variable regions of immunoglobins after rearrangement
Leads to affinity maturation
201
mechanism of affinity maturation
increased affinity - increased antigen uptake, processing, presentation
Decreased affinity - decreased antigen uptake, processing, presentation . Neglected B cell will not proliferate, antigen specificity will decline in population
202
Isotype switching and somatic hypermutation are dependent on
AID
203
Isotype switching
- Causes irreversible changes in DNA, removing intervening C regions
204
Lack of RAG
SCID - No T or B cell produced
205
Lack of TdT
significantly reduced diversity in B cell repertoire
206
Lack of AID
no somatic hypermutation or isotype switching, produce only low affinity IgM, called hyper IgM immunodeficiency
207
events that rely on changes in DNA
Somatic recombination
Junctional diversity
Somatic hypermutation
isotype switching
208
Events that rely on changes in RNA
dual expression of IgD and IgM
Expression of transmembrane vs secreted forms of IgM
209
Immature B cells co-express IgM and IgD
No class switching has yet occurred. these are changes in RNA,
All C regions are maintained at this point
210
B cell - negative selection location
bone marrow
211
B cell - positive selection location
secondary lymphoid organs
212
Hyper IgM (HIM) Immunodeficiency
increased amount of IgM, unable to produce IgG, Ig, and IgE
CD40 ligand defect.
X linked recessive trait
- isotype switching fails to occur
- T cell response reduced
- macrophage activation reduced
- neutropenia
213
Interaction with FDC provides
maturation and survival signals for positive selection
