Lecture 11/12: Tolerance, Autoimmunity, Hypersensitivity

Question 1

Immune tolerance

Answer 1

Unresponsiveness to self Ag
2 major types:
1. Central
2. Peripheral

Question 2

Central tolerance

Answer 2

Involves generative immune organs; thymus/bone marrow

Question 3

Peripheral tolerance

Answer 3

Involves peripheral tissues

Question 4

T cell central tolerance

Answer 4

Mediated by thymus
- Strong self rxn -> neg. select. via deletion or Treg development
Req.:
1. Thymus location
2. APC self peptide presentation
3. Autoreact. TCR on T cell

Question 5

2 apoptosis mechanisms in selection

Answer 5

1. Mitochondrial Intrinsic
   - Deficit in cell survival signals; mt induced to release apoptotic proteins
2. Death Receptor Extrinsic
   - Repeated FAS activation via FAS-L btwn 2 cells

Question 6

T cell peripheral tolerance

Answer 6

Lack of co-stim. or inhib. stim. -> tolerance -> anergy or apoptosis

Question 7

Anergy

Answer 7

Functional inactivation; triggered by absent co-stim. or presence of inhib. stim.

Question 8

Inhibitory signals for lymphocyte anergy

Answer 8

CTLA-4, PD-1 lymphocyte surface receptors induce anergy
- CTLA-4 binds and can sequester away B7 from APC
- PD-1 blocks TCR signal 1 AND CD28 signal 2

Question 9

CTLA-4 vs PD-1 roles

Answer 9

CTLA-4 primes CD4+ more than CD8+ from Tregs (secondary lymphoid organs)

PD-1 mostly functional during CD8+ effector phase, w/o Treg involvement (secondary lymphoid, periphery)

Question 10

Tregs

Answer 10

Created via tolerance mainly in the thymus; Foxp3 marker
- Inhib. T, B, and NK cells
- Foxp3, IL-10, TGF-beta inhibitors
- Have more IL-2Rs vs other T cells
- IL-2 -> Treg proliferation/maintenance -> effector T suppression

Question 11

B cell central tolerance

Answer 11

Self-Ag rxn -> receptor editing or deletion

Question 12

B cell peripheral tolerance

Answer 12

Anergy or deletion

Question 13

Autoimmunity

Answer 13

Immune response to self-Ags; usually req. BOTH genes (tolerance failure) and environmental trigger (tissue injury -> self-react. activation)

Question 14

Contributor vs causal genes

Answer 14

Genes that may contribute to disease in complex ways vs cause a disease

Question 15

Relative gene risks of various autoimmune diseases

Answer 15

• Ankylosing spondylitis: rel. risk 90
• Rheumatoid arthritis: rel. risk 4-12
• T1 diabetes mellitus: rel. risk 35
• Pemphigus vulgaris: rel. risk 14

Question 16

Causal single genes for various autoimmune diseases

Answer 16

[Rare]
NOD2 -> Crohn’s (intestinal microbe resist. defect)
CTLA-4 -> T1D, RA (autosomal dominant immune dysreg. syndrome)
FAS -> Autoimmune LymphoProliferative Syndrome (ALDS)

Question 17

How do infections trigger/exacerbate autoimmunity?

Answer 17

1. Increase in general inflam. -> more signal 2
2. Molecular mimicry
3. Self-peptide release from injured cells to immune privileged sites

Question 18

Rheumatoid arthritis

Answer 18

Chronic cartilage inflam.
- Cytokines -> recruitment, MMP/PG release
- Treatment w/ anti-TNF or anti-IL-17

Question 19

Cytokine-targeted drugs for autoimmune treatments

Answer 19

Question 20

Sensitivity vs hypersensitivity

Answer 20

Sensitized = subsequent Ag exposure elicits stronger rxn after 1st resposne
Hypersensitivity = disorder where sensitivity -> poorly controlled response

Both req. 2 exposures

Question 21

4 types of HSN

Answer 21

I: allergic (anaphylactic, immediate)
II: Ab mediated -> cell mediated
III: immune complex
IV: delayed; T-cell mediated
I-IV = fastest to slowest

Question 22

Abs for HSN rxn types

Answer 22

I: IgE
II: IgG > IgM
III: IgG > IgM
IV: tissue injury by T cells

Question 23

Type I HSN

Answer 23

Allergic rxn to injected, ingested, inhaled Ags
- Mediated by IgE -> mast cell FcεR1 -> inflam., vasodilat. cytokines

Question 24

Omalizumab

Answer 24

Anti-IgE drug used for food allergy prevention therapy

Question 25

Mast cell mediators

Answer 25

Rapid: 1. Vasoactive amines (preformed, e.g. histamine) 2. Proteases (preformed, e.g. tryptase) 3. PGs (de novo synth.) 4. Leukotrienes (de novo synth.) Slower: 5. Cyto/chemokines (de novo synth., e.g. TNF alpha, IL-4/5)

Question 26

HSN I biphasic response

Answer 26

1. Immediate 2. Late phase (PMNs, eosinophils, Th2s, basophils due to cyto/chemokines)

Question 27

Anaphylaxis

Answer 27

Systemic shock due to complement anaphylotoxins mediating an allergic reaction

Question 28

Type II HSN

Answer 28

Ab binds tissue, cell, or other Ags -> pathological or abnormal physio. response w/o inflam. e.g. hemolytic anemia, Good pasture's, Graves', myasthenia gravis, pernicious anemia, rheumatic fever

Question 29

Type III HSN

Answer 29

Immune complex deposition; usually systemic - Affects microvasc. beds - e.g. SLE, polyarteritis nodosa, post-strep glomerulonephritis

Question 30

Type IV HSN

Answer 30

Delayed type, T-cell mediated; rxn 1-3 days after Ag contact e.g. poison ivy, TB - Often chronic, progressive, self perpetuating - e.g. MS, rheumatoid arthritis, T1DM, Crohn's, TB