Tolerance and Autoimmunity Flashcards
How is the immune system able to accomplish tolerance?
- the immune system must recognize all pathogens including all pathogens that may evolve but it should not elicit response against self.
- this is possible bc of the enormous diversity in lymphocyte antigen receptors (T and B cells) which exists bc of random DNA rearrangements on receptor gene segments. However. Sometimes autoreactive lymphocytes are generated
- the immune system has developed ways to supress these autoreactive lymphocytes and this is known as immunologic tolerance. and when this tolerance fails that is known as autoimmunity.
Why is immunologic tolernce important? and list 3 problems that can occur when tolerance is lost
Abnormal immune responses to self-antigens or non-pathogen antigens can lead to disease (autoimmune disease)
- autoimmunity: loss of tolerance to self antigens
- allergy: immune responses to environmental antigens (that really should be tolerated)
- Transplant rejection and graft vs host disease: immune responses in transplantation
what is the difference in location between central tolerance and peripheral tolerance
- Central tolerance occurs in the igenerative lymphoi organs (bone marrow and thymus)
- peripheral tolerance occurs in the peripheral lymph tissues (lymph nodes, spleen, MALT, peripheral tissues)
What is central tolerance for T cells and how is it different for B cells?
- a mechanism of tolerance that occurs when immature lymphoctes in the generative lymphoid organs encounter an anitgen
- T lymphocytes that recognize high avidity (binding) self-antigens are killed through apoptosis so they can’t cause autoimmune rxns.
- except for T regulatory cells which are self-reactive CD4 T cells that suppress immune responses and express Foxp3 (the breaks)
- If a B cell however binds to self with high avidity it can undergo receptor editing and the light chain of the immunoglobin locus rearranges to form a new antibody (or it could just be deleted like a T cell)
- SO: Central tolerance is when the body tries to make sure your T cells won’t attack you. Occurs in generative lymph. T cells atomatically apoptose when to bind tight to self and B cells get another chance to edit. except for T reg which you want to bind to self bc those are the breaks .
What is peripheral tolerance?
- when self-reactive T/B cells encounter self antigen in the periphery (bad) the body tried to stop these T cells through 3 mechanisms
- Apoptosis:
- Fas/Fas ligand
- Cytokine withdrawal
- AICD
- Anergy: functional inactivation of T/B lymphocyte
- Suppression: lymphocytes suppress other lymphocytes (ex: Treg supressing the autoreactive T cell)
- Apoptosis:
Describe the role of the AIRE gene including what would happen if you were missing it. What disease is associated with this?
AutoImmune Regulatory Gene (AIRE)- the transcription factor that induces expression of self-antigens by the thymic medullay epithelial cells (how the body is able to make self ie liver to show to the immature T cells so they can be checked for autoreactivity)
- Failure of central tolerance: without AIRE you can’t express self in the thymus so central tolerance doesn’t occur. 1. Self-reactive T cells are not deleted and 2. Self-reactive regulatory cells are not generated.
- Disease: APECED
- autoimmune hypoparathyroidism
- autoimmune adrenal insufficiency
- candidiasis
Describe what is necessary for T cell activation
2 signals!
-
TCR seeing antigen on MHC (on APC)
- MHC is on the APC and TCR is on the T cell
-
Co-stimulation: CD28-B7
- CD28 is on the T-cell and B7 is on the APC
- Note B7 is also called CD80/86
- Bc B7 is on the APC it is upregulated by an encouter w a microbe
- When APCs lack co-stimulatory molecules (B7) leads to anergy
What is anergy?
- Anergy is the functional inactivation of lymphocytes, occurs when APCs lack co-stimulatory molecules (like B7 which is supposed to bind to CD28 on the T cell)
- When APC lacks B7 ( which normally binds to CD28)
- When you have CTLA-4 instead of CD28 (CTLA-4 binds and inactivates B7)
- either way you are doing the same thing. you are preventing T-cell activation by stopping co-stimulation
- OR PD-1 checkpoint inhibitors which are induced in T cells and are inhibitory.
WHat happens when PAMPS are recognized by PRR compared to self being recognized
PAMP:PRR = more B7 on ACP surface so ACP can activate T cell
self=anergy
PAMP=Pathogen Associated Molecular Pattern
PRR= Pathogen recognition receptor (ex: TLR, or Nod etc)
Another component to peripheral tolerance is deleting T/B cells after an immune response is over. How does this happen (3 mechanisms)
- Activation-Induced Cell Death: repeated activation of mature T cells by self-antigen triggers apoptosis in the T cell, resulting in removal of those slef-reactive lymphocytes.
- Fas/FasL CD4+ T cell activation upregulates expression of the Fas “death receptor” and its ligand FasL. Fas-FasL binding is a potent activator of cellular apoptosis
- Cytokine withdrawal: Properly activated T cells (TCR+CD28) express IL-2 which is a growth and survival factor. When the immune stimulus is gone IL-2 isn’t made anymore and there is apoptosis
What disease is associated with mutation in Fas or FasLigand?
Autoimmune lymphoproliferative syndrome (ALPS)
- widespread lymphadonopathy, splenomegaly, and autoimmune cytopenias (hemolytic anemia and thrombocytopenia)
- Without active Fas/FasL you can’t release pro-apoptotic signals resulting in lymphoyte cell death and you get a build up of lymphocytes
- increased IgG, IgA, IgM and CD4-/CD8- (naive T cells)
- Failure of peripheral tolerance
WHat are Treguatory cells and how are they involved in peripheral tolerance
- They express transcription factor Foxp3
- generated by self-antigens in the thymus (remember AIRE, they need AIRE)
- Activated in periphery by self-antigen and IL-2
- Utilize multiple mechanism to supress immune
- contact dependent: Treg bind to mature T cells to induce inhibitory signaling
- contact independent: Treg secretes cytokines that inhibis T cell activation
What diseases is associated with a lack of T regulatory cells
IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
- mutation in Foxp3 therefore loss of Treg cells
- boys in infancy (bc X-linked)
- Hypergammaglobulinemia, very high IgE levels
- inflammatory bowe syndrome, eczema, food allergies, type I diabetes, thyroditis, autoimmune hemolytic anemia and thrombocytopenia-death w/o bone marrow transplant (basically just your immune system is out of control and attacking everything)
Are there tolerogenic self antigen and immunogenic foreign anitgens in the generative organs?
Tolerogenic self antigens: yes
Immunogenic foreign: no
Do tolerogenic self antigen and immunogenis foreign anigens use presentation with second signals? (co-stimulation)
Tolerogenic self antigens: no
Immunogenic foreign: yes
Describe the pathology of arthritis
- pathology-panus formation and aggregates of mononuclear cells (lymphocytes and macrophage)
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