Tolerance is the remarkable process to tolerate the body against the self antigens.

Bone marrow and thymus and when tolerance is generated to recognize against self antigens and
it is generated in the

MHC molecules
1 MHC Class 1
They are present in every nucleated cell in our body and this molecule decide weather the cell is
self or non self in absence of these molecules the cells are non self and can be recognized as
mutated, pathogenic or cancerous cell
They consists of large alpha chain . this consist of alpha 1, alpha2 ,alpha 3 domain with that there
is beta 2 domain that is genetically chromosome no 15
MHC Class 1 are molecular identity / molecular pattern that are very specific in each individual
. they are expressed on chromosome no on 6 A C, B locus and .
1 They undergo spontaneous arrangement and produce hyper variability that produces variety
of mrna that results the formation of variety of molecules each having distinct structures based
on their groove
2: They are responsible for allelic specificity that varies on individual genetics for example
person x has Mhc class A1A3 combination and the other has A4A8 combination so molecules
are hyper variable and also allelic specific .
They also have identical constant point that are same in every person . this constant region is
responsible for interaction with cd8 molecule
The hyper variable region of molecule that has specific group is responsible in antigen binding.
This will vary molecule to molecule,
Now we will examine the inheritance concern with the production of MHC CLASS 1
Person x Identity card class 1 Person z Identity card class 1
M P M P
A3,C32,B22 A27,C4,B38
A7,C19,B5 A7,C21,B15

Class 2 molecules
They are only expressed in antigen presenting cells : macrophages, dendritic cells , Langerhans
cells.
Different cells express different sets of gene
Antigen presenting cells
Class 2 has d region consists of dr , dq , dp region .there are many alleles of d region. For
example x person has dr2 and z person has dr4
So there are total 12 molecules on tissues out of which 6 are class 1 and 6 are class 2
So the person immune system having a specific genetic makeup of class 1 and class 2 will
only recognize those genetic make up as self and other than that non self
MAJOR HISTO COMPATIABLITY
If person X is diagnosed with renal failure So person Y will donate the kidney tissue to person
x but person x immune system is not histo compatible with the donate tissue of person y and
considered it foreign or non self
So on this why immune system is a major hinderance in transplantation so the transplanted
patient is given immunosuppressors to stop the immune response during transplantation in this
why person get transplanted but it highly gets vulnerable to diseseases as its immune system is
suppressed
Function of class 1 :

So the Mhc molecules report the indigenous proteins made by the cell on the surface of
the cell so that the immune system will know that the cell is normal and its properly making
proteins and its our body own cells proteins
Every cell is visited by immune cells like natural killer cells if natural killer cells find
that the cell has presented the MHC class 1 molecule so it gets happy and not react. They ensure
that the class1 are our own body cells. If grafted tissues has different class 1 molecules so the
natural killer cells study the grafted cells and learns that the grafted cells has not self class 1
molecule so natural killer cells will destroy the grafted tissue.
Some times some virus try to be clever , so lets say that the virus enters in the cells and
the viral infected cells viral proteins will be represented by class 1 molecule to the cell surface,
so the natural killer cell now that the cell is attacked by virus , some virus are really smart, like
hiv they produce some special proteins and switch off the class 1 genes and the virus will infect
the cell and there will be no class 1 so the cell fails to show the expressed proteins on the surface
and in this way the virus escapes immunity, the proteins are are not reported and still the natural
killer cells destroys the cell.
When a cell become malignant , it produces mutant and altered proteins they will bind with class
1 and gets reported
Some cancer cells switch off the class 1 gene and the immune system will be blind as the cell
proteins are not represented. So all of our cells must represent our own class1molecules .

1 virus , 2 malignant cells 3 transplanted cells

T Cells RECPETORS
THEY FUNCTION TO RECOGNIZE PROTEINS
ALL THOSE TCR DURING THE DEVELOPMENT AND MATURATION OF T CELLS ,
THAT ARE FAILED TO RECOGNIZE OUR SELF PROTEINS ARE DESTROYED.
WITHIN THE THYMUS , ONLY THOSE T CELLS ARE ALLWOWED TO GO THAT
SHOW TOLERANCE AGAINST SELF PROTEINS. SO EVERY PERSON HAS POOL OF T
CELLS THAT SHOW SELF TOLERANCE .
SO IF THE CELL IS IFECTED BY VIRUS THE TCR WILL COME AND THE CELL WILL
BE REPORTED AND THE CD8 MOLECULE ENGAGE TO CLASS 1 CONSTANT
DOMAIN AND SIGNAL THE CD3 TO ACTIVATE CYTOTOXIC T CELL
T CYTOTOX CELLS AND IT WILL RELEAESE PERFOREIN PROTEIN TO THE
TARGER CELL AND THEY FUNCTION TO PERFORETE THE CELL MEMBRANE AND
THE MEMBARNE INTEGRITY WILL BE LOST. SO MULTIPLE PERFOREIN DRILL THE
INFECTED CELL MEBRANE AND THE CELL WILL NOT SURVIVE . AND IN
ADDITION THEY WILL FURTHER RELEASE PROTEINS CALLED GRANZYMES
THEY ARE VERY DANGEOUS AND ACTIVATATE APOPTOSIS
WHENEVER OUR IMMUNE SYSTEM

Class 1 MHC CLASS 2 MHC

1: CLASS 1 IS PRESENT ON EVERY CLASS 2 MOLECULES ARE PRESENTED

NUCLEATED CELL ONLY ON THE MEMBRANES OF
ANTIGEN PRESENTING CELLS
2: THEY BIND WITH ENDOGENOUSE THEY BIND TO EXTRACELLULAR
 SYNTHESIZED PROTEINS PEPTIDES FRAGMENTS
3: CALASS 1 HAS SINGLE ANTIGEN CALSS 2 HAS ANTGEN BINDING SIDE
BINDING SITE PROVIDED BY ALPHA CHAIN AND
BETA CHAIN
4:THEY HAVE ALPHA CHAIN CODED ALPHA AND BETA BOTH CHAIN
BY MHC REGION BUT BETA CHAIN CODED BY MHC REGION
CODED BY CHROMOSE NO 15
6:THEY PRESENT ANTIGEN TO THEY PRESENT ANTIGEN TO T HELPER
CYTOTOXIC T CELL CELLS

BIOLOGICAL IMPORTANCE OF CALSS 1 AND CLASS 2

1: play role in antigen presentation
2: role of HLA system in auto immune disease for example HLA B27, HLA DR4 ( rhemoutide
arthritis
3: Transplantation
4: they are also important in developing immune response for example person 1 has class 2
molecules that love to stick with pollen antigen and then results type 1 hyper sensitivity allergic
asthma they activate the t helper cells that link b cells and they produce plasma cells produce
ige antibodies on mast cells

TOLERANCE

1: antigen specific receptors are generated prior to the encounter of lymphocytes with specific
antigens
1:our immune system can generate clones that can virtually recognize any antigen in the
universe
Lymphocytes having receptors against self antigens are also generated in our body
This lymphocytes having receptors against our own body and are called auto reactive self
reactive lymphocytes
Our immune system has the ability to react against enormous and diverse foreign antigens while
it is tolerant to the self antigens
The state of not relating against self antigens is known as self tolerance
If this phenomena failed it is called auto immune diseases
Self tolerance
1: central tolerance
Central refers to the primary lymphoid organs where development of lymphocytes takes place
These organs are thymus and bone marrow
These provide environment and molecular signals for the maturation of lymphocytes
Tolerance induced during early developmental of lymphocytes
Includes mechanisms that eliminate most auto reactive b and t cell development but central
tolerance is not proof

Central t cell tolerance

t cell are originated in the bone marrow and later goes to thymus where they get mature and and
produce t cell receptors , developing t cells in the thymus is known as thymocytes
they generate randomly antigenic specificity
t cell only recognize peptide antigen along with MHC molecules
known as peptide antigen mhc complex
explanation:
when precursor T cells from bone marrow enter the thymus they produce t cell receptor of
random antigenicity
during maturation of t cells in thymus they undergo elaborate screening process
Non selection , positive selection , negative selection
All nucleated cell express MHC Class1 molecules ,
Bone marrow derived dendritic and macrophages in the thymus express MHC Class 2 molecules
In the thymus the immure t cell react with self peptide molecule and develop tolerance
According to scientists the fate of the t cells depends on
The strength which immature t cells interact with self peptide MHC molecules
NON SELECTION
If immature t cells fails to recognize and bind self antigen molecule, they undergo programmed
cell death or apoptosis , most of these cells have non functional TCRS and lack receptors
recognizing MHC MOLECULES
POSITIVE SELECTION:
If t cells successfully recognize and bind to self peptide MHC molecules a survival signal is
generated to the nucleus of t cells
Binding is not too strong nor too weak
T cells learns to focus on self MHC molecules

NEGATIVE SELECTION
: T cells whose TCRs bind too strongly to MHC complexes, and will likely be self-reactive, are
killed in the process of negative selection
These t cells undergo apoptosis
Such t cells are potential auto reactive cells

NOTE
All self antigen are not expressed in the thymus
Some self antigens appear in other tissues or at other stages in the development of cells

Peripheral tolerance:
Active mechanism:
Control mechanism
 Females immune
system gets tolerable to
antigens, it gets
tolerogenic,
tolerogenicity increases,
Antigenicity decreases.
Tolerance can also be
induced to non self
antigens after birth.
 Tolerance is both
antigen and self clone
specific
So the fetus get exposed
to diseases?
Immune competent or
tolerant
B cell : receptor editing
Auto reactive clones
Clonal deletion
 Allergy
Immune regulation
Infection:
Antigen recognition
Dendritic cell : in case
injury antigen
presenting cell
activation
Antigen presentation
cell engulfs and
 represent the antigen
along with MHC
PRR recognize the
antigen
When attachment cells
receptors are present on
the surface of host .
foreign / self
 We study PRR and
recognize pathogens
cytokines release .
Dendritic cell release
cytokines , chemokines
released, maturation
results . PRR respond
to pathogens,
costimulatory
molecules and present
 the antigen to t cells,
PPR distinguish
foreign/ self antigens.
Plant pathogen binding
receptors but we don’t
have PPR to respond
and that agent is non
infectious
It is a foreign particle
and also engulfed but
 due to it is not bound
with PRR so it cant
cause infection.
Signal 1
If there is no infection,
Auto reactive signal,
costimulatory
molecules are absent
PRR
So we can say the alle
The cells that
Immune deviation: less harmful response either shifting those
To immune privilege areas, immune suppresser drugs, cytokines,
Treg cells negative regulation.
Isotype , tissue method
HLA typing
Immune privilege