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Discuss the mechanisms of immune tolerance (central tolerance (primary or…
Discuss the mechanisms of immune tolerance
What is immune tolerance
process by which the immune system differentiate between self and non-self antigens
How does self tolerance happen
self tolerance happens in two steps central tolerance and peripheral tolerance
central tolerance
primary or central lyphoid organs where development of lymphocytes
either bone marrow or thymus. This where T and B cells express antigen receptors
organs provide growth factors and other molecular signals for lymphocytes maturation
central T cell tolerance
T lymphocytes produced in the bone marrow and mature in the thymus
thymus rearrange their T cell receptor genes
T cell recognise peptide antigens as peptide MHC complex
binding them the peptide displayed on the target cell
precursor T cells from bone marrow enter the thymus
T cells mature and express TCRs of random antigenic specificity
B cell central tolerance
B cell made and matured in the bone marrow
Mechanisms
receptor editing
antigen receptor of auto-reactive immature B cell modified
immature B cells have the ability to rearrange their immunoglobulin genes doe to the V and J gene segments in the light chain locus
old light chain is replaced a new light chain . if the new B cell receptor is generated by this light chain gene rearrangement is non-reactive
clonal deletion
B cell receptor produced is still self reactive further light rearrangement is done by the immune system
rearrangement can't be done apoptosis. if this happens using apoptosis this is called clonal deletion
anergy
self reactive B cells that bind to movement self antigen are made unresponsive by the central B cell tolerance
further development is arrested this state in which immature self tolerance B cells become inactivated to their specific antigen
B cells enter peripheral circulation where they live for a few days and later die by apoptosis
Peripheral tolerance
secondary organs this includes lymph nodes and the spleen
mechanism
capture pathogen these organs are the sites where the lymphocytes come in contract with foreign antigen are initiated
Peripheral T cell tolerance
auto-reactive T cells do not attack self tissues
Mechanisms
peripheral clonal deletion
infection cytokines are generated which are recognised by pattern recognition receptors
cytokines are release which induces APC (denritic cells)
express co-stimulatory molecule on their surface once activated they collect the antigen from the site of infection
auto-reactive T cell whose T cell receptor is specific for the self antigen displayed by dendritic cell
T cell receiving first signal for activation
no second signal because dendritic cells are absent which lead apoptosis there is no immune response
Immune deviation
harmful immune response is converted to less harmful immune response
Immune privilege
anatomical regions that less subject to immune responses e.g. CNS and brain
Anergy
some of the T cells survive but they become inactivated cannot differentiates into effector cells
lymphocyte remain inactive even in contact with it's specific antigen is known as anergy
this is the absence of signals for complete T cell activation
regulatory T cells
control the responses of activated T cells regardless of the antigenic specificity they block the proliferation of these cells and secrete immunosuppressive cytokines
Immunesuppressive cytokines
interleukin 10 and transforming growth factor beta have immunesuppressive effects for example these cytokines
inhibits macrophages activation inflammatory cytokine secretion down regulates interacellular signalling in responding T cell blocks APCs function
Peripheral B cell tolerance
B cells do not encounter all the self antigens in the bone marrow
B cells come in contact with tissue specific cell surface proteins and secreted proteins
B cell activation and they migrate to the peripheral lymphoid organs and bind to a multivalent self antigen strongly they go through apoptosis
if they don't bind they go on to mature
Immature T cells screening
negative selection
T cell receptor bind to self peptide self MHC molecules very strongly
trigger an autoimmune reaction which leads apoptosis
dead cells are phagocyte by macrophages in the thymus
non-selection
immature T cells fail to recognize and bind self peptide on self MHC molecules undergo apoptosis
T cells will have non- functional TCRs or lack receptors recognising MHC molecules
positive selection
immune T cells recognise these peptide MHC molecule a survival signal is conveyed
to the nucleus of the immature T cell and cell divides and grows further
interaction is not too strong or weak
after positive selection
t cell move from the thymus and migrate to the secondary lymphoid organs
self antigens are not expressed in the thymus appear in other tissues
auto-reactive T cell escape central tolerance and migrate to peripheral lymphoid organs