Autoimmunity

Question 1

What is central tolerance?

Answer 1

Self-tolerance induced in central lymphoid organs due to the killing of self-reactive lymphocytes. Prevents emergence of lymphocytes with high affinity receptors

Question 2

What is the impact of a partial defect in central tolerance?

Answer 2

Onset of autoimmunity

Question 3

What is peripheral tolerance?

Answer 3

Unresponsiveness to self antigens in the periphery induced via recognitions of antigens without adequate levels of costimulators or repeated stimulation.

Question 4

What is the result of complete loss of peripheral tolerance?

Answer 4

Increased risk for autoimmunity

Question 5

What are the 3 outcomes of central tolerance?

Answer 5

1. No selection and cell dies
2. Negative selection and cell dies
3. Positive selection and cell released to periphery

Question 6

What type of selection is a driver for T reg development?

Answer 6

Strong positive selection (almost near negative selection levels)

Question 7

What surface receptors and txn factor are associated with Treg cells?

Answer 7

CD4+ and CD25+. Fox P3 txn factor

Question 8

What is the function of the autoimmune regulator (AIRE) protein?

Answer 8

Txn factor that brings tissue specific antigens to the thymus so reactive t cells are deleted

Question 9

What is autoimmune polyendocrine syndrome?

Answer 9

Mutation in APECD so there’s defective AIRE causing the destruction of multiple endocrine tissues including the beta islet cells

Question 10

What is anergy?

Answer 10

A state of unresponsiveness to antigenic stimulation. Mechanism to maintain immunologic tolerance to self.

Question 11

What are three T cell outcomes if the are presented a self antigen or Ag without costimulation?

Answer 11

1. Anergy
2. suppression via T reg
3. Deletion via apoptosis

Question 12

What are two ways that non-costimulation can lead to anergy?

Answer 12

1. signaling block

2. reception of an inhibitory signal

Question 13

What is CTLA4?

Answer 13

Inhibitory receptor on CD4/CD8 and Treg cells

Question 14

How does CTLA4 function?

Answer 14

Binds B7 with more affinity than CD28 in unactivated APCs and causes B7 down regulation for unresponsive T cells

Question 15

What is the impact of deleted CTLA4?

Answer 15

Increased risk for autoimmunity

Question 16

How do Treg cells inhibit or dampen the immune response?

Answer 16

CTLA4 expression, TGF-beta release, IL-10 release, express high affinity IL-2R to mop up extra IL-2

Question 17

What are two ways T cells can be killed?

Answer 17

1. Deficiency in survival signals= activated pro-apoptotic proteins (intrinsic apoptosis)
2. Fas/ Fas Ligand interaction (extrinsic apoptosis) (Fas=CD95)

Question 18

What happens if there is a mutation interrupting Fas/FasL binding?

Answer 18

profound autoimmunity

Question 19

What happens in central B cell tolerance if there is a strong BCR binding to self antigen?

Answer 19

Either receptor editing (via RAG proteins and new light chain combos) or apoptosis

Question 20

What happens if there is recognition of soluble self antigens in central tolerance in b cells?

Answer 20

Anergic b cells

Question 21

T helper cells are essential for B cell maturation in the periphery, what are three outcomes if B cells bind antigens without T helpers?

Answer 21

Anergy, apoptosis, or expression of inhibitory receptors. Anergic B cells are banned from lymphoid follicles and usually die

Question 22

What is autoimmunity and what is its clinical presentation?

Answer 22

Breakdown of tolerance where the antigen targeted is the clinical presentation

Question 23

What is one factor that will increase the chance of autoimmunity occurring?

Answer 23

If binding of the self-antigen occurs with infection, it is more likely to induce autoimmunity due to increased B7 expression

Question 24

Genes associated with an increased risk of autoimmunity are involved in what mechanisms?

Answer 24

Peripheral mechanisms

Question 25

Genes causing autoimmunity are involved in what mechanisms?

Answer 25

Central tolerance mechanisms

ex. AIRE, FOXP3, FAS

Question 26

What genotype is one of the clearest associations with autoimmunity?

Answer 26

HLA genotype

Question 27

What HLA genotype is ankylosing spondylitis associated with?

Answer 27

HLA-B27 = 90% relative risk

Question 28

What genotypes are associated with an increased risk and protection from diabetes type I?

Answer 28

DR3/4 variant = increased risk

DR2/x variatint= protection

Question 29

What is an adjuvant?

Answer 29

substance to enhance B&T cell activation (NOT an antigen) by promoting APC accumulation and activation at the antigen site.

Question 30

How do adjuvants work?

Answer 30

Stimulate expression of T cell-activating costimulators and cytokines or promoting peptide-MHC complexes. **how vaccines work

Question 31

What are some implications of a chronic immune response?

Answer 31

Break down of sequestration barriers
New antigens being revealed= chriptic epitopes
Evolving tissue destruction
New self-antigens involved= epitope spreading
Excess soluble antigen complexes and joints in pain and kidneys

Question 32

What are three treatments for autoimmune response?

Answer 32

1. non-steroidal anti-inflammatory drugs (anti-TNF for RA)
2. corticosteroids and immunosuppressants
3. Biological therapy (anti-cytokine/ cell depletion)