8 - MHC Flashcards
Humoral Immmunity
Adaptive Immunity
AB-mediated
Major player = B-Lymphcytes
Responds to EXTRAcellular Microbes
FXN:
Blocks INFECTIONS via ELIMINATION
of extracellular microbes
CELL-MEDIATED Immunity
Adaptive Immunity
Cellular Immunity
Major Player = T-Lymphocytes
Responds to INTRAcellular Microbes
2 main Fxn:
ACTIVATE Macrophages to kill phagocytosed microbes
+
KILL infected cells & eliminate reservoirs of infection
TYPES of APC’s
Cell-Mediated Immunity
Antigen Presenting Cells
Dendritic Cells
Macrophages
B-Lymphocytes
2 Functions of APC’s
Dendritic Cells / Macrophages / B-Lymphocytes
Naive T-Cell Activation
Differentiation into effector T-Cells
(Dendritic Cells)
Effector T-Cell Activation
Activation of MACROPHAGES + B-cells
Macrophages = Cell-Mediated Immunity
B-Cells = Humoral Immunity
- *MHC**
- *4 Roles**
DISPLAYS ANTIGEN TO T-CELLS
MAIL ROLE
Allorecognition & Tolerance
Governs T & B Cell interactions
Controls +/- Selection of T-cells
MHC vs HLA
MHC = Complex or Set of Cell-surface proteins
HLA
Human Leukocyte Antigens
SPECIFIC MHC FOR HUMANS
HLA Genes
MHC is located on Chromosome 6 = highly POLYmorphic
Class 1 MHC Genes
HLA-A // HLA-B // HLA-C
Class 2 MHC Genes
HLA-DP // HLA-DQ // HLA-DR
Class 3 genes exist but they encode for NON-MHC molecules
Humans express 2 Haplotypes
1 ALLELE from EACH PARENT
HLA Polymorphism
Refers to there being:
MANY ALLELES
for each
CLASS 1 & CLASS 2
Resulting in MANY DIFFERENT COMBINATIONS
200+ genes on chromosome 6
HLA Haplotype
Refers to the:
PARTICULAR COMBO of MHC Alleles Present
2 Haplotypes in Each Human
(2 Sets of genes)
1 MATERNAL SET + 1 PATERNAL SET
on chromosome 6
HLA CO-Dominance
Proteins encoded by BOTH Maternal + Paternal genes are
EXPRESSED EQUALLY
Always 1 from each
VERY UNLIKELY that child will have THE SAME, unless TWINS
- *MHC1 & MHC2**
- *Share these General Properties**
Structure:
EXTRAcellular peptide Binding Cleft
IG-Like Domain
TRANSmembrane Cytoplasmic Domain
Class 1 MHC Structure
- *Polymorphic alpha chain** non-covalently attached to:
- *NON-POLYMORPHIC B-2 Chain**
- *alpha chain** is encoded by MHC/HLA genes on Chromosome 6:
- *Beta chain** encoded by CHROMOSOME 15
- *Cleft** formed by MHC/HLA gene region
- *ALPHA CHAIN ONLY**
- *Ig-Like Domain**
- *Alpha - 3 Region BINDS** CD8+ T CELLS
Class 2 MHC Structure
Polymorphic alpha chain non-covalently attached to the:
POLYmorphic Beta Chain
Alpha + Beta chain:
BOTH ENCODED on CHROMOSOME 6
- *Peptide Binding Cleft** is composed of
- *ALPHA & BETA CHAIN**
IG-like domain:
Beta-2 Region binds CD4 T-cells
- *Which MHC Class ?**
- *IG Like Domain binds to CD4 T-CELLS?**
CLASS 2 MHC
Beta-2 Region binds CD4+ Tcells
*class 1 mhc binds CD8+ T cells*
Non-Structural DIFFERENCES
Between MHC CLASSES
Class 1 MHC
Expressed on virtually ALL NUCLEATED CELLS
RESTRICTED to interaction with or activation of:
CD8+ Cytotoxic T-lymphocytes
(kill cells infected with INTRAcellular microbes = virus/tumors)
Class 2 MHC
Expressed ONLY on Dendritic Cells / B-lymphocytes / Macrophages
Restricted to interaction with or activation of
CD4+ Helper T-Lymphocytes
(naive cells recognize AG’s presented by APC –> Differentiation)
WHich MHC Class?
Expressed on ONLY
Dendritic Cells / B-lypmphocytes / Macrophages
MHC CLASS 2
Class 1 is expressed on virtually ALL NUCLEATED CELLS
MHC-Peptide Binding Features
6 of them
Broad SPECIFICITY
Peptide Structure Promotes INTERACTION
INTRAcellular Binding
STABLE Interaction
MINIMAL Repitition
LACK Discrimination
Broad Specificity
1 of 6 MHC-Peptide Binding Features
MHC molecules can
ONLY Bind ONE peptide at a time
Each MHC molecule can
Bind to MANY DIFFERENT TYPES of PEPTIDES
Peptide Structure Promotes INTERACTION
1 of 6 MHC-Peptide Binding Features
Amino acid size of peptide:
- *Class 1**
- *8-10 Residues** (less)
- *Class 2**
- *10-30 Residues**
- *LARGE MOLECULES**
Complementary AA Patterns = ANCHOR
INTRAcellular Binding
1 of 6 MHC-Peptide Binding Features
- *Peptide** is aquired during MHC
- *Biosythesis & Assembly**
Peptide derived from microbes in
host cell-
CLASS 1 = Cytosolic Proteins
Class 2 = INTRAcellular Vesicles
Stable Interaction
1 of 6 MHC-Peptide Binding Features
LONG DISSOCIATION Half Life
Hours - Days
between the MHC + Peptide
VVVV
Maximizes CHANCE for T-CELL RECOGNITION
of the peptide
Minimal Repitition
1 of 6 MHC-Peptide Binding Features
Only a few peptide-MHC complexes can activate
Specific T-Cell
Only a small fraction of Peptide-MHC complexes
display the SAME PEPTIDE
Lack Discrimination
1 of 6 MHC-Peptide Binding Features
Displays BOTH:
SELF + FOREIGN peptides
- *SELF > foreign**
- Can’t tell if it is Self or Foreign*
it relies on the
SENSITIVE & SPECIFIC T-CELLS
to recognize the foreign antigen
CD8 or CD4?
Kills cells infected with INTRAcellular Microbes
EX: Virus + Tumors
CD8+
bound by Class 1 , A-3 region
CD4, from CLASS 2
pathway to eliminate EXTRAcellular microbes
MHC Class 1
Antigen Processing Pathway
1) Production of Antigenic Proteins within the CYTOSOL
2) Proteolytic Digestion of Cytosolic Proteins
3) Transport of peptides from Cytosol –> ER
4) Assembly of Peptide-MHC Class 1 Complex in the ER
5) Surface Expression of Peptide-MHC Complexes
MHC CLASS 2
Antigen Processing Pathway
1) Generation of Vesicular Proteins -
* *endocytosis** of EXTRAcellular proteins
2) Proteolytic Digestion of Proteins in Vesicles
3) Biosynthesis** & **Transport of MHC2 Molecules –> ENDOSOMES
4) Association of Processed Peptides + Class 2 MHC molecules in vesicles
5) Expression** of Peptide-MHC complex on the **Cell Surface
MAIN DIFFERENCES
Between MHC1 & MHC2 Pathways
MHC1
MHC1
Source of Protein Antigens
CYTOSOLIC PROTEINS
mostly synth in the cell, may enter cytosol from phagosomes
Enzymes Responsible for PEPTIDE LOADING of MHC
Cytosolic Proteasome
SITE of Peptide Loading of MHC
ENDOPLASMIC RETICULUM
MAIN DIFFERENCES
Between MHC1 & MHC2 Pathways
MHC2
MHC2
Source of Protein Antigens
ENDOSOMAL + LYSOSOMAL proteins
mostly INTERNALIZED from EXTRAcellular environment
Enzymes Responsible for PEPTIDE LOADING of MHC
Endosomal + Lysosomal Proteases
SITE of Peptide Loading of MHC
specialized VESICULAR COMPARTMENT
Comparitive Table
MHC1 vs MHC2
STEP 1
Class 1 Pathway of Antigen Presentation
Production of ANTIGENIC PROTEINS within the CYTOSOL
Majority synthesized WITHIN cells
some phagocytosed & xported into the cytosol
Source is from:
VIRUS or MICROBES
from a past infection
STEP 2
Class 1 Pathway of Antigen Presentation
Proteolytic DIGESTION of Cytosolic Proteins
Proteolysis within proteasome –> makes peptides
Proteasome
Large + multiprotein enzyme complex, acts as a HOUSEKEEPER
degrades dmg / improperly folded protein
very RAPID synthesis –> 20% rate of MISFOLDING
defective products are marked with UBIQUITIN
–> degraded
STEP 3
Class 1 Pathway of Antigen Presentation
Transport of Peptides from Cytosol –> ER
Peptides generated in cytosol while MHC1 synthesized in ER
- *TAP**
- *Transporter** associated with ANTIGEN PROCESSING
- *ATP-Dependent** protein within the ER-Membrane
DELIVERS PEPTIDES
Cytosol –> ER LUMEN
STEP 4
Class 1 Pathway of Antigen Presentation
Assembly of Peptide-MHC1 Complexes in the ER
TAP + TAPASIN –> complexes TAP + MHC1
Peptides enter through TAP & bind awaiting adjacent MHC1
Peptide-MHC complex is RELEASED from TAPASIN
–> EXITS THE ER
STEP 5
Class 1 Pathway of Antigen Presentation
Surface Expression of Peptide-MHC1 Complexes
- *Exocytic Vehicles** move the stable MHC1 complexes
- -> CELL SURFACE
to be recognized by:
AG Specific CD8+ T-CELLS
STEP 1
Class 2 Pathway of Antigen Presentation
Generation of VESICULAR PROTEINS
Binding of native AG to APC
–> APC captures the protein from EXTRAcellular environment
INTERNALIZATION to ENDOSOMES
Membrane bound vesicles that communicate with lysosomes
STEP 2
Class 2 Pathway of Antigen Presentation
Proteolytic DIGESTION of Cytosolic Proteins
Internalized proteins are degraded in
LYSOSOMES & Late Endosomes
to make PEPTIDES
Active process is mediated by:
Proteases = CATHEPSINS
MHC1 uses PROTEOSOMES,
to break down proteins into peptides
(Same)
STEP 3
Class 2 Pathway of Antigen Presentation
Biosynthesis & Transport of MHC2 Molecules to ENDOSOMES
MHC2 synthesized within ER
Invarient Chain is bound to MHC2
which PREVENTS peptides to bind to MHC2
VVVV
Is then transported via:
Exocytic Vesicles (no TAP) –> Endosomes
STEP 4
Class 2 Pathway of Antigen Presentation
Association of Processed Peptides w/ MHC2 in Vesicles
Exocytic vesicles fuses with:
LATE ENDOSOME / LYSOSOME vesical
- *CLIP** = MHC2 + Invarient Chain
- *HLA-DM** exchanges CLIP for A PEPTIDE
- invarient chain is degraded by cathepsin*
Antigenic Peptide binds MHC2
STEP 5
Class 2 Pathway of Antigen Presentation
Expression of Peptide-MHC2 Complexes on CELL SURFACE
Vesiculotubular extensions move the stable
Peptide-MHC2 Complexes from Lysosome
Expressed on surface for recognition by
SPECIFIC CD4+ T-cells
