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PDAT4 > 8 - MHC > Flashcards

8 - MHC Flashcards

1
Q

Humoral Immmunity

Adaptive Immunity

A

AB-mediated

Major player = B-Lymphcytes

Responds to EXTRAcellular Microbes

FXN:
Blocks INFECTIONS via ELIMINATION
of extracellular microbes

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2
Q

CELL-MEDIATED Immunity

Adaptive Immunity

A

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

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3
Q

TYPES of APC’s

Cell-Mediated Immunity

A

Antigen Presenting Cells

Dendritic Cells

Macrophages

B-Lymphocytes

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4
Q

2 Functions of APC’s

A

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

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5
Q
  • *MHC**
  • *4 Roles**
A

DISPLAYS ANTIGEN TO T-CELLS
MAIL ROLE

Allorecognition & Tolerance

Governs T & B Cell interactions

Controls +/- Selection of T-cells

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6
Q

MHC vs HLA

A

MHC = Complex or Set of Cell-surface proteins

HLA
Human Leukocyte Antigens
SPECIFIC MHC FOR HUMANS

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7
Q

HLA Genes

A

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

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8
Q

HLA Polymorphism

A

Refers to there being:
MANY ALLELES
for each
CLASS 1 & CLASS 2

Resulting in MANY DIFFERENT COMBINATIONS

200+ genes on chromosome 6

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9
Q

HLA Haplotype

A

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

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10
Q

HLA CO-Dominance

A

Proteins encoded by BOTH Maternal + Paternal genes are
EXPRESSED EQUALLY

Always 1 from each
VERY UNLIKELY that child will have THE SAME, unless TWINS

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11
Q
  • *MHC1 & MHC2**
  • *Share these General Properties**
A

Structure:
EXTRAcellular peptide Binding Cleft

IG-Like Domain

TRANSmembrane Cytoplasmic Domain

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12
Q

Class 1 MHC Structure

A
  • *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
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13
Q

Class 2 MHC Structure

A

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

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14
Q
  • *Which MHC Class ?**
  • *IG Like Domain binds to CD4 T-CELLS?**
A

CLASS 2 MHC
Beta-2 Region binds CD4+ Tcells

*class 1 mhc 
binds CD8+ T cells*
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15
Q

Non-Structural DIFFERENCES
Between MHC CLASSES

A

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)

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16
Q

WHich MHC Class?
Expressed on ONLY
Dendritic Cells / B-lypmphocytes / Macrophages

A

MHC CLASS 2

Class 1 is expressed on virtually ALL NUCLEATED CELLS

17
Q

MHC-Peptide Binding Features

6 of them

A

Broad SPECIFICITY

Peptide Structure Promotes INTERACTION

INTRAcellular Binding

STABLE Interaction

MINIMAL Repitition

LACK Discrimination

18
Q

Broad Specificity

1 of 6 MHC-Peptide Binding Features

A

MHC molecules can
ONLY Bind ONE peptide at a time

Each MHC molecule can
Bind to MANY DIFFERENT TYPES of PEPTIDES

19
Q

Peptide Structure Promotes INTERACTION

1 of 6 MHC-Peptide Binding Features​

A

Amino acid size of peptide:

  • *Class 1**
  • *8-10 Residues** (less)
  • *Class 2**
  • *10-30 Residues**
  • *LARGE MOLECULES**

Complementary AA Patterns = ANCHOR

20
Q

INTRAcellular Binding

1 of 6 MHC-Peptide Binding Features​

A
  • *Peptide** is aquired during MHC
  • *Biosythesis & Assembly**

Peptide derived from microbes in
host cell-

CLASS 1 = Cytosolic Proteins

Class 2 = INTRAcellular Vesicles

21
Q

Stable Interaction

1 of 6 MHC-Peptide Binding Features​

A

LONG DISSOCIATION Half Life
Hours - Days
between the MHC + Peptide
VVVV

Maximizes CHANCE for T-CELL RECOGNITION
of the peptide

22
Q

Minimal Repitition

1 of 6 MHC-Peptide Binding Features​

A

Only a few peptide-MHC complexes can activate
Specific T-Cell

Only a small fraction of Peptide-MHC complexes
display the SAME PEPTIDE

23
Q

Lack Discrimination

1 of 6 MHC-Peptide Binding Features​

A

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

24
Q

CD8 or CD4?

Kills cells infected with INTRAcellular Microbes

EX: Virus + Tumors

A

CD8+
bound by Class 1 , A-3 region

CD4, from CLASS 2
pathway to eliminate EXTRAcellular microbes

25
Q

MHC Class 1
Antigen Processing Pathway

A

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

26
Q

MHC CLASS 2
Antigen Processing Pathway

A

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

27
Q

MAIN DIFFERENCES
Between MHC1 & MHC2 Pathways

MHC1

A

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

28
Q

MAIN DIFFERENCES
Between MHC1 & MHC2 Pathways

MHC2

A

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

29
Q

Comparitive Table
MHC1 vs MHC2

A
30
Q

STEP 1
Class 1 Pathway of Antigen Presentation

A

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

31
Q

STEP 2
Class 1 Pathway of Antigen Presentation

A

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

32
Q

STEP 3
Class 1 Pathway of Antigen Presentation

A

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

33
Q

STEP 4
Class 1 Pathway of Antigen Presentation

A

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

34
Q

STEP 5
Class 1 Pathway of Antigen Presentation

A

Surface Expression of Peptide-MHC1 Complexes

  • *Exocytic Vehicles** move the stable MHC1 complexes
  • -> CELL SURFACE

to be recognized by:
AG Specific CD8+ T-CELLS

35
Q

STEP 1
Class 2 Pathway of Antigen Presentation

A

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

36
Q

STEP 2
Class 2 Pathway of Antigen Presentation

A

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)

37
Q

STEP 3
Class 2 Pathway of Antigen Presentation

A

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

38
Q

STEP 4
Class 2 Pathway of Antigen Presentation

A

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

39
Q

STEP 5
Class 2 Pathway of Antigen Presentation

A

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

PDAT4 (34 decks)

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