Lecture15: Immunologic Tolerance and Autoimmunity

Question 1

Central tolerance is induced in immature self-reactive lymphocytes in the ____

Answer 1

primary lymphoid organs

Question 2

Peripheral tolerance is induced in mature self-reactive lymphocytes in

Answer 2

peripheral sites

Question 3

Recogniction of self Ags by immature T cells in the thymus leads to _____ and ____

Answer 3

1. Death of the cells by negative selection
2. the development of Treg cells that enter peripheral tissues

Question 4

What is AIRE?

Answer 4

is only expressed in thymocytes and it is responsible for making the protein fragments for all body cells to help with negative selection

Question 5

Central Tolerance for T cells takes place in the

Answer 5

Thymus

Question 6

Thymocytes that show no affinity at all (nonfunctional thymocytes) undergo

Answer 6

apoptosis

Question 7

during the central tolerance only thymocytes that are activated below a certain threshold are _____

Answer 7

• positively seleted and migrate into periphery as mature T cells
  
  • most become CD4+ and CD8+ but a small percentage of T cells on the upper end of the affinity/activation curve express FoxP3 and develop into natural CD4+CD25+CTLA4+ Treg cells

Question 8

___ are key mediators of peripheral tolerance

Answer 8

• Treg cells
  
  • may inhibit T cell activation by APCs and inhibit T-cell differentiation into CTLs
  • may prevent T cells from providing help to B cells in production of Abs

Question 9

iTreg Cells

Answer 9

• Induced Treg cells are formed in the periphery
• FoxP3 expression can be induced by naive CD4+ cells in viroro by antigen recognition and the presence of TGF-beta (note this only occurs if IL-6 is not present and if it is present then induces expression of Retinoic acid receptor (RAR) and Th17 differentiation)

Question 10

Central B cell Tolerance

Answer 10

• Immature B cells that recognize self Ags in the bone marrow with high Avidity have two outcomes
  
  • die by apoptosis
  • undergo receptor editing and change the spcificity of their BCR
    
    • This repleacent of the IgL-chain genes occurs until non-self recognizing receptors are produced or the cell dies
• Weak recognition of self Ags in bone marrow may lead to anergy (funcitonal inactivation) of the B cells

Question 11

Peripheral B cell Tolerance

Answer 11

• Mature B cells that recognize self Ag in peripheral tissues in the absence of Th cells may be rendered funcitonally unresponsive or die by apoptosis
• The CD22 inhibitory receptor is phosphorylated by Lyn and then rectruits SHP-1 tyrosine phosphatase attenuating BCR signaling
• Therefore, defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and the CD22 inhibitory receptor lead to autoimmunity

Question 12

AIRE deficieny causes

Answer 12

autoimmune polyendocrine syndrome

Question 13

Decreased clearance and imparied tolerance induction by apoptotic cells can lead to autoimmunity and is caused by deficiency in

Answer 13

complement C1q and C4

Question 14

The AIRE regulates the expression of

Answer 14

Tissue-restricted Ags (TRAs)

Question 15

If a T cell recognizes a self Ag without costimulation, The T cell

Answer 15

• becomes unresponsive to the Ag because of a block in signaling form the TCR complex. Blocking may be the result of
  
  • Recruitment of phosphatases to TCR complex
  • activaiton of ubiquitin ligases that degrade proteins
  • Engagement of inhibitory receptors CTLA-4
• anergic T cells remains viable but is unable to respond to the self Ag

Question 16

CTLA4 is a ___ family receptor

Answer 16

CD28

Question 17

Polymorphisms in the CTLA-4 are associated with several autoimmune diseases in humans, including ____ and ____

Answer 17

Type 1 DM and Graves’ disease

Question 18

CTLA-4 is expressed on Treg cells and mediates the ____ funciton of these cells by

Answer 18

suppressive funciton of these cells by inhibiting the activation of naive T cells

Question 19

How is autoimmunity prevented

Answer 19

• Immunogic ignorance
  
  • Physically separaated antigens from T cells
• Deletion
• Inhibition
• Suppression
  
  • inhibitory cytokines IL-10 and TGF-beta

Question 20

IL___ is critical for survival and functional competence of Treg cells

Answer 20

IL-2

Question 21

Question 22

Question 23

The strongest association with autoimmunity are ___ genes

Answer 23

MHC genes

Question 24

Microbial Ags can initiate autoimmune disorder through

Answer 24

• Molecular mimcry
• Polyclonal (bystander) activation
  
  • polyclonal activation of autoreactive lymphocytes (cytokine field)
• Release of previously sequestered Ags

Question 25

Question 26