Tolerance/Autoimmunity Flashcards
1
Q
Central v Peripheral Tolerance
A
- Central tolerance - developed in primary lymphoid organs in maturation (bone marrow and thymus)
- If immature B or T cell recognizes self antigen they…
- Apoptose
- B cells can recombine - receptor editing
- T cells can become regulatory T cells - Peripheral tolerance - when mature lymphocytes encounter antigen in secondary lymph tissues or peripheral tissues
- Can result in…
- Anergy (functional inactivation)- alive but incapable of responding to antigen
- Apoptosis
- Suppression by regulatory T cells
2
Q
2 Paths of T Cell Central Tolerance
A
- Negative selection- apoptosis of self-reactive CD4+ and CD8+ cells that interact strongly w/ self peptide on MHC class II or I respectively
- Some immature CD4+ cells that are self-reactive do not die —> become CD4+ regulatory T cells —> move to peripheral tissues
3
Q
AIRE
A
- autoimmune regulator protein; responsible for expression of specific peripheral tissue antigens in the thymus
- **AIRE mutation —> autoimmune polyendocrine syndrome
4
Q
T Cell Anergy
A
- Binding antigen w/o co-stimulation —> TCR loses ability to transmit signals (sometimes due to ubiquitin ligases modifying proteins of pathway or tagging them for destruction)
- May also lead to inc expression of inhibitory receptors (PD-1 and CTLA-4) which will inhibit activation from later antigen recognition
5
Q
Regulatory T Cells
A
- Generation and proliferation of regulatory T cells depends on IL-2 and TGF-beta
- Have Foxp3 transcription factor (mainly in thymus but also in secondary lymphoid tissues)
- Formed if intermediate affinity for self antigen (high affinity die)
- 3 mechanisms of action
- CTLA-4 receptors bind B7 and delete it —> reduce co-stimuation of other T cells
- Have IL-2 receptors to use up IL-2 so it cannot be used to active other T cells
- Produce IL-10 and TGF-beta to prevent activation of other T cells, macrophages and dendritic cells
6
Q
CTLA4 and PD-1
A
- CTLA-4 - (expressed transiently on activated CD4+ cells and constantly on regulatory T cells)- also binds B7 but w/ higher affinity than CD28 so when B7 is low it only binds CTLA-4; inactivates T cells by blocking and removing B7 molecules and potentially delivering inhibitory signals to T cell
- PD-1 - (expressed on CD4+ and CD8+ after antigen stimulation) - has ITIM (inhibitory) motif —> inhibitory intracellular signaling
7
Q
2 Mechanisms of Peripheral T Cell Apoptosis
A
- Antigen recognition w/o co-stimulation —> production of pro-apoptotic proteins —> proteins leak form mitochondria —> caspase activation (normally co-stimulation cancels this out w/ production of anti-apoptotic proteins but that is absent here)
- Antigen recognition w/o co-stimaultion —> expression of death receptors + ligands —> also leads to activation of caspases (common example - Fas binds Fas-ligand on T cells
**Defects in apoptosis are termed autoimmune lymphoproliferative syndrome
8
Q
Central B Tolerance
A
- Receptor editing
- Re-express RAG genes —> resume light chain recombination —> new Ig light chain added to existing heavy chain
- Common (happens in 25-50% B cells during maturation)
- If editing fails…apoptosis of B cells with high affinity for self
- Anergy
- If bind self w/ low avidity, B cells survive but receptor expression is reduced; becomes functionally unresponsive
9
Q
Peripheral B Tolerance
A
- Incapable of responding to self antigen in peripheral tissues b/c…No T cell help as second signal (helper T cells eliminated or not responsive to self antigen) —> these B cells become anergic —> leave lymphoid tissue and die in periphery w/o survival stimuli
- Somatic hypermutation during immune response in germinal centers —> receptors for self antigen
- Usually die b/c no follicular helper T cells rescue them OR the Fas of germinal B cells bound by Fas-ligand of T cells and kills these B cells
10
Q
Tolerance to Commensal Bacteria
A
- Natural bacteria and viruses in our GI tract, respiratory tract and on skin
- Mature lymphocytes do not react to microbes in gut b/c…
- Separated from immune system by epithelial layer in some cases
- Abundance of IL-10 producing regulatory T cells
- Some dendritic cells receive inhibitory signals from binding of certain TLRs rather than activation
11
Q
4 Mechanisms of Tolerance to Fetal Antigens
A
- Generation of peripheral Foxp3+ regulatory T cells specific for paternal antigens
- Exclusion of inflammatory cells from pregnant uterus
- Poor antigen presentation in placenta
- Inability to create harmful Th1 responses in healthy pregnant uterus
12
Q
Pathogenesis of Autoimmuntiy
A
Combo of susceptibility genes (interfere w/ development of self tolerance) + environmental stimuli (infection or tissue injury)
13
Q
Genetic Component of Autoimmunity
A
ASSOCIATIONS
- Autoimmune diseases associated NOT caused by certain HLA alleles
- Ex) rheumatoid arthritis, Type I diabetes, pemphigus vulgaris, ankylosing spondylitis
- Other non-HLA genes associated w/ autoimmunity:
- PTPNN22
- NOD2
- IL23R
- CTLA4
- CD25 (IL-2 receptor alpha chain)
- C2/C4 complement proteins
- Fc-gamma- RIIB
14
Q
4 Mendelian Diseases of Autoimmunity
A
- AIRE- autoimmune polyendocrine syndrome - reduced expression of peripheral self antigens in thymus in maturation
- CTLA4-Autosomal dominant immune dysregulation syndrome - impaired inhibtory checkpoint
- FOXP3- X-linked polyendocrinopathy and enteropathy (IPEX) - deficiency of regulatory T cells
- FAS- autoimmune lymphoproliferative syndrome - defective apoptosis of self-reactive B and T cells in periphery
15
Q
How does environment contribute to autoimmunity? (5)
A
INFECTION
- Local inflammation/immune response —> more B7 co-stimulators and APCs which can now help stimulate self-reactive T cells
- Infectious microbes may have peptides that look similar to self antigens —> cross reaction (molecular mimicry)
- Ex) rheumatic fever
- Innate response to infection may alter chemical structure of self antigens
- May be sequestered but then self antigen released once innate immune response —> now activate T cells
- Inc abundance or changes of micro biome may affect tolerance
