Topic 8 Major Histocompatibility
Complex
Introduction
A patch of tissue taken from one
individual and transplanted to another is destroyed by the recipients immune
system because the cells in the donor tissue express molecules on their surface
that are different from those expressed by the recipient. These molecules act as antigens, and thus
determine whether the tissue will be immunologically compatible with the
recipient - they act as Histocompatibility antigens, encoded in Histocompatibility
genes. Although destruction of transplanted
tissue is not the physiological function of the MHC (Major
Histocompatibility Complex) molecules, their true function does have something
to do with tissue compatibility, so the name is not so far off the mark after
all. What then is the physiological
function of MHC molecules? This
section will answer this question. We
will focus on the structure as
well as the function of Major Histocompatibility Complex genes and their
products, which play a central role in the genetic control of the immune
response.
Objectives
On completion of this section and
the required reading found in the textbook key, you should be able to:
n explain the connection between a trait and
a gene using the specific example that MHC genes encode for molecules that
allow specific immune responses;
n describe the use of inbred mice for the
elucidation of the genetics of the immune response;
n describe how congenic strains of mice are
developed;
n describe and draw MHC-I molecules;
n describe the function of MHC-I molecules;
n describe and Draw MHC-II molecules;
n compare the detailed differences in the
structure of the aggreotope binding sites of MHC-I and MHC-II;
n describe the function of class III genes
and in which cells they are expressed.
n describe MHC restriction;
n discuss the differences between MHC
restriction of CD4+ T cells and MHC restriction of CD8+ T cells;
n draw maps of either the MHC gene complex in
mice or HLA gene complex in humans;
n describe how the collection of MHC genes
of an individual dictates either the ability or inability of the animal to
respond to a particular antigen;
n describe an experiment that shows MHC
restriction: between T and B cells, between T cells and macrophages between
cytotoxic T cells and virally infected cells;
n discuss the biological relevance of MHC
molecules;
MHC molecules exhibit a range of
structural diversity at the species level that is roughly equivalent to the
range of antibody diversity at the level of the individual animal. Discuss this
statement.
Required Reading
Please refer to the textbook key for
specific readings for this section.
P Key Words
|
alleles alloantigens.
bone
marrow chimeras Class
I molecules Class
I regions Class
II molecules Class
II regions Class
III molecules Class
III regions Determinant
selection model H-2
complex D
region I
region K
region L
region |
S
region locus Immune
response genes congenic
mice Human
Leukocyte Antigens Major
Histocompatibility complex MHC
restriction negative
thymic selection positive
thymic selection public
specificities private
specificities region Specificities superantigens |
P Key Concepts
n Foreign antigens must be specially
processed before they can be presented to the antigen-sensitive cells of the
immune system.
n Antigen fragments generated inside these
cells are bound to specialized receptors
called MHC molecules in the cell cytoplasm and then transported to the
surface of antigen-presenting cells.
n Two major categories of cell surface
transmembrane molecules are encoded by the MHC: class I molecules consist of a
single polypeptide chain associated with a
2-microglobulin molecule on the surface of nearly all
nucleated cells; class II molecules consist of two polypeptide chains and have
a more limited cellular distribution.
n T-cell receptors on CH4+ helper
T cells recognize and respond to foreign antigens only when bound to an MHC
class II molecule on the surface of the antigen-presenting cell.
n CD8+ cytotoxic T cells have
receptors that recognize foreign antigen only in association with MHC I
molecule.
DID YOU KNOW?
When we look at the evolutionary history of the immune system it
seems that it has always served the sole purpose of defense against
infection. No other external factor
shaped it. The second major feature of
the immune system is that it appears to have evolved through a process of
elaboration. It has achieved its
protective power by incorporating a variety of defenses that existed in the
invertebrates. Having evolved in the
presence of these older, nonadaptive defenses, the immune system incorporates
some of their elements for its own purposes.
As the immune system grew in importance and complexity, it underwent a
series of internal reorganizations, which involved compromises or trade-offs of
one kind or another. The fact that the
metabolic resources of an organism are not unlimited makes such economic
choices necessary. Investment in
effector system, the cutting edge where killer cells and antibodies wallop
bacteria and viruses, must be balanced by an investment in regulatory systems
necessary for keeping the entire enterprise under control.
Where nature fails to provide evidence to support the inquiry into
evolution, immunologists have borrowed a tool from economists; computer
modeling. France Celada of Hospital for
Joint Diseases in New York City and Philip E. Seiden of the IBM Thomas J. Watson
Research Center have formulated a cellular automaton for closely modeling the
cellular events that take place within the immune system. Sets of simulated T cells, B cells and
antigen - presenting cells appropriately endowed with receptors and MHC molecules
are shaken up with antigen and then allowed to undergo a series of
interactions. The automaton responds
well to antigenic stimulation, mounting recognizable primary and secondary
responses.
More interesting results come when it is asked deeper questions -
for example, how many MHC types per individual are optimal? The program answers this question by
balancing the advantage of being able to present more and more peptide against
the disadvantage of deleting more and more of the T cell repertoire. Recall that in addition to presenting
antigen, the MHC molecule identifies tissue as self. So an increase in the number of MHC molecules means an increase
in the number of self-antigens. A
corresponding number of T cells must be therefore deleted if autoimmunity is to
be avoided. Furthermore, loss of MHC
types ultimately reduces the flexibility of response to invading
organisms.
After a few runs, the model comes up with a number of MHC types
between four and eight, which agrees remarkably well with what has been
observed. Although not the first
mathematical model of the immune system, this is by far the most user-friendly
toll available for exploring these evolutionary issues. Its real test will come when it attempts to
answer questions to which the solutions are not known.
A related problem is why the antigen - presenting groove in MHC
molecules accommodates a sequence of just nine amino acids. The hard-nosed biochemist might argue that
this size is an accident of the geometry of the MHC molecule. The soft-nosed evolutionary biologist would
wonder whether that explanation alone is sufficient. Instead he or she might argue that the length of the grove may
reflect a balance of selective pressure between two opposing needs: on the
other hand, to conserve as much of the T cell repertoire as possible, and, on
the other, to prevent parasites from building proteins invisible to the T cell
system. For example, if a groove
accommodated only six amino acids, nearly all possible hexapeptides might be
present in self-proteins, with the result that nearly all T cells would be
deleted. But if a grove accommodated 14
amino acids, parasites could evolve so as to avoid using bindable peptides in
their proteins.
Review Questions
1. Textbook Study Questions
Review questions at the end of the
Chapter 9. The answers with
explanations are available at the end of the textbook.
2. Multiple Choice Questions
1. CD8 is a receptor for
A) antigen
B) MHC class II molecules
C) antibody
D) TCR
E) MHC class I molecules
2. The term MHC
restriction refers to the
A) inheritance of MHC antigens
B) need for antigen to be
recognized in association with MHC molecules
C) need for MHC genes to
control complement activity
D) problems associated with
allograft rejection
E) need for MHC molecules in
order to reject grafts
3. Exogenous antigen
processing mainly occurs within
A) T lymphocytes
B) neutrophils
C) plasma cells
D) macrophages
E) none of the above
4. Class I MHC molecules
are found on
A) B cells and macrophages
B) erythrocytes, B cells, and
T cells
C) T cells only
D) all nucleated cells
E) neutrophils, T cells, and B
cells
5. Class II MHC molecules contain
A) one gamma chain and one
light chain
B) one alpha chain and one
Beta chain
C) two light and two heavy
chains
D) one epsilon chain
E) B2-microglobulin
3. Definitions/Short Answer Questions
1. Null cells are not MHC
restricted. Explain.
2. Even though the immune
system rejects transplanted kidneys and hearts its function is not to protect
us against graft. Why do we need
Histocompatibility antigens?
3. If we do not need
protection against attack from foreign organs and tissues, why are MHC-I
molecules so polymorphic?
4. Why are inbred/congenic
mice important to immunological studies?
5. Draw and label a diagram of
a class I MHC molecule as it is found in the membrane.
6. Draw and label a diagram of
a class II MHC molecule as it is found in the membrane.
7. What is the connection
between immunity and MHC genes.?
8. How is the polymorphism or
diversity of MHC, different from the generation of diversity in antibodies?
9. How do MHC-II molecules
allow immune cells to communicate with each other? Why is this communication
important?
10. Class III MHC molecules are
not cell membrane proteins. What are they and what do they do?
11. T-cells do not recognize
free antigen, as antibody receptors do. Speculate why.
12. Briefly discuss MHC
restriction.
13. Why do T cells have such an
elaborate way of reacting with antigen?
14. Describe T cell
differentiation in the thymus using CD4 and CD8 markers. T cells can react only
with protein fragments. What is this process called? How does it occur? Which
pathway leads to antigen interaction with MHC-I molecules? Which pathway leads
to interaction with MHC-II molecules?
Where to Go from Here
Once you have completed the review,
take some time and complete the objectives. If you are having trouble with any
of the concepts, contact your instructor.
Remember to regularly check your
Instructor Assignment Information for assignments and due dates for completing
them.
When you are confident that you can
complete the objectives, proceed to the next topic.