adaptive immunity central objective: protect against foreign invaders create memory of invasion to...
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Adaptive ImmunityAdaptive Immunity
•Central objective:
•Protect against foreign invaders
•Create memory of invasion to prevent recurrent infection
Adaptive ImmunityAdaptive Immunity
Central problems:
•Distinguishing Self vs. Non-self
•Generating Diversity
Adaptive ImmunityAdaptive Immunity
Unique Features:Specific receptors recognize foreign invaders:– B cell receptor (BCR)
– T cell receptor (TCR)
Adaptive ImmunityAdaptive ImmunityThere are two forms of immunoglobulin (also called antibodies) which function as Ag receptors.
• Form I is located on the B cell surface (also called the BCR) and
• Form II is secreted from the B cell.
• The TCR is only expressed in the cell surface.
Basic Features of Ig Basic Features of Ig ProteinsProteins
•2 H chains and 2 L chains•Bilateral symmetry•Globular domains-each domain is 100-110 aa residues•L chain has 2 domains•H chain has 4-5 domains including a hinge
-the hinge is a flexible stretch of polypeptide chain
ANTIGENS (Ag), ANTIGENS (Ag), IMMUNOGEN, HAPTENIMMUNOGEN, HAPTEN
Antigen: A substance capable of interacting with an Ag receptor.
Epitope
Hapten/CarrierHapten/CarrierA haptenhapten is a substance which can physically interact with antibodies (Ab) or with TCR but does NOT elicit an immune response from the B cells or T cells, respectively. The carriercarrier is immunogenic.
Haptens/CarrierHaptens/Carrier•Small organic molecule of simple structure.
•Does not induce an antibody response by themselves.
•However, can induce Ab response when coupled to a •protein carrier.
•Three types of Abs produced:1) anti-Hapten2) anti-protein-carrier3) anti-hapten+carrier
IMMUNOGENIMMUNOGEN
An immunogen is a substance which interacts with the B cell receptor (BCR) or the T cell receptor (TCR) and elicits a response from these cells. Thus, an immunogen is an Ag which causes either a B cell mediated humoral response or a T cell mediated response or both.
CHARACTERISTIC FEATURES CHARACTERISTIC FEATURES OF AGOF AG
•Ags interact with the ligand binding sites in Ab and TCR.
•Ags can be large molecules which contain several epitopes which are substructures (also called antigenic determinants) capable of interacting with the Ab receptor or the TCR.
•The physical parameters of the Ab (TCR) binding site define the Ag
binding constants (Ka and Kd).
CHARACTERISTIC FEATURES CHARACTERISTIC FEATURES OF AGOF AG
Ag valence is the number of epitopes or reactive sites on the Ag molecules. A single Ag might have multiple epitopes.
Epitopes
BCR and TCR are key to BCR and TCR are key to understanding immune understanding immune
system functionsystem function
Figure 1-27
CHARACTERISTIC FEATURES CHARACTERISTIC FEATURES OF AbsOF Abs
In the body, Ig is a pool of proteins with a diverse set of binding capabilities.
The Ag Binding The Ag Binding ConundrumConundrum
The immune system must accommodate at least 10e6 Ag binding specificities
How does it do it?How does it do it?
Diversity of Ag Diversity of Ag Binding Resides in Binding Resides in
the V Regionsthe V RegionsThe N-terminal portion of the H and L chains fold to form the Agbinding pocket.
Substructure of V Substructure of V regionsregionsin Igin Ig
Diversity in V regions is non-random and primarilylocated in the hyper-variableregions (or complementaritydetermining regions [CDRs]).
Diversity of Ig Diversity of Ig BindingBinding
CDRs form the Ag binding domain of the V region.
Generation of Ab Generation of Ab DiversityDiversity
Where does diversity of Ag Where does diversity of Ag binding come from?binding come from?
One Source of One Source of Diversity:Diversity:
Combinatorial Association of 500 L chains with 1000 H chain equals 5x10e5
Combinatorial Combinatorial Association of H Association of H
and L chainsand L chains•Assume: 500 L chains + 1000 H chains= 5x10e5 antigen binding sites
• However, there are only ~30,000 genes in the human genome
Another Source of Another Source of Diversity: Diversity: HypothesisHypothesis
L and H chain V genes are L and H chain V genes are composed of multiple gene composed of multiple gene segmentssegments
i) Land L chain V genes are generated from V and J segments
ii) H chain V genes are generated from V, D and J segments
The Tonegawa The Tonegawa Experiment:Experiment:
circa circa 11976976
B cell
EmbryoC
V+C
V
Bam HI
The Tonegawa The Tonegawa ExperimentExperiment
1 2 3 4 5 67
8
C
V+C
0
20
40
60
80
100
120
140
160
C
V+C
C
V+C
Probes
Generation of Generation of Diversity of BCRDiversity of BCR
L and H chain V genes are composed of multiple gene segments
i) L chain V genes are generated from V and J segments
( 30 V( 30 V/4J = 30x4=150)/4J = 30x4=150)
ii) H chain V genes are generated from V, D and J segments (50 VH/30 D/ 4 J= (50 VH/30 D/ 4 J= 50x30=1500x4=6000)50x30=1500x4=6000)
L and H chain V genes are composed L and H chain V genes are composed of multiple gene segmentsof multiple gene segments
Mechanism of V(D)J Mechanism of V(D)J JoiningJoining
DNA rearrangement:DNA rearrangement:
via deletion looping out mechanism
Deletion andlooping out
Inversion
Other Sources of Other Sources of Diversity...Diversity...
Note:Assembly of V genes from mini-gene segments and combinatorial assoc. is insufficient to account for Ab diversity
Mechanism of V(D)J Mechanism of V(D)J JoiningJoining
The VDJ joining process is sloppy and generates additional diversity at the junctions of the joined DNA segments. This raises the potential diversity to 2x10e7 Ag binding sites.
Mechanism of V(D)J Mechanism of V(D)J Joining:Joining:
VDJ joining conforms to the 12/23 Rule
V(D)J V(D)J Joining is Joining is Catalyzed Catalyzed by the RAG by the RAG Enzymes:Enzymes:
Mechanism of V(D)J Mechanism of V(D)J Joining:Joining:
Hairpins Hairpins are opened are opened with the with the help of help of ArtemisArtemis
Hairpins cont…Hairpins cont…
•Hypomorphic mutations give rise to a partial loss of function
•Ommens syndrome arises from a hypomorphic mutations in the Rag genes
•A leaky form of SCID arises from a hypomorphic mutation in DNA-PK
Hypomorphic MutationsHypomorphic Mutations
Generation of TCR Generation of TCR Diversity:Diversity:
TCRs are generated by V(D)J joining of mini-gene segments
Primary Primary Immunodeficiency:Immunodeficiency:
Severe combined Severe combined immunodeficient: scidimmunodeficient: scid
Phenotype: absence of B cells and T cells, thus no humoral or cell mediated immunity
Underlying cause?
BCR and TCR Break the BCR and TCR Break the Rules of Mendelian Rules of Mendelian
GeneticsGeneticsMonospecific Ag Monospecific Ag receptors:receptors:
Only one H chain and one L chain is expressed per B/T cellwhereas each cell has 2 alleles for H and L chains
Adaptive ImmunityAdaptive Immunity
•Unique Features:
•Antigen specific receptors:–Exhibit allelic exclusionallelic exclusion–Are monospecificmonospecific with respect to Ag recognition