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75 Cards in this Set

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MHC is important in ___________
self vs. non-self recognition

*T cell recognition of Ag includes recognition of self MHC
originally identified by ___________ for their work with__________
Gorer and Snell/blood cell Ags
Type of MHC found to be important in rejection of foreign tissue
type II
MHC also known as _______
genes for this found on chromosome ____
HLA – human leukocyte antigens /6
What are the three different groups of genes on the MHC locus
class I MHC
class II MHC
class III MHC =
class I MHC gene
-expressed on most nucleated cells
-present Ag to CD8+ T cells (ex. Tc)
-HLA-A, HLA-B, and HLA-C in humans
class II MHC gene
-expressed primarily by professional APCs (Mf, B cell, DC)
-present Ag to CD4+ T cells (ex. Th)
-HLA-DP, HLA-DQ, and HLA-DR in humans
class III MHC gene
-secreted proteins found in the serum
-complement proteins, some cytokines (TNF), proteins involved in Ag processing (TAP, LMP2 and LMP7), etc
MHC class I proteins
are a single chain associated with another
protein not encoded for by the MHC locus (B2-MICROGLOBULIN;
invariant chain, chromosome 15)
MHC class II proteins
are heterodimers coded for by the a and b
genes encoded for by genes within the MHC locus
MHC proteins are highly polymorphic, meaning
MANY FORMS OF GENES(alleles) at each locus
MHC genes are _________, meaning both alleles are expressed at once
CODOMINANT
Since MHC genes are so closely linked there is ________
LOW RECOMBINATION FREQUENCY

* you inherit intact genes from mother and father
Both Allels of MHC genes provide us with a __________
HAPLOTYPE
MHC genes are POLYGENIC. Explain
-They include multiple similar genes (ex. HLA-A and HLA-B, etc)

-On human cells, get 6 different class I MHC and 12 different class II MHC proteins

-Since there are multiple DRb genes that can be found in one individual (each can associate with the same a chain), the number expressed on humans can be higher
HLA locus has classical and non-classical MHC genes. Classical genes involve and include
T cell recognition of Ag

HLA-A, B and C
HLA-DP, DQ, and DR
HLA locus has classical and non-classical MHC genes. non-classical genes involve
NK cells recognintion and others
allotype
genetic sequence of a
Gene within a species
polymorphisms give us ______ in the population
diversity
Transplantation of
foreign tissue will be _____
if MHC’s
don’t match
rejected
Humans are ______ and therefore, inherit ___ of parents MHC genes
outbred/one half
chance of siblings having same haplotype (= histocompatible)
1:4*

*if no recombination
True or False, in humans, it is usually fine to give parents organs/tissues to child
False - most of the time can’t give parents organs/tissues to child
Because humans are outbred and have been around for a long period of time, there is so much diversity that the chance of identical haplotypes in two unrelated individuals is ________.
almost zero
because of “racial segregation” throughout history, tissue transplants often need to be __________.
from a member of that racial background
MHC class I proteins describe it and how you get surface expression
large a chain associated with the invariant beta2-microglobulin

must get association of these two to get surface expression
What are the three domains of class I protein
alpha1, alpha2, and alpha3
b2-microglobulin is structurally similar to ____.
alpha3
*has homology with Ig constant region
alpha1 and alpha2 form the _________.
peptide binding cleft

*holds 8-10 a.a. peptide
a3 is highly conserved and ________.
interacts with CD8
MHC class II proteins are _________ consisting of alpha and beta chains
HETERODIMERS
MHC class II proteins are divided into:
alpha1/alpha2 and beta1/beta2
alpha1/beta1 is the _______
Ag binding cleft
alpha2/beta2 is where
CD4 contacts
a given MHC can bind a variety of different antigenic peptides therefore it is _________.
promiscuous
class I cleft is ______ at ends. Therefore, it holds smaller peptides (8-10 a.a.)
It also has ________ at ends, often at position #2 and #9
blocked/ anchor residues
Class II cleft is _____ at ends. It can hold ________(average of 13-18a.a.).
Anchor residues can be _________. It often has a negatively charged a.a. at position #4 and a hydrophobic residue at position #9
open/ larger peptides/ anywhere in peptide (not conserved as with class I)
Class I peptides are ________.
endogenous intracellular peptides
In the ____ is where class I and the Ag peptide associate
ER
_______ are the “preferred” length of class I peptide and binds strongest
NONAMERS
MHC class I peptides peptides “bulge” which aids in _________. Residue 1/2 and 8/9 contact (bind) to
TCR RECOGNITION/ MHC
Class I MHC polymorphisms have a higher variability in _________.
alpha1/alpha2 (area that contact Ag)
In class II peptides the basics of the peptide/MHC interaction is similar to class I. However, they hold __________.
EXOGENOUS PEPTIDES
-peptides degraded by the endocytic pathway
-usually at least 13 a.a. or larger
-9 a.a. within cleft
ID: Class I or Class II

a1/ a 2 - Peptide binding domain
Class I molecules
ID: Class I or Class II

a1/ B1 - Peptide binding domain
Class II molecules
ID: Class I or Class II

Nature of peptide binding cleft:
Closed at both ends
Class I molecules
ID: Class I or Class II

Nature of peptide binding cleft:
open at both ends
Class II molecules
ID: Class I or Class II

Peptide motifs involved in binding to MHC molecule:

Anchor residues at both ends of peptide
Class I molecules
ID: Class I or Class II

Peptide motifs involved in binding to MHC molecule:

Anchor residues distributed along the length of the peptide
Class II molecules
ID: Class I or Class II

Nature of bound peptide:

Extended structure in which both ends interact with MHC cleft but middle arches up away from MHC.
Class I molecules
ID: Class I or Class II

Nature of bound peptide:

Extended structure that is held at a constant elevation above the floor of the MHC cleft.
Class II molecules
Cells that have high expression of class I
T cells, B cells, Macrophages, DC, neutrophils, Ag presenting cells
Cells that have high expression of class II
B cells, Ag presenting cells, & Epithelial cells of the tymus
True or False: Human T cells can be induced to express class II
True
Factors involved in MHC gene regulation
Transcription factors
Cytokines
Viruses
Cancer cells
TRANSCIRPTION FACTORS regulate expression. For example, defects in ________ and ______ will result in a lack of MHC class II. This can cause _________ which results in severe immunodeficiency
CIITA class II transactivator)/ RFX / bare lymphocyte syndrome
Cytokines can effect MHC gene expression in what way
can increase/decrease MHC expression

For example:
-IFNs can increase class I expression
-IFNg (Th1) can increase class II expression on Mf
and decrease class II on B cells
- IL-4 (Th2) can increase class II on B cells
VIRUSES and CANCER CELLS can effect MHC gene expression in what way
can decrease MHC expression
MHC also called
“immune response genes”
Some strains of mice (humans?) will respond to an Ag and others won’t
WHY?
1) DETERMINANT SELECTION THEORY– does an individual’s MHC bind to a particular Ag peptide

2) HOLES-IN-THE-REPERTOIRE THEORY– absence of the “correct” TCR to bind to Ag
Some _______ associated with certain MHC haplotypes. However, this is not completely diagnostic because other (unknown) factors play a role in determining presence of disease.
autoimmune diseases
Inbreding reduces _______ and, therefore, may increase susceptibility to disease
MHC diversity
What happens if an individual does not have the “right” MHC?
no peptide binding and no T cell activation = disease
Presence of the ____ allele is associated with a 90X relative risk of ankylosing spondylitis.

Presence of the ____ allele is associated with a 130X relative risk of narcalepsy.
DR2
T cells can recognize “internal” antigens
by _________
Ag processing.
Endogenous versus exogenous Ags
Endogenous Ags are made in the cell (e.g., viral proteins). They involve class I MHC. Exogenous Ags are Ags that are brought in the cell and processed by APCs
T cells can recognize “INTERNAL” antigens
How?
Ag processing-- The APC chops up the protein anyways so even if the Ag is on the inside of the molecule it will still be recognized -- this is the IMPORTANCE OF AG PROCESSING and the ROLE OF THE APCs
MHC class I processing pathway
AKA: the cytosolic pathway
Proteins targeted for degredation have UBIQUITIN attached to them. The UBIQUITIN-protein complex then travels to the PROTEOSOME. The PROTEOSOME is a large enzyme complex that degrades these proteins with the help of LMP7 & LMP7--enzymes that associate with the proteosome to cut proteins near hydrophobic residues (which is needed for class I anchors)
How do peptides associate with MHC I?

Degraded peptides go to rER where it is bound by _____ the transporter associated with Ag processing for class I peptides.
The ____-______ complex allows the peptide to associate with class I. The class I-peptide travels to Golgi and then cell surface.
TAP / TAP-PEPTIDE
Endocytic pathway
primarily done by APCs where exogenous proteins are taken from outside the cell and processed
Class II peptides usually are degraded by way of the ______ in which exogenous proteins are taken from outside the cell and processed by either ______, ______ (phagocytic) or _______(receptor mediated endocytosis) which bring in Ag in endocytic vesicle (endosome).

After fusion of endosome with lysosome (low pH), the PROTEIN WILL BE DEGRADED to
yield peptides of ~13-18a.a. long
ENDOCYTIC PATHWAY
DENDRITIC CELLS/ MACROPHAGES/B CELLS
How do exogenous Ags associate with class II MHC?

__________ associates with newly made class II MHC preventing endogenous peptides from binding.

As the MHC/LI complex leaves the golgi the INVARIENT CHAIN (LI)partially degraded to yield _____ which occcupies class II binding groove.

Ii and CLIP are then ___________ , allowing exogenous Ags to associate with class II.
Invariant chain (Ii) /CLIP/ DEGRADED IN ENDOCYTIC COMPARTMENT
What type of TCRs are involved in the presentation of non-peptide Ags (e.g., glycolipids)?
gamma delta
How do gamma delta TCRs can recognize non-protein Ags?
They don’t use classical MHC
use they use CD1 MOLECULES.
CD1 MOLECULES
-also associates with b2-microglobulin
-genes on chromosome #1 (not within MHC locus)
-expressed on professional and non-professional APCs and B cells, thymocytes, epithelial cells
-5 different types of CD1
-expression depends on the type/class of CD1
-lipids from M. tuberculosis and M. leprae found to be presented with CD1
-NK cells may also recognize Ag with CD1