Final Exam Immunology Flashcards
eosinophil
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
basophil
- 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
Mast cells
- 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
Macrophage
Phagocytosis and killing of microorganisms
Dendritic cells
activates T cells to initiate the adaptive immune system
Macrophages and dendritic cells
- Both phagocytic
- Macrophages: bactericidial activity
- Dendritic: No bactericidial activity
“professional antigen presenting cells”
dendritic cells
Neutrophils
- 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
Three major funcitons of neutrophils
- Migrate from blood to site of infection
- Phagocytosis followed by intracellular degranulation
- Produce reactive oxygen radicals through respiratory burst - NADPH-oxidase
diapedesis
leukocyte extravasation - movement of leukocytes out of the circulatory system and toward sites of inflammation or infection
Neutrophil Migration
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.
LFA-1 + ICAM1
low affinity integrin LFA1, binds to ICAM1, when a chemokine receptor and chemokine have interacted.
Bacteria killing process
- receptor binding
- engulfment
- phagocytosis
The real killing is when granules fuse with phagosome
Killing of microbes process
- 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.
enzymes
degrade bacterial components
defensins
poke holes in bacterial membranes
lactoferrin
sequester iron away from bacteria
Respiratory burst
- When NADPH oxidase is activated, and production of bactericidal compounds begin
- Superoxide + Hydrogen peroxide
- ## HOCl - hypochlorous acid
Neutrophil death: two fates
Macrophage ingestion
Exits the body as Pus
DIseases with Neutrophil dysfunction
CGD
Chediak Higashi
LAD
CGD
NADPH oxidase defects
No respirator burst , greatly reduced bacterial killing
Chediak Higashi syndrome
phagocytosis and granule defects
unable to engulf and kill bacteria
LAD deficiency
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
the complement system is a grouo of _ found in serum involved in:
zymogens
- Control of inflammation - Recruitment of phagocytes
- Enhanced pathogen uptake and clearance - Opsonization
- Lyttick attack of cell membranes (killing bacteria)
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
Perfect ligand for C1q in the classical pathway
IgM
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
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
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
‘/[
how is the alternative pathway activated?
Spontaneously. Without the help of a ligand-binding molecule
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)
example of anaphylatoxin
C3a
C3 convertase classical
C4b2a
Alternative C3 convertase
C3bBb
How complement activation induces phagocyte recruitment
- anaphylatoxins (C3a, C5a) act on blood vessels to increase vascular permability
- Increased permeability - increased leakage from blood vessels and extravasation of complement and other plasma proteins to the site of infeciton
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
C3 cleavage
C3a - recruits phagocyte s
C3b - tags bacterium for destruction (opsonization or membrane attack)
lyttick membrane attack
C5-C9
C1 inhibitor
Binds to activated C1r, C1s, removing them from C1q and to activated MASP2, removing it from MBL
Factor H
binds C3b, displacing Bb for cofactor I
Factor I
Serine protease that cleaves C3b and C4b
CD59 (protectin)
Prevents formation of membrane attack complex
binds to C5b678, preventing recruitmen of C9 from the pore
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
C1,C2,C4 deficiency
Immune complex disease
C3 deficiency
Susceptibility to Capsulated bacteria
C5-C9 deficiency
Susceptibilty to Neisseria
Facor I deficiency
Similar to C3 (susceptbility to capsulated bacteria)
Which complement components are associated with which functions?
C3a, C5a = recruitment
C3b = opsonization
C5b,6,7,8,9 = membrane attack
immediate innate response
0-4 hrs
Very minor tissue damage is repaired
Induced innate immune response
4hrs - 4 days
minor tissue damage is soon repaired
Adaptive immune response
4 days +
Major tissue damage is gradullay repaired
Gram +
peptidoglycan, lipotheichoic acid
gram -
Lipopolysachharide
PAMP
hypomethylated CpG DNA
Microbes contain genetically conserved patterns called
PAMPS - pathogen associated molecular patterns
PAMPS are recognized by
PRR (pattern recognition receptors) of the innate immune system: Macrophages, NK cells, neutrophils, DC
Types of PRRs
TLRs and Cytosolic receptors
Uptake receptors
Facilitate uptake of particles
- complement receptors
- scavenger
- mannose
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
TLR structure
Amino end - pathogen recognition domain outside of the cell
carboxyl end: TIR domain on cytosolic side of cell
TLR structure
Amino end - pathogen recognition domain outside of the cell
carboxyl end: TIR domain on cytosolic side of cell
TLR2 + TLR6
Lipoteichoic acid
Gram positive bacteria
TLR4
Lipopolysachharide
Gram - Bacteria
TLR7
ss viral RNA
RNA virus
TLR8
ss viral RNA
RNA
TLR9
Unmethylated CpG rich DNA
Bacteria + DNA virus
TLR3
DS viral RNA
RNA VIRUS
TLR5
Flagellin
Bacteria
which TLR are on plasma membrane
TLR2+6
TLR4
TLR5
Which TLR are on endosomes
- TLR3,7,8,9
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
TLR4 SIGNALING by the TRIF and MyD88 cascade
Synthesis and secretion of TNF-alpha and other inflammatory cytokines
NOD like receptors recognize
bacterial cell wall
inflammasomes recognize
pathogens as well as intracellular damage or injury
RIG I , MDA5 recognize
Viral nucleic acids
activation of NfkB results in
gene transcription
proinflammatory cytokines
IL6
IL1
TNF
IL12
IFNy
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
immature DC
- Tissue resting
- Highly endocytic
- Low expression
- poor stimulators of T cells
Mature DC after exposure to inflammatory stimuli, PAMPS
- Homes to lymph node
- endocytosis shuts down
- High level coexpression
- Highly stimulatory for T cells
antiviral acts in both
autocrine and paracrine
MDA5 + RIG-I
cytoplasmic pattern recognition receptors
Type I interferons are very helpful for
Viral infections
Antiviral immune response
- Type I interferons! (alpha and beta)
- work in both autocrine and paracrine manner
after viral infection…
TLRs or cytoplasmic receptors can acativate transcription factors
- IRF –> move to nucleus and activate IFN alpha and beta
anti viral state by type I interferons
- inhibition of viral protein synthesis
- degradation of viral RNA
- inhibition of viral gene expression and virion assembly
RIG I facilitates activation of
IRF3 and NFkB
IRF3 - type I interferon
NfkB - inflammatory cytokines
TLRs that have strong type I interferon response
TLR7 and TLR3
only TLR that doesnt associate with MyD88
TLR3, it associates with TRIF
interferon responses from virus infected cells
- increase expression of ligands for receptors on NK cells
- Activate NK cells to kill virus infected cells
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
Important functions of NK cells
- killing of infected or damaged cells
- activating (killing) /inhibitory receptor (no killing)
- whichever one has stronger signal determines the fate of the cell - production opf cytokines to activate macrophages
- NK produce IFNy to stimulate activation of macrophages and their killing
KIRs
killer cell immunoglobin like receptors
Can be activating or inhibitory, depending on their tail
Inhibitory receptors (KIR) have
long cytoplasmic tails
activating receptors (KIR) have
short, cytoplasmic tails which interact with adapter molecules to facilitate signaling
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
rebuck skin window
measures migration of leukocytes to sites of inflammation/injury
CD18 deficiency
integrin beta 2
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
Factor I deficiency
inhibits C3 convertase
Leads to C3 depletion
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.
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
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.
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
What are antigen presenting cells?
- Dendritic Cells
- Macrophages
- B cells
CD8 T cells bind
A3 of MHC class I
CD4 T cells bind
Beta2 of MHC class II
Endocytic antigen processing
exogenous or MHC class II
Cytosolic antigen processing
endogenous or MHC class I
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
Invariant chain
blocks binding of peptides to MHC Class II in the ER
in vesicles, invariant chain is cleaved, leaving the CLIP fragment bound.
CLIP blocks
binding of peptides. toMHC class II in vesicles
HLA-DM facilitates release of CLIP, allowing peptides to bind
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
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)
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
peptides produced in the cytosol are transported into the
ER
Cytosolic pathogens
- degraded in: Cytosol
- Peptides bind to MHC class I
- Presented to CD8 T cells
- effect on APC: Cell death
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
End result of antigen processing
display of MHC peptide complex for TCR recognition
MHC - Major histocombatability Complex
- Present peptides derived from pathogens to T cells
- HLA in humans
- MHC I and II
MHC class I structure
1 transmembrane region
CD8 binds to Alpha3
Peptide binding cleft: Alpha 1 and Alpha 2
MHC class II structure
Peptide binding cleft: A1 + B1
2 transmembrane regions
CD4 binds to Beta2
MHC class II structure
Peptide binding cleft: A1 + B1
2 transmembrane regions
CD4 binds to Beta2
Pwptide binding cleft MHC I
Alpha 1 + Alpha 2
Strict binding site: 8-10 aa in length
Peptide binding cleft MHC class II
Alpha 1 + beta 1
Flexible binding site - 10-24+aa in length
Where is the variability in MHC class I ?
Alpha 1 and alpha 2
Where is the variability in MHC class II?
Beta. 1
MHC is both
polymorphic and polygenic
genetic polymorphism
variants or alternative forms of a gene present in a population at a stable frequency
haplotype
allele
haplotype - the collective set of MHC alleles present in an inidivudal chromosome
alllele: one type of variant
MHC class I isotypes
HLA-A
HLA-B
HLA-C
Highly polymorphic
MHC class II isotypes
HLA-DP
HLA-DQ
HLA-DR
MHC I expression
Expressed by all cells
Can be upregulated by type I interferon (IFNa or IFNb)
MHC class II expression
Expressed by antigen presenting cells. (Macorpahges, DC, B cells) can be upregulated by IFN-y + CIITA
MHC genes are expressed
co-dominantely
Immunoproteasome
Induced by INF-y
Exhange of beta subunits: improves generation of peptides that bind to MHC class I
Different caps: speed export of peptides
Results of innate immune response
complement - induces inflammation
Produce inflammatory cytokines (IL1,6 and TNFalpha)
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
Immature DC
- Tissue resident, resting
- Highly endocytic , phagocytic
- **Low level expression **of molecules
- Poor stimulators of T cells
Mature DC
Homes to lymph node
Endocytosis shut down
High level expression of costimulatory molecules
Highly stimulatory for T cells
Primary lymphoid organs
Thymus
Bone Marrow
sites at which leukocytes undergo hematopoiesis (development and differention) and/or selection. Houses naive leukocytes
secondary lymphoid organs
spleen, lymph nodes etc. Sites at which naive , activated, and memory cells are housed
T cell receptor
Alpha and beta chain
Variable + constant regions + transmembrane region
Antigen binding site consists of both alpha and beta chains
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
Life stages of B and T cells
- Generating receptor
- Selection
- Activation
- Differentation
generating receptor
Rearrangement
selection
making sure the receptor does not react with self
activation
providing all of the signals needed to cause clonal expansion
differentation
signals recieved during activation dictate the differentiation of the cell and its specific function
Gene rearrangement in somatic cells generate potential
for great diversity
B cells recognition of antigen :
“see” naive antigen through BCR
T cells antigen recognition
see antigenic peptides (digested or processed pieces of antigens) presented by MHC molecules
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
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
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
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
Fab region
comsists of both heavy and light chains
Fc region
consists of only heavy chains
antigens bind to what region on antibody
variable region of heavy and light chains
antigens bind to what region on antibody
variable region of heavy and light chains
Fab name meaning
fragment antigen binding
Fc name
fragment crystallizable
Membrane bound BCR associates with
signaling molecules Ig-alpha and Ig-beta
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
The most diversity is in _ of CDR
CDR3
The highest number of Ab;Ag contacts are usually within the CDR3 region
5 major classes of human antibodies
IgG
IgM
IgD
IgA
IgE
monomeric IgM
antibody + J chain, whereas pentameric IgM is just five antibodies together.
Dimeric IgA is held together by
J chain
Valency and avidity
Monovalent interactions has a low avidity
pentameric IgM is polyvalent and has very high avidity of interaction
IgA specific function
transport across mucosa, neutralization
IgD specialized function
antigen receptor on naive B cells, sensitized basophils
IgE
immediate hypersensitivity, sensitizes mast cells
IgG
neutralization, opsonization, complement activation and neonatal immunity (crosses placenta)
IgM
antigen receptor on naive B cells, complement activation
antibody diversity is due to
Combinatorial diversity - multiple germ line segments
Junctional Diversity
Somatic hypermutaiton
VDJ
heavy chain
VJ
light chain
Heavy chain recombination
D-J
V-DJ
VDJ
light chain recombination
V-J
VJ
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
opsonization
the process by which bacteria are altered by opsonins so as to become more readily and more efficiently engulfed by phagocytes
two types of light chains
Kappa and lambda
Recombination process
DETAILED
- Heavy chain undergoes Rearrangement. D-J
- Then V is added to become VDJ
- After heavy chain, light chain rearrangement occurs. The only thing that occurs is V-J.
Sequence of events during VDJ recombination
Synapsis
Cleavage
Hairpin
Joining
VDJ synapsis
two selected coding segments and their adjacent RSSs are brought together by chromosomal looping
VDJ cleavage
RAG1/2 complexes generate double stranded breaks in DNA, forming hairpin loops
VDJ hairpin processing
Artemis opens hairpins at coding ends
VDJ joining
non-homologous end joining
Ku70, Ku80, DNA ligase
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
Junctional diversity
Occurs at CDR3 - allowing greater variability than that encoded by gene segments
Diversity is increased by addition of nucleotides
Mediated by TdT
what is junctional diversity mediated by
TdT
antibody deficiency leads to
increased susceptibility to extracellular bacterial pathogens - Pyogenic infections
Strep. pneumoniae
Staph. aureus
Strep. Progenies
SCID
RAG Deficiency –>No B or T cells
CD40:CD40L
B cells need two signals for full activation by T dependent antigens
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
X linked agammaglobulinemia (XLA)
defect in BTK
- B cells become arrested at the pre B cell stage
NO DETECTABLE B CELLS - No antibody
Big picture of B cell development
repertoire assembly
negative selection (BM)
positive selection (2ndary organs)
searching for infection
finding infection
attacking infection
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
alternative splicing to give both delta and mu chains
before activation
alternative splicing to secrete Ig
Isotype switching
Somatic hypermutation
after activation
Somatic hypermutation
Induced by AID
Results in point mutations most often within the variable regions of immunoglobins after rearrangement
Leads to affinity maturation
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
Isotype switching and somatic hypermutation are dependent on
AID
Isotype switching
- Causes irreversible changes in DNA, removing intervening C regions
Lack of RAG
SCID - No T or B cell produced
Lack of TdT
significantly reduced diversity in B cell repertoire
Lack of AID
no somatic hypermutation or isotype switching, produce only low affinity IgM, called hyper IgM immunodeficiency
events that rely on changes in DNA
Somatic recombination
Junctional diversity
Somatic hypermutation
isotype switching
Events that rely on changes in RNA
dual expression of IgD and IgM
Expression of transmembrane vs secreted forms of IgM
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
B cell - negative selection location
bone marrow
B cell - positive selection location
secondary lymphoid organs
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
Interaction with FDC provides
maturation and survival signals for positive selection
