Transcript Major Histocompability Complex (MHC)

Major Histocompability Complex
(MHC)
*Protein images comparing the MHC I (1hsa) and MHC II (1dlh) molecules
What is MHC?
Group of genes that code for
proteins found on the surfaces of cells
that help the immune system
recognize foreign substances.
MHC proteins are found in all higher
vertebrates.
In human beings the complex is also
called the human leukocyte antigen
(HLA) system.
MHC history
histocompatibility, derived from the Greek word histo
(meaning “tissue”) and the English word compatibility
describe their function in transplantation reactions and
does not reveal their true physiological function
In the 1950s skin graft experiments carried out in mice
showed that graft rejection was an immune reaction
mounted by the host organism against foreign tissue.
The host recognized the MHC molecules on cells of the
graft tissue as foreign antigens and attacked them.
Succesful transplant (organ/tissue) has as similar
tissue type as possible
Key Words
Alleles: alternate forms of a gene that produce alternate
forms of the protein
Tissue Type: set of MHC molecules of an individual
HLA: (human leukocyte antigens) proteins that are displayed
on the cell surface and define an individual’s tissue type
complement system: a collection of soluble proteins found in
the blood that targets foreign cells and breaks open their
membranes
Killer T-Cell (lymphocyte)
Helper T-Cell (lymphocyte)
MHC Classifications
Class I
Class II
Class III
Class I MHC molecules span the membrane of almost every
cell in an organism
class II MHC molecules span the membrane restricted to cells
of the immune system called macrophages and
lymphocytes.
In humans these MHC molecules are encoded by several
genes all clustered in the same region on chromosome 6.
FYI: Each gene has an unusually large number of alleles
(alternate forms of a gene that produce alternate forms of the
protein).
Thus, it is very rare for two individuals to have the same
tissue type (whole set of MHC molecules of person)
Also contains a variety of genes that code for other
[complement proteins, cytokines (chemical messengers),
and enzymes] they are called class III MHC molecules.
Class I
Are present on the membrane of almost
every cell in an organism
job is to present fragments of proteins that
are synthesized inside the cell.
Killer T-Cells/Cytotoxic T-Cells have the
receptors for the class I MHC proteins, and
check them periodically
Damaged/infected cells will display
unfamiliar peptide antigens, e.g. fragments
of viral proteins, and are attacked and
destroyed
purpose is to identify abnormal body cells
Class II
Class II MHC proteins are found only on immune
cells (found only on B lymphocytes, macrophages, and
other cells that present antigens to T cells )
These cells present peptide antigens derived from
foreign digested particles (eg. From virus or bacteria)
on the membrane
helper T-cells, which have receptors for class II MHC
proteins will then stimulate immune response in Bcells.
Purpose: stop the immune system running out of
control and attacking the body's own cells
If the presented antigen is recognized as foreign by the
helper T-cell (meaning it says to attack the foreign
pathogen) then the phagocyte allowed to survive.
If it presents a self antigen (meaning it would tell the
other T-cells to attack the source of antigen.
MHC- I
MHC-II
MHC-I
Heavy chain
(alpha) and
“microglobulin”
(beta two)
Heavy is 45
kilodaltons, has
three domains +
a
transmembrane
component (40
aa) + a cytoplasmic tail (30
aa)
The three alpha
domains are
called: 1, 2, &
3
1 and 2 interact to
present
processed Ag
Process Ag is
optimally a
monomer
Microglobulin (12 kDa) associates non-covalently with 3
Microglobulin and 3 are part of immunoglobulin
superfamily
Microglobulin is the only member of the superfamily that
does not have a component linking it to a membrane
MHC-II
An alpha and beta chain, 33 kDA and
28 kDa, respecitvely.
Chains are non-covalently associated.
Each chain has two domains.
1-1 interact to present processed Ag
Processed Ag is optimally 13-18 aa
2 & 2 are part of immunoglobulin
super family
The “cleft”… where processed Ag is presented
Composed of two alpha helices plus eight beta sheets
“Two bananas on a plate”
MHC-I: 1-2
MHC-II: 1-1
Clefts can be superimposed; thus, two genetic solutions
to a common need
MHC I -Self
Cell
Normal Cell
MHC I
Presenting Normal Protein
Check
Self - OK
Helper T Cell
MHC I - Virus
Normal Cell
Cell
MHC I
Presenting Normal Protein
Virus
MHC I
Virus Infected Cell
Cell
MHC Checking
Presenting Defect Protein
Helper T Cell
Infected – Initiate Immune Response to
Eliminatate Cell
MHC II – B Cell
Antigen
MHC II
B Cell
Antibody
Presenting Self Protein
Recognition
Bacteria
B Cell
Pathogen
Degraded
MHC II
B Cell
B Cell
MHC Checking
Helper T Cell
Stimulate Antibody Production
Phagocytosis
Presenting Foreign Protein
Helper T Cell
B Cell
Targets
Pathogen
MHC II – Killer T Cell
Pathogen
(Bacteria)
Phagocyte
Phagocytosis
MHC II
Phagocyte
Presenting Foreign Protein
Helper T Cell
MHC Checking
Non Self – Activate immune response
Helper T Cell
Killer T Cell
Killer T Cell
Killer T Cell
Attack Pathogen
Conclusion Class I and II
The class I and II MHC genes encode human
leukocyte antigens (HLAs), proteins that are displayed
on the cell surface and define an individual’s tissue
type . There are many possible tissue types in the
population because each HLA exists as a large number
of varieties. Everyone's immune system is tolerant of
its own HLAs, but if foreign HLAs are detected then
the cells displaying them are attacked and destroyed.
This is why the body rejects grafts and transplants from
donors that have not been matched for tissue type.
Conclusion Class I and II
The class I and II MHC proteins also perform the
important function of antigen presentation. This is
how the immune system finds out what is happening
inside our cells even though it can only survey them
from the outside. Proteins inside the cell are broken
into short fragments and displayed as peptide antigens
by MHC proteins on the surface. This helps the
immune system to discriminate between normal (self)
antigens and those that are foreign and potentially
dangerous.
Class III
encode several components of the
complement system, a collection of
soluble proteins found in the blood that
targets foreign cells and breaks open
their membranes.
Adjacent to the class III region is a
group of genes that control
inflammation.
Further genes with various immune
and non-immune functions are dotted
throughout the complex.
MHC Genes Defects
Defects in certain MHC genes lead to
autoimmune disorders in which the
body fails to recognize self-antigens.
Ex. multiple sclerosis, some forms of
arthritis and diabetes, and inflammatory
bowel disease.
References
Twyman, Richard. "The major histocompatibility
complex ". Wellcome Trust. 16 November 2009
<http://genome.wellcome.ac.uk/doc_wtd020754.html>.
"major histocompatibility complex (MHC)."
Encyclopædia Britannica. 2009. Encyclopædia
Britannica Online. 16 Nov. 2009
<http://www.britannica.com/EBchecked/topic/359034/m
ajor-histocompatibility-complex>.