Describe AIRE
AIRE is a transcription factor in mTEC that controls the expression of self-antigens in thymic medullary epithelial cells. Essential for negative selection/self-tolerance.
What happens if AIRE gets deleted or inhibited?
Negative selection/self-tolerance does not occur possibly leading to autoimmunity.
Ex. APECED
Describe APECED
An AR autoimmune disorder caused by mutations in AIRE gene. Its clinical presentation varies greatly.
Classic Triad:
- mucocutaneous candidiasis
- adrenal failure
- hypoparathyroidism.
What is the fate of CD4 T cells that are self-reactive during negative selection?
- Apotosis
2. Differentiate into regulatory T cells (“natural Treg”)
What are the lymphocyte markers of Treg T cells?
- CD3+CD4+CD25high
2. FoxP3+
What cytokines are secreted by Treg?
IL-10 & TGF-B
What are the three outcomes of peripheral T lymphocyte (Induced) tolerance?
- Anergy
- Suppression
- Deletion/Apotosis
What costimulator molecules are expressed on T cells and APCs, respectively to assist in activation?
CD28:B7
What inhibitory molecules are expressed on Treg cells and APCs, respectively, to assist in suppression?
CTLA4:B7
What is a monoclonal antibody against CTLA4 to enhance T cell activation and antitumor immunity?
Ipilimumab
What drug is CTLA4 agonist that interrupts CD-28 mediated costimulation, causing T cell energy?
Abatacept (bind to B7)
What are the components of Abatacept?
- human CTLA4
2. Fc region of IgG1
What is another name for B7 protein on APCs?
CD80/CD86
What cytokines are required to induce peripheral T reg?
- IL-2
2. TGF-B (allows Fox P3 gene expression of Treg)
What are 3 mechanisms of peripheral T reg in suppression?
- Production of inhibitory cytokines (IL-10, TGF-B)
- Expression of CTLA4
- Consumption of IL-2
Describe IPEX
An XR disorder caused by mutations in FoxP3 gene.
Classic Triad:
- Enteropathy (diarrhea)
- Dermatitis (Eczematous rash)
- Endocrine disease (diabetes or thyroid-related)
What are 2 mechanisms of apoptosis in peripheral T lymphocytes
- Intrinsic Cell Death: Apoptotic inducing proteins are released from mitochondria (within T cell).
- Extrinsic Cell Death: Apoptosis induced by the interaction of FasL (death receptor ligand) and Fas (death receptor) on T cells.
Describe ALPS
A disorder caused by mutations in Fas/FasL gene leading to defective apoptosis causing chronic accumulation of lymphoid cells.
Clinical presentations:
- Enlarged tissues (splenomegaly, hepatomegaly, lymphadenopathy)
- Blood cell autoimmunity (hemolytic anemia, thrombocytopenia, neutropenia)
- Increased risk for lymphomas
What are the three outcomes of Central B Lymphocyte Tolerance?
- Apoptosis/Deletion
- Anergy (reduced receptor expression/signaling)
- Receptor Editing
What immunoglobulin is produced by Marginal Zone B Cells when they become plasma cells?
IgM
What is receptor editing?
The process in which B cells can go through to become Non-Celf Reactive B cells.
What are the three outcomes of Peripheral B Lymphocyte Tolerance?
- Apoptosis/Deletion
- Anergy
- Suppression (has inhibitory receptors)
- Same outcomes as Peripheral T Lymphocyte Tolerance
What are three single-gene defects that cause autoimmunity that we have to know?
- AIRE (APECED)
- FOXP3 (IPEX)
- FAS (ALPS)
What are 2 mechanisms of microbial/environmental-induced autoimmunity?
- Induction of costimulators on APCs
- Microbes activate APCs to express costimulator, and APCs present self-antigens instead. This can cause self-reactive T cells to get activated leading to autoimmunity. - Molecular Mimicry
- Microbial antigens may cross-react with self antigens (mimicry) and initiate self-reactive T cells that attack self tissues.
