Immunological Tolerance, Autoimmunity, & Sensitivity

Question 1

What makes mature T cells sensitive to peripheral tolerance?

Answer 1

antigen recognition without adequate costimulation

Question 2

What are the 3 mechanisms for T cells that recognize antigens without APC costimulation?

Answer 2

Anergy: functional unresponsiveness
Suppression: block in activation
Deletion: apoptosis

Question 3

2 mechanisms of peripheral T cell anergy

Answer 3

1) lose their ability to deliver activating signals
2) inhibitory receptors on T cell are engaged
- inhibitory receptors: CTLA-4 and PD-1

Question 4

Function of CTLA-4

Answer 4

• constitutive expression
• higher affinity to B7 than CD28
• blocks and removes B7 (induction phase)
• “leaky tank”
• acts in secondary lymphoid organs
• inhibits CD4 and CD8s equally

Question 5

Function of PD-1

Answer 5

• chronic activation and prolonged inflammation
• “brake”
• inhibits signal transduction pathways (effector phase)
• acts in peripheral tissues
• affects more CD8s than CD4s

Question 6

Describe regulatory T cells

Answer 6

• most are CD4
• require FoxP transcription factor for development
• develop in thymus or periphery
• express high levels of CD25
• survival and function dependent on IL-2

Question 7

How do regulatory T cells suppress T cell function?

Answer 7

• produce certain cytokines that inhibit activation of immune cells (IL-10, TGF-b)
• expression and function of CTLA-4
• deleting supply of IL-2

Question 8

What are the 2 mechanisms in T cell deletion in peripheral tolerance?

Answer 8

1) anti-apoptotic proteins are not induced –> lack of survival signs –> apoptosis
2) coexpression of death receptor-ligand (Fas + FasL) –> apoptosis
- Fas = death receptor
- FasL = ligand expressed on activated T cells

Question 9

Strong vs Weak reactivity of immature B cells

Answer 9

Strong
-"like being homeschooled by mom"
-receptor editing can change Ig specificity by expressing a new Ig light chain
-if incorrect again -- apoptosis
Weak
-anergy = functional unresponsiveness

Question 10

Recognition of protein antigen without T cell help renders mature B cells sensitive to ___________

Answer 10

peripheral tolerance – anergy, deletion, or regulation by inhibitory receptors

Question 11

What are the genetic factors of autoimmunity?

Answer 11

• multiple gene loci implicated
• particular HLA alleles linked to increased risk
• polymorphisms in certain non-HLA genes linked to increased risk
• mutations in certain non-HLA genes cause disease

Question 12

What are the environmental and host factors of autoimmune disease?

Answer 12

• infection and inflammation – costimulators, molecular mimicry, altered self
• tissue injury – release sequestered antigens
• gender – females at much higher risk

Question 13

Describe hypersensitivity reactions

Answer 13

• injurious or pathological immune responses

- occurs in immune responses to foreign antigens and self antigens

Question 14

4 types of hypersensitivity

Answer 14

Type I: immediate hypersensivity
Type II: antibody-mediated diseases
Type III: Immune complex-mediated diseases
Type IV: T-cell mediated diseases

Question 15

Describe Immediate Hypersensitivity

Answer 15

• IgE mediated hypersensitivity
• allergies or atopy
• most common immune disorder
• vasodilation and vascular leakage cause hives, hypotension/anaphalaxis, & bronchoconstriction/asthma
• mucosal secretion – tears, rhinorrhea, sputum, vomiting and diarrhea (in food allergy)

Question 16

Describe antibody-mediated hypersensitivity

Answer 16

• most often caused by auto-reactive antibodies that bind to a self antigen in a tissue
• rarely – caused by antibodies specific for cross-reactive foreign antigens (molecular mimicry)

Question 17

Describe Immune Complex-Mediated Hypersensitivity

Answer 17

• circulating antigen-antibody complex deposited in blood vessels
• formed between soluble protein antigens and their antibodies
• stuck in wall of small blood vessels where filtration pressure is high
• activate complements and phagocytes – promote inflammation

Question 18

Describe T cell-mediated hypersensitivity

Answer 18

Cytokine-mediated inflammation
-cytokines induce inflammation
-neutrophils and ROS cause tissue injury
T cell-mediated killing of host cells
-results in cell death and tissue injury