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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
**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
26
**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_**
27
**MAIN DIFFERENCES** Between **MHC1 & MHC2 Pathways** ## Footnote **_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**
28
**MAIN DIFFERENCES** Between **MHC1 & MHC2 Pathways** ## Footnote **_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**
29
**Comparitive Table MHC1 vs MHC2**
30
**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
31
**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
32
**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**
33
**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**
34
**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_**
35
**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**
36
**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)
37
**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**
38
**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**
39
**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_**

PDAT4 (34 decks)

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