21. Immunotolerance Flashcards
Define Immunotolerance?
Lack of immunological reactions towards and antigen
What are three examples of tolerance?
Tolerance to self antigens
Tolerance to Environmental Antigens
- Failure leads to coeliac etc
Tolerance to antigens that previously invoked and immune response
- Allograft
What are the two types of T cell tolerance and where do they develop?
Central Tolerance - Thymus - Self reactive cells deleted - Thymic education Peripheral Tolerance - Peripheral tissues - Self reactive cells are subsequently incapable of responding to those antigens
What are the two ways central tolerance of T cells is achieved?
1) Thymic deletion of self reactive T-cells
2) Generation of Tregs
What is negative selection?
T cells that bind with high avidity to self antigens are deleted
Results in CD4 and CD8 cells being self-tolerant
How are self-reactive T cells deleted?
Apoptosis via Bim
What self-antigens are located in the thymus?
Lots of antigens distributed in tissues
Even peripheral tissue antigens are expressed in the thymus so immature T cells reactive can be deleted via AIRE
What is AIRE?
Autoimmune Regulator Protein
Causes self antigens - organ specific antigens to be transcribed at a low level in the thymus. allowing presentation to maturing T cells
What could be the cause of a multiorgan autoimmune disease then?
You guessed it!!
Mutations in the AIRE
- Autoimmune polyendocrine syndrome (APS)
- Characterised by antibody + lymphocyte mediated injury to multiple endocrine organs
What is positive selection in the thymus?
If TCR binds with low affinity - self - MHC molecule
It is rescued from cell death
What order do the selections go in?
Positive selection
Negative Selection
CD4 cells that are self reactive but arent deleted, what do they develop into?
TREGs!
Express CD25 and FoxP3
Inhibit responses against self tissues in periphery
Does deficiency of AIRE prevent development of thymic Tregs?
No
So what the hec determines the fate of self reactive Tregs?
Dunno
So t cells emerging from the thymus, how do they feel about self MHC and self peptides?
Low enough affinity so they are not self reactive
Some probablity of high affinity interaction with self - MHC + foreign peptide
If a T cell coming from the thymus has high affinity for self-MHC + self peptide, what sort of cell is it probs gonna be?
Treg (CD25 + FoxP3)
~10% of CD4 T cell population
What are the 3 ways in which T cells can develop peripheral tolerance?
Anergy
Supression
Deletion
What is the mechanism of T cell anergy?
Recognition of TCR + costimulators (B7-1, B7-2 by CD28)
If CD4 T cell exposed to antigen in absence of costimulation, may be incapable of responding to antigen
When T cels recognise self antigens, may engage inhibitory receptors of CD28 FAMILY (CTLA4), terminates T cell response
What growth factor do Tregs primarily use?
IL-2 have IL-2 receptor (CD25) not IL-7
What transcription factor do Tregs express?
FoXp3
What is IPEX?
A rare autoimmune disease in humans
Immunodysregulation Polyendocrinopathy Enteropathy X-Linked syndrome
Mutation in FOXP3 gene
Fatal - Hectic autoimmunity
- Commonly seen as type 1 diabetes
What are some other examples of autoimmune phenomena?
Coombs, thrombocytopenia, tubular nephropathy
What are the mechanisms of Treg action?
Express high levels of CTLA-4
- Inhibit APC stimulation of T cells by binding B7 via CTLA4, blocking CD28
Consume IL-2
- Starves responding T-cells of this factor
Produce high levels of IL-10
- Inhibits IL-12 - mediates IFN-y
- Inhibits expression of costimulators and class 2 MHC molecules on APC
Produces high levels of TGF-B
- Inhibits proliferation and effector functions of T cells
- Regulates differentiation of Th1 and Th2 cell subsets
- Inhibit macrophages
Do Treg cells inhibit the proliferative responses of other T cells in vitro?
Yes
What are the primary cellular markers that define Treg cells?
CD25+ and CD4+
What are the primary cell markers that define TH cells?
CD4+ and CD25-
Is suppression of proliferation by CD4+ and CD25+ Tregs contact dependent?
Yes
How is peripheral tolerance determined by deletion?
T cells that recognize self antigens in absence of inflammation, or those that are repeatedly stimulated by antigens undergo apoptosis
What are the two major pathways to cell deletion?
Mitochondrial (intrinsic) pathway
Death Receptor (Extrinsic) pathway
What is the mitochondrial pathway to cell deletion?
Normally, costimulation results in expression of bcl-2 and bcl-Xl, preventing apoptosis
Absence of co-stimulation, results in low bc-2 and bcl-XL exression = Bim activation promoting apoptosis
What is the Death Receptor (extrinisc) pathway to cell deletion?
When T cells repeatedly stimulated
Expression of death receptors (FAS)
Expresses FasL ligand
Triggers cascade of caspases = apoptosis
Could the death receptor/extrinsic pathway be present in B cells?
Yes
What are the two types of B-cell tolerance?
Central Tolerance
Peripheral Tolerance
What is B-cell central tolerance?
Mechanism involving changing or deletion of self reactive B cells in the bone marrow
What is B-cell peripheral tolerance?
Mechanism rendering cells unresponsive or apoptotic due to the recognizing self antigens in absence of helper T cells
What can B cells undergo when becoming tolerant in the bone marrow (central tolerance)?
Receptor editing
Deletion
Anergy
What is receptor editing in B cell central tolerance development?
If B cells recognize self antigens with high avidity, they can reactivate RAG1 and RAG2 genes, initiating a new round of VJ combination
New light Ig chain expressed - creating new specificity
What is deletion in B cell central tolerance development?
Failure of receptor editing leads to B cell apoptosis
We dunno though
What is Anergy in B cell tolerance development?
If B cells recognise self antigens, they become functionally unresponsive. Leave bone marrow in anergic state
What occurs in peripheral B cell tolerance?
B cells that encounter self antigens in peripheral tissues become anergic or apoptotic
May also express inhibitory receptors that prevent B cell activation (CD22)
The abundant knowledge we have about tolerance of the immune system, how can we apply this knowledge clinically?
Suppress organ transplant rejection
Treating patients with autoimmune disorders
- LUPUS + type 1 diabetes
Asthma and other “immediate”-type allergies
plz save
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