Tolerance and Autoimmunity

Question 1

Immunologic Tolerance Definition

Answer 1

Ability of an individual to ignore “self” while reacting to “non-self” antigens

Question 2

Central Tolerance

Answer 2

• T and B cell development events (negative selection)
• Restricted to primary organ (thymus and bone marrow)
• Majority of mature cells react ONLY with foreign Ag (bc they are tolerant)

Question 3

Peripheral Tolerance

Answer 3

• Mature T cell and B cell event in periphery
• Restricted to secondary organs (spleen, lymph node, and non-lymphoid tissue)

Question 4

Central Tolerance Mechanisms

Answer 4

• T Cells: Clonal Deletion (positive/negative selection)
• B Cells: Clonal Deletion, Anergy, Receptor editing
• Clonal Diversion: Self-reactive Th cells become regulatory T cells

Question 4

Outcome of Positive Selection (T Cell)

Answer 4

Attention of T cell focused on recognizing MHC-self peptide complex and not just free Ag

Weakly interacting cells survive

Question 5

Outcome of Positive Selection (T Cell)

Answer 5

Attention of T cell focused on recognizing MHC-self peptide complex and not just free Ag

Weakly interacting cells survive

Question 6

Outcome of Negative Selection (T Cell)

Answer 6

T cells that recognize self-Ag are eliminated

Strongly interacting cells die off

Question 7

Avidity Definition (B Cell)

Answer 7

Strength of Interaction

Determined By:

Affinity of BCR and self-Ag

Density of BCR

Nature of self-Ag (membrane bound vs soluble Ag)

Concentration of self-Ag

Question 8

What happens to B cell with high avidity?

Answer 8

Deletion/Receptor Editing

Question 8

What happens to B cell with high avidity?

Answer 8

Deletion/Receptor Editing

Question 9

What happens to B cell with moderate avidity?

Answer 9

Anergy

Question 10

What happens to B cell with moderate avidity?

Answer 10

Anergy

Question 11

What happens to B cell with low avidity?

Answer 11

Clonal ignorance (no threat)

Question 11

What happens to B cell with low avidity?

Answer 11

Clonal ignorance (no threat)

Question 12

Why is peripheral tolerance needed?

Answer 12

Some mature T cells will:

have a TCR that can respond to self-Ag

Encounter high self Ag that overwhelms TCR

Encounter strong secondary signals in response to infection

This is why we need peripheral tolerance to maintain tolerance throughout body

Question 13

Peripheral Tolerance Mechanisms

Answer 13

• Anergy
• Deletion
• Regulatory T cell (will inactivate other lymphocytes specific for the same self-Ag it is)
• Immune privilege sites (certain tissues that will kill rogue cells (brain, eye, ovary, placenta, testes)

Question 13

Bcl2/Bim mediated apoptosis

Answer 13

imbalanced expression or pro-apoptotic proteins, destabilizes mitochondrial membrane resulting in apoptosis.

Question 14

Fas mediated apoptosis

Answer 14

Engagement of death receptors

Question 15

When can Tolerance be a bad thing?

Answer 15

Undesirable tolerance of tumors

Question 16

Does induced tolerance last forever?

Answer 16

No, with time it wanes and eventually disappears

Question 17

Autoimmunity Definition

Answer 17

Failure of self-tolerance mechanism(s) that results in an immune response against “self”

Question 18

Autoimmunity Causes

Answer 18

Multiple Gene Defects (rarely caused by single gene defect)

Exception: defect in Fas/FasL, AIRE, FOXp3 expression

Question 19

Disease: APS-1 (single gene defect)

Answer 19

Gene: AIRE (autoimmune regulator)

Mechanism: Decreased expression of self-antigens in the thymus (neg selection)

Question 19

Disease: APS-1 (single gene defect)

Answer 19

Gene: AIRE (autoimmune regulator)

Mechanism: Decreased expression of self-antigens in the thymus (neg selection)

Question 20

Disease: IPEX (single gene defect)

Answer 20

Gene: FOXP3

Mechanism: decreased generation of Tregs

Question 21

Disease: ALPS (single gene defect)

Answer 21

Gene: FAS, FASL

Mechanism: Failure of apoptotic death of self reactive T or B cells

Question 21

Disease: ALPS (single gene defect)

Answer 21

Gene: FAS, FASL

Mechanism: Failure of apoptotic death of self reactive T or B cells

Question 22

Environmental causes of Autoimmunity

Answer 22

• Inducing the release of sequestered self-Ag (trauma)
• Induction due to infection
  
  • Molecular Mimicry

Question 23

Molecular Mimicry Example: Rheumatic Fever

Answer 23

Host Antigens: Cardiac myosin, tropomyosin, keratin

Pathogens: Streptococcus pyogenes

Question 24

Organ Specific Autoimmunity Examples

Answer 24

• Type I Diabetes
• Goodpasture’s syndrome
• Multiple sclerosis
• Graves’ disease
• Hashimoto’s thyroiditis
• Autoimmune hemolytic anemia
• Myasthenia gravis

Question 25

Systemic Autoimmunity Examples

Answer 25

• Rheumatoid Arthritis
• Systemic Lupus
• Sjogren’s syndrome

Question 26

What are the main mechanisms of autoimmunity?

Answer 26

Antibody mediated or T cell mediated (CD4 or CD8)

Question 27

Myasthenia Gravis (Autoimmune)

Answer 27

Antibody Mediated

Target Antigen: Acetylcholine receptor

Mechanism: Antibody blocks binding of ACh to the receptor (AKA nerves cannot connect to muscle cell, causing weakness in skeletal muscles)

Question 28

Graves’ Disease (autoimmune)

Answer 28

Antibody Mediated

Target Antigen: TSH receptor

Mechanism: Antibody mediated stimulation of TSH receptor (too much thyroid hormones=hyperthyroidism)

Question 29

Type I Diabetes (autoimmune)

Answer 29

T Cell Mediated

Target Antigen: Pancreatic beta-cells

Mechanism: Destroys beta-cells

Question 30

Goal of immunotherapies for autoimmune disease

Answer 30

REDUCE symptoms and PRESERVE organ function

Drug Goals: Monoclonal Ab, CTLA4, Regulatory Cytokines, Restoration of tolerance (biotherapeutics pretty much)