Major Histocompatibility Complex

1. Major Histocompatibility Complex
Noha Lotfy Ibrahim

2. Transplantation antigen (Histocompatibility antigen):
Antigens which cause immune response to the graft and
determine the survival of the graft.They are alloantigen
which is specific for each individual.

Several important concepts

3. MHS (Major histocompatibility antigen system )：
A group of complex histocompatibility antigens which
cause rapid and strong immunoreaction to the graft.
Mhs (Minor histocompatibility antigen system)：
A group of complex histocompatibility antigens which
cause slow and weak immunoreaction to the graft.
Several important concepts

4. MHC (Major histocompatibility complex)：
A large cluster of linked genes located in some
chromosome of human or other mammals encode
for MHS and relate to allograft rejection, immune
response, immune regulation and cell-cell
recognition.
Several important concepts

5. HLA (Human leucocyte antigen)：
The MHS of human which is associated with allograft
rejection, immune response, immune regulation and cell-
cell recognition.
HLA complex：
The MHC of human,a cluster of the genes which encode
for HLA and relate to allograft rejection, immune
response, immune regulation and cell-cell recognition.
Several important concepts

6. Skin from an inbred mouse grafted onto the same strain of mouse
Skin from an inbred mouse grafted onto a different strain of mouse
ACCEPTED
REJECTED
Genetic basis of transplant rejection
Inbred mouse strains - all genes are identical
Transplantation of skin between strains showed that
rejection or acceptance was dependent upon
the genetics of each strain

7. 6 months
Transplant rejection is due to an antigen-specific immune response
with immunological memory.
Immunological basis of graft rejection
Primary rejection of
strain skin
e.g. 10 days
Secondary rejection of
strain skin
e.g. 3 days
Primary rejection of
strain skin
e.g. 10 days
Naïve mouse
Lyc
Transfer lymphocytes
from primed mouse

8. Immunogenetics of graft rejection
F1 hybrid
(one set of alleles
from each parent)
A x B
Mice of strain (A x B) are immunologically tolerant to A or B skin
Parental
strains
A B
X
A x B
ACCEPTED
REJECTED
A B
Skin from (A x B) mice carry antigens that are recognised as foreign by
parental strains

9. Major Histocompatibility Complex
Cluster of genes found in all mammals
Its products play role in discriminating self/non-self
Participant in both humoral and cell-mediated
immunity
MHC Act As Antigen Presenting Structures
In Human MHC Is Found On Chromosome 6
Referred to as HLA complex
In Mice MHC Is Found On Chromosome 17
Referred to as H-2 complex
MHC

10. 1. Induce the differentiation and maturation of T cell
to form functional T cell repertoire
2. Present antigen to initiate immune response with
a phenomena known as MHC restriction
Endogenous Ag is presented to CD8
+
T cell by
MHC class Ⅰ molecule
Exogenous Ag is presented to CD4
+
T cell by
MHC class Ⅱ molecule
Biological function of MHC

11. T cells respond to MHC antigens
Graft rejection in vivo is mediated by infiltrating T lymphocytes
The in-vitro correlate of graft rejection is the
MIXED LYMPHOCYTE REACTION
+
Irradiated stimulator cells
from an MHC-B mouse
T cells do not respond
T
Responder cells
from an MHC-A mouse
+
Irradiated stimulator cells
from an MHC-A mouse
T
Responder cells
from an MHC-A mouse
T cells respond
MHC antigens are involved in the activation of T cells
T
TTT
TT
T
T

12. MHC-binding peptides
Each human usually expresses:
3 types of MHC class I (A, B, C) and
3 types of MHC class II (DR, DP,DQ)
The number of different T cell antigen receptors is estimated to be
1,000,000,000,000,000
Each of which may potentially recognise a different peptide antigen
How can 6 invariant molecules have the capacity to
bind to 1,000,000,000,000,000 different peptides?

13. A flexible binding site
NO because: at the cell surface, such a binding site would be unable to
• allow a high enough binding affinity to form a trimolecular
complex with the T cell antigen receptor
• prevent exchange of the peptide with others in the extracellular milieu
Is there a binding site that is flexible enough to bind any peptide?

14. A flexible binding site
A binding site that is flexible at an early, intracellular stage of maturation
Formed by folding the MHC molecules around the peptide.
Floppy Compact
Allows a single type of MHC molecule to
• bind many different peptides
• bind peptides with high affinity
• form stable complexes at the cell surface
• Export only molecules that have captured a
peptide to the cell surface
Venus fly trap

15. Genes Of MHC Organized In 3 Classes
Class I MHC genes
Glycoproteins expressed on all nucleated cells
Major function to present processed Ags to T
C
Class II MHC genes
Glycoproteins expressed on MF, B-cells
Major function to present processed Ags to T
H
Class III MHC genes
Products that include secreted proteins that have
immune functions. eg. Complement system,
inflammatory molecules
MHC

16. Class I MHC Genes Found In Regions A, B and C In
Humans (K and D In Mice)
Class II MHC Genes Found In Regions DR, DP and DQ
(IA and IE In Mice)
Class I and Class II MHC Share Structural Features:
Both have 2 polypeptide chain, single peptide binding
groove, polymorphic region include the peptide binding
region and a constant region, trans-membrane region
and cytoplasmic region
Class III MHC Have No Structural Similarity To Both Class
I and II
Class I, II and III MHC

17. Comprised of 2 molecules
a chain (45 kDa), highly polymorphic, contain Ag-
binding groove
b
2
-microglobulin (12 kDa) which encoded on
chromosome 15
Non-covalently associated with each other
Association Of a Chain and b
2
Is Required For Surface
Expression
a Chain Made Up Of 3 Domains (a1, a2 and a3)
b
2
-microglobulin Similar To a3
a1 And a2 Form Peptide Binding Cleft
Fits peptide of about 8-10 a/a long
a3 Highly Conserved Among MHC I Molecules
Interacts with CD8 (T
C
) molecule
Class I MHC Molecule

18. Comprised of a and b chains

a chain and b chain associate non-covalently
 a and b chains Made Up Of Domains
a1 and a2 (a chain)
b1 and b2 (b chain)
a1and b1 Form Antigen Binding Cleft
a and b Heterodimer Has Been Shown To
Dimerize
CD4 Molecule Binds a2/b2 domains
Class II MHC Molecule

19. Cell Membrane
Peptide
MHC class I MHC class II
MHC molecules
Peptide
binding groove

20. a1
a3
a2
MHC-encoded a-chain of 45kDa
Overall structure of MHC class I molecules
b2m
b2-microglobulin, 12kDa, non-MHC encoded,
non-transmembrane, non covalently bound to a-
chain
Peptide antigen in a groove formed
from a pair of a-helicies on a floor
of anti-parallel b strands
a-chain anchored to the cell membrane

21. b2
b1
and a b-chain of 29kDa
MHC-encoded, a-chain of 34kDa
a2
a1
Overall structure of MHC class II molecules
a and b chains anchored to the cell membrane
a2 & b2 domains have structural & amino acid
sequence homology with Ig as it has hypervariable
region in its N-terminal
No b-2 microglobulin
Peptide antigen in a groove formed from a pair of
a-helicies on a floor of anti-parallel b strands

23. CD4
+
T cell(Th)
CD8
+
T cell(Tc)
T cell
Receptor
Peptide
MHC
Class II
T cell
Receptor
Peptide
MHC
Class I
Antigen Presenting
Cell
Antigen Presenting
Cell
CD4 CD8

24. Ⅰ. Class Ⅰ gene region
Classical HLA class Ⅰ genes-------HLA-A,B,C
Non-classical HLA classⅠgenes-----HLA-E,F,G
MHC class Ⅰ chain related genes
Ⅱ. Class Ⅱ gene region
Classical HLA classⅡ genes---HLA-DP,DQ,DR
Genes associated with antigen processing
Ⅲ. Class Ⅲ gene region
Complement genes-----C4,C2,Bf
Inflammation-associated genes----TNF,HSP70
MHC

25. Class Ⅰ gene region
1.Classical HLA class Ⅰ genes
------HLA-A,B,C
Participate in endogenous antigen presenting and
immune regulation.

26. 2. Non-classical HLA class Ⅰ genes
----HLA-E,F,G
Participate in immune regulation
Associated with maternal-fetal immune tolerance.
3. MHC class Ⅰ chain-related genes (MIC)
MICA, MICB, MICC, MICD, MICE
Associated with cytotoxicity effect of NK cell.
Class l gene region

27. 1. Classical class Ⅱ genes----HLA-DP,DQ,DR
Participate in exogenous antigen presenting
and immune regulation.
Class Ⅱ gene region

28. 2. Genes associated with antigen
processing
(1)The genes associated with endogenous
antigen-processing and presenting

TAP（Transporter associated with antigen
processing
LMP（Large multifunctional proteasome or
（ low molecular weight polypeptide)
Class ll gene region

29. (2) The genes associated with exogenous
antigen-processing and presenting
HLA-DM----Processing and presenting of
exogenous Ag
HLA-DO----Inhibit the function of HLA-DM
Class ll gene region

30. Class Ⅲ gene region
1. Encoded genes of complement
------C4B,C4A,Bf,C2
2. TNF genes family
3. Heat-shock protein(HSP) genes family

31. Differential distribution of MHC molecules
Cell activation affects the
level of MHC expression.
The pattern of expression
reflects the function of MHC
molecules:
•Class I is involved in the
regulation of anti-viral
immune responses
•Class II involved in
regulation of the cells of the
immune system
Anucleate erythrocytes can
not support virus replication
- hence no MHC class I.
Some pathogens exploit this -
e.g. Plasmodium species.
Tissue MHC class I MHC class II
T cells +++ +/-
B cells +++ +++
Macrophages +++ ++
Other APC +++ +++
Thymus epithelium + +++
Neutrophils +++ -
Hepatocytes + -
Kidney + -
Brain + -
Erythrocytes - -
Table 1. Cell distribution of MHC.

32. Expression Is Regulated By Many Cytokines
IFNa, IFNb, IFNg and TNF Increase MHC
expression
Transcription Factors That Increase MHC gene
Expression
CIITA (Transactivator), RFX (Transactivator)
Some Viruses Decrease MHC Expression
CMV, HBV, Ad12
Reduction Of MHC May Allow For Immune System
Evasion

MHC Expression

33. Peptides Presented Thru MHC I Are Endogenous
Proteins
As Few As 100 Peptide/MHC Complex Can
Activate T
C
Peptide Features
size 8-10 a/a, preferably 9
Peptides Bind MHC Due To Presence Of Specific
a/a Found At The Ends Of Peptide. Ex. Glycine @
Position 2
Class I MHC Peptides

34. Peptides Presented Thru MHC II Are Exogenous
Processed thru endocytic pathway
Peptides Are Presented To T
H
Peptides Are 13-18 a/a Long
Binding Is Due To Central 13 a/a
 Longer Peptides Can Still Bind MHC II
Like A long hot dog
MHC I Peptides Fit Exactly, Not The Case With
MHC II Peptides
Class II MHC Peptides

35. 2

36. Immunological Problems & Diseases
There are several ways in which the immune system may
fail:
When the pathogen is too violent (multiplies too fast,
causes too much damage), or evades the immune
system (e.g., via mutation). Solution: vaccination or
medication.
Immune deficiencies: inherited or acquired.
Improper response to foreign (non-pathogenic) antigens:
Hypersensitivity and Allergy.
Improper response to self: Autoimmune diseases.
Rejection of transplanted tissues.
Failure to detect cancers.
[Cancer of immune cells.]

37. Immune Deficiencies
Inherited: due to:
Cellular - when the defective gene is only in T cells;
Humoral - when the defective gene is only in B cells;
Combined - when the defect is in a gene common to
all lymphocytes, e.g., RAGs (recombination activation
genes).
Acquired - due to:
Hemopoietic diseases;
Treatments: chemotherapy, irradiation;
Infection: AIDS - caused by the Human
Immunodeficiency Virus (HIV) which attacks helper T cells.
The virus gradually kills more T cells than the body can
produce, the immune system fails, and the patient dies
from infections that are normally not dangerous.

38. Immune Hypersensitivity
Hypersensitivity is an improperly strong response.
Immediate hypersensitivity:
Mediated by antibodies.
Types:
allergy - up to anaphylactic shock.
Induction of antibody-mediated cytotoxicity.
Sickness due to accumulation of immune
complexes.
Delayed hypersensitivity:
Mediated by T cells.
Hyper-activity of CTLs and macrophages.
Contact sensitivity.

39. Allergy
Allergy is an immune response
to harmless antigens.
Mechanism: IgE bind Fce
receptors on mast cells and
basophils, and causes
release of granules with
inflammatory agents.
The “real” role of IgE is
probably to fight parasites
such as helminths. (In
developing countries, people
hardly ever suffer from
allergies.)

40. What happens when the body’s lymphocytes
fail to recognize its own cells and tissues as
such?
Autoimmune diseases

41. Autoimmune diseases
Normally, the immune system does not attack the self.
This is ensured by elimination of auto-reactive
lymphocytes during their development ( negative
selection).
However, there is a large group of diseases in which the
immune system does attack self-cells: autoimmune
diseases.
The attack can be either humoral (by auto-antibodies)
or cellular (by auto-reactive T cells).
The attack can be directed either against a very specific
tissue, or to a large number of tissues (systemic
autoimmune disease), depending on the self-antigen which
is attacked.

42. What could cause the immune
system to attack the self?
Genetic predisposition
Coding for the variety of MHC molecules
Ability of a T cell to respond is determined by MHC
genotype. It has been determined by differences in
the ability of allelic variants of MHC molecules to
present autoantigenic peptides
Demographics
most common among middle aged women
Additional viral infections
Disease specific environmental factors
Aging, stress, hormones, pregnancy

43. What could cause the immune system
to attack the self?
Changes in self-antigens, that make them look like non-self to
the immune system, due to:
Viral or bacterial infection
Irradiation
Medication
Smoking …
Changes in the immune system:
Normal auto-antibodies exist; mutations in B cells
producing them may create pathogenic auto-
antibodies.
Problems with control of lymphocyte development
and differentiation.

44. What could cause the immune
system to attack the self?
Failure of autoantibodies and T cells to
recognize own cells
Autoantibodies and T cells launch attack
against own cells
Perhaps due to overactive or an
overabundance of helper T lymphocytes

45. How Are Autoimmune
Diseases Diagnosed?
Symptoms
Detection auto-Abs and very rarely Tcells
BY ELISA OR RIA
 in some case a biological / biochemical
assay

46. Causes and Treatment
Possible Causes:
Inefficient lymphocyte
programming
“Self proteins” circulate
without having been
exposed to system
(ex: sperm, eye lens,
thyroid)
Reactions between
self-antigens and
antibody production
against foreign
antigens
Potential Treatments:
Control inflammation
(ex: diabetes mellitus)
Immunosuppressive
Medication
(ex: corticosteriods,
cyclosporin,
methotrexate)
Therapeutic Antibodies
against specific T cell
molecules
(with fewer side effects)

47. Autoimmune diseases
Specific:
Juvenile diabetes (attacks insulin-producing cells)
Multiple sclerosis (attacks myelin coating of nerve
axons)
Myasthenia gravis (attacks nerve-muscle junction)
Thyroiditis (attacks the thyroid)
Systemic: Immune complexes accumulate in many tissues
and cause inflammation and damage.
Systemic Lupus Erythematosus (anti-nuclear antibodies):
harms kidneys, heart, brain, lungs, skin…
Rheumatoid Arthritis (anti-IgG antibodies): joints, hearts,
lungs, nervous system…
Rheumatic fever (cross-reaction between antibodies to
streptococcus and auto-antibodies).

49. Loss of Self Tolerance
Most self peptides are presented at levels too
low to engage effector T cells whereas those
presented at high levels induce clonal
deletion or anergy.
Autoimmunity arises most frequently to
Tissue-specific antigens with only certain
MHC molecules that present the peptide at an
intermediate level recognized by T cells
without inducing tolerance.
Immunologic tolerance: No immune response
to a specific antigen

51. Lymphocytes recognize and respond to particular
microbes and foreign molecules, i.e.,
they display specificity
A foreign
molecule that
induces an
immune
response is
known as an
antigen
RECOGNITION

52. RECOGNITION
Multiple antibodies may recognize the same
antigen by different epitopes (small accessible
portions of the larger molecule)

53. B cells produce antibodies, that are either secreted
out of the cells or remain embedded in the B cell
membranes, and that bind to antigens
RECOGNITION

54. •B cells produce antibodies, that are either secreted
out of the cells or remain embedded in the B cell
membranes, and that bind to antigens
•T cells have T-cell receptors, embedded in their
cell membranes, that bind to antigens
RECOGNITION

55. RECOGNITION
Secreted antibodies con-
stitute a group of proteins
called immunoglobulins
Antibodies have 2 heavy
chain and 2 light chain
subunits
Each subunit has a
constant region and a
variable region
The variable region can
bind to an antigen

56. Construction of antibodies (and T-cell receptors)
Millions of antigens are recognized by randomly combining
the protein products of hundreds of genes
RECOGNITION of non-self molecules
Card analogy: although there are only 52 cards in the
deck, random combinations can produce an
enormous number of different hands

57. In a healthy immune system, as B and T cells
mature they are destroyed by apoptosis if they
attack self molecules
RECOGNITION of self molecules
Healthy, mature B and T cells then have the
capacity to distinguish self from non-self
molecules

58. Almost all cells in an individual human’s body have
major histocompatibility complex (MHC)
glycoproteins embedded in their cell membranes
RECOGNITION of self molecules
Class I MHC molecules are found on
almost every nucleated cell
Class II MHC molecules are restricted to a few
specialized cells, including macrophages,
dendritic cells, B cells, etc.

59. MHC glycoproteins migrate to the cell
membrane after they are produced
RECOGNITION of self molecules
MHC glycoproteins pick up molecules from the
cytosol that are presented at the cell’s surface
T cells bind to MHC glycoproteins and
the molecules they present
An individual’s own MHC glycoproteins, and
molecules of its own body that the MHC
glycoproteins present, are treated as self

60. Helper T cells bind to cells that carry
Class II MHC glycoproteins
RECOGNITION of non-self molecules

61. ATTACK & MEMORY
The B and T cells that first recognize a given foreign antigen
are short lived, whereas immune memory cells can have long
lifetimes
Illustrated
here for B
cells, but the
process for
T cells is
similar

62. MHC Association with Autoimmune
Disease
The level of autoantigenic peptide presented
is determined by polymorphic residues in
MHC molecules that govern the affinity of
peptide binding.
 Autoimmune diseases are associated with
particular MHC genotypes.

63. MHC Association with Autoimmune
Disease
Only a few peptides can act as autoantigens
so there are a relatively few autoimmune
syndromes.
Individuals with a particular autoimmune
disease tend to recognize the same antigens
with the same MHC.