Download Microbiology: Major Histocompatability Complex (MHC) pg. 1 Marc

Microbiology
8/26/2008
Major Histocombatibility Complex (MHC)
Transcriber: Marc Vance
39:39
Quiz (#2):
1.) The dominant immunoglobulin isotype in human saliva and tears is:
a. Monomeric IgG
b. Polymeric IgA with J chain and Secretory Component
c. Monomeric IgM
2.) The isotype of immunoglobulin in human newborn cord blood that is transferred through the
placenta is:
a. IgM
b. IgG
c. IgE
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Extra question - What would happen if IgM could transfer through the placenta into the fetus?
You could have hemolysis because a lot of antibodies to ABO blood groups are IgM antibodies,
and incompatibilities between ABO blood types can occur between mother and fetus, in which
case you’d have hemolysis of the fetal red blood cells.
Slide 1: Title Slide
Slide 2: MHCs (Major Histocompatability Complexes) have two different classes, MHC I and MHC II, each
with its own expression and function.
B and T cells recognize antigen differently. The antigen receptor on B cell is immunoglobulin
(Ig), a transmembrane protein secreted by plasma cells. T cell antigen receptor, TCR, is also a
transmembrane protein that is displayed on CD4 helper T cells and the CD8 cytotoxic T cells.
Slide 3: B cells can recognize native protein antigens in solution or on bacterial or viral cell surfaces. The
secreted antibody is an effector molecule by itself, meaning it can operate at a distance. For example,
you can do an ELISA assay you can order your antibodies from California and use them in Birmingham.
This won’t work while doing a T cell assay. Most of your plasma cells are in your bone marrow where
they secrete antibodies, which can react quickly to neutralize infections all over the body. So antibodies
are designed to act at distance.
Slide 4: A 3-D image of antigen-antibody interaction (a lysozyme and an Ig shown here, illustrating that
antibody recognizes 3-D conformations). There are many different antibody epitopes, meaning that
there are various patterns on that lysozyme that a B cell could recognize.
Slide 5: T cells, unlike B cells, do not recognize native protein antigens. T cells recognize “processed
antigen” - broken down peptides from degraded antigens that are bound to MHC proteins.
Microbiology: Major Histocompatability Complex (MHC)
Marc Vance
Slide 6: The lysozyme shown here could be recognized in its 3-dimensional conformation by an
antibody. For a T cell to recognize it, it must be denatured and broken up by proteases into peptides. If
this was a foreign lysozyme, our T cells could recognize certain peptide sequences, but only after they
are bound to MHC.
Slide 7: A T cell receptor (here it is called TCR 2) is shown recognizing an antigenic peptide complexed
on a MHC molecule of an antigen presenting cell.
Slide 8: T cells require direct cell-to-cell interaction to perform their antigen-specific functions.
Slide 9: The MHC complex was discovered during study of inbred strains of mice. The colonies were
virtually genetically identical, but due to recessive mutations from inbreeding some of the colonies
developed tumors at a high incidence rate while others didn’t. In an attempt to understand the nature
of the tumors (and therefore cancer), they were transplanted from a tumor-stricken mouse to a tumorfree mouse. In some colonies the tumor was rejected, on others it would grow. Healthy tissue was then
transplanted from a tumor-free mouse onto a tumor-stricken mouse, and that was rejected as well. This
showed that the growth/rejection of the tissue was not related to the tumor; it was the MHC complexes
in the tissue that signaled it to be foreign.
In transplantation between two individuals, these MHC molecules are the major antigen that
you need to match if you want the tissue to be accepted. This helps to explain the name – it’s the
“major” factor to overcome to make sure the tissue is “histocompatible”. It’s called a “complex” because
several genes on chromosome 6 are linked together that encode the proteins that comprise it.
While transplantation immunology was how MHCs were discovered, their main function is to
display peptide antigens (self and non-self) to T cells, which survey all the body’s cells for this reason.
Self antigens elicit no response from T cells, whereas non-self will trigger an immune response.
Slide 11: MHC Class I is expressed by all nucleated cells in the body (not expressed by erythrocytes). Its
function is to present peptides to CD8+ T cells, which are primarily cytotoxic “killer” T cells (Tc cells).
The Tc cells kill virus infected-cells, tumor cells, or any abnormal cells. The images show a Tc cell killing
virus infected cells.
It is important that all of our nucleated cells express MHC Class I because virtually any nucleated
cells could become infected with a virus.
Slide 12: MHC Class II is expressed on much fewer cell types. It’s mainly expressed by antigenpresenting cells (APCs; 3 main types - dendritic cells, B cells, macrophages). MHC Class II presents
peptide to CD4 T cells (helper T cells, aka Th cells). The APCs present antigen to Th cells, at which point
the Th cells can either 1.) Help B cells proliferate, differentiate, isotype switch, or 2.) Help activate
macrophages.
Remember, MHC Class II –> CD4, MHC Class I –> CD8
pg. 2
Microbiology: Major Histocompatability Complex (MHC)
Marc Vance
Slide 13: Shown is a Th cell helping a B cell. The B cell’s MHC Class II complex binds with the Th cell’s
TCR. The Th cell then secretes IL-4 (a cytokine which promotes isotype switching) directly into the B cell.
Slide 14, 15: Both MHC classes are membrane-bound glycoproteins with 4 domains: 2 membrane
proximal domains and 2 membrane distal domains that form a peptide binding cleft. Class II MHCs have
two chains – alpha and beta, each with two domains. The peptide sits in a cleft in between the two
chains. Class I MHCs have a longer alpha-chain with three domains; the peptide binding site is made
entirely out of the alpha chain. Class I has a short beta domain (Beta-2 microglobulin). The overall
structure of the two MHC classes are very similar.
Slide 16: The 3-D structure of MHC is ideal for binding/loading proteins.
Slide 17: A “top” view. The peptide “sits” in the cleft. This is what the T cells “see” and recognize.
Slide 18: Peptides bound by MHC Class I are bound at each end, while the ends of peptides in the MHC
Class II cleft are not bound, it “lays on top” of the MHC protein.
An aside – MHC’s must have a peptide associated with it to reach the cell surface. Most of the time it
displays a self peptide; only during infection is it a foreign peptide.
Slide 19, 20, 21: A B cell is shown expressing both Class I and Class II MHCs. At resting state (no
infection), both MHCs are exhibiting self peptide. When an antigen (tetanus toxoid, for example) binds
to this B cell’s Ig, it is internalized and degraded into peptides. Newly synthesized MHC Class II’s pick up
this new foreign peptide and begin to display it on the cell surface.
Meanwhile, your T cells are always patrolling the body for foreign antigens. When a Th cell with
affinity for this tetanus peptide comes along, it can bind to the B cell and activate it through cytokines. B
cells then proliferate and then differentiate into plasma cells.
Slide 22: MHC polymorphisms are allelic variations in MHC genes. This makes organ transplantation
difficult. Comparing chromosomes from each parent, the MHC gene sequences are different; hence
even siblings would have differences in MHCs. Only identical twins could have the exact same MHC
proteins. These polymorphisms are concentrated in the peptide binding regions.
Slide 23: A plot of average person-to-person variability in MHC Class I proteins – most are in the alpha-1
and alpha-2 (which makes up the peptide binding site). This allows different MHC proteins to bind
different peptides – which is a good thing (slide 26 explains why).
Slide 24: The gene complex that makes the HMC – called HLA (Human Leukocyte Antigen; they were
originally found on leukocytes). Class I has three different genes; they each encode an alpha-chain,
which then associates with beta-2 microglobulin. So every chromosome will yield three different Class I
molecules. Class II has three different pairs of alpha and beta chains (DR, DQ and DP); therefore 3
different Class II molecules are expressed per chromosome as well. And since we have two sets of
chromosomes (one from each parent), each cell has 6 Class I’s and 6 Class II’s and they are all coexpressed. This diversity of MHC molecules increases the probability of protein binding.
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Microbiology: Major Histocompatability Complex (MHC)
Marc Vance
Slide 25: These MHC polymorphisms are at the population level – if we sequenced the variable regions
from 100 B cells, each B cell would have a different variable region. All of one person’s MHC genes are
the same but comparing person-to-person there is a lot of variation.
Note that there are no gene rearrangements with MHC as were seen in the T cell and B cell receptor
genetics.
Slide 26:.Roughly 1 out of every 3 to 5 T cells can react to foreign MHC, whereas maybe 1 in 1000 T cells
can recognize a foreign peptide. This is why transplantation is so difficult - it is so easy to illicit an
immune response from a mismatched MHC protein. This helps to illustrate the need for
immunosuppressant drugs.
A positive of the MHC polymorphisms is that you can change the peptide binding specificity. If
we only had one MHC, a viral pathogen could mutate until it was no longer recognized and it would
basically be invisible to us. This genetic diversity at a population level helps to ensure that a mutated
virus could not infect and kill all humans. Some people might get killed by a virus because their T cells
couldn’t detect it, but others’ T cells would. This MHC polymorphism benefits us as a species.
An aside - The most common tissue clinically transplanted is the blood. No immunosuppressants are
needed for blood transfusions. This is because red blood cells are non-nucleated and they don’t express
MHC. They elude natural killer cell’s attention because erythrocytes also lack other target receptors that
the NK cells look for
Slide 27: The reason for the dual system of Ab-Ag and MHC is illustrated here. With a viral infection, you
have infected cells filled with virus as well as extracellular virus molecules to deal with. You need to 1.)
Tag and phagocytize the free viruses, which requires Ig, and 2.) Eliminate the infected cells, which is
done by Tc cells which need MHC to do their job. Without both of these sides of the immune system,
you could not effectively clear the virus.
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