Tolerance and Autoimmunity

Question 1

Define Immunogenic?

Answer 1

Elicits an immune response

Question 2

Define Tolerogenic?

Answer 2

Does not elicit a functional lymphocyte response

-As a result lymphocytes are either killer, inactivated, or there is no reaction at all (Immune ignorance)

Question 3

What two locations are best examples of immune ignorance?

Answer 3

The eyes and the testis

Question 4

Compare Central tolerance to Peripheral tolerance

Answer 4

Central: occurs during lymphocyte development in primary lmyphoid organs (thymus and BM)

Peripheral: Occurs in periphery (Secondary lymphoid organs or non-lymphoid tissue

Question 5

What happens to the thymus as we age?

Answer 5

It involvues with age, becomes for adipose tissue

Question 6

What is positive selection in the thymus?

Answer 6

When T cells recognize MHC for self with low affinity

Question 7

What is negative selection in the thymus?

Answer 7

When T cells recognize MHC with strong affinity and undergo apoptosis (this is not 100% efficient and hence you need peripheral tolerance)

Question 8

What are the three populations of T cells that come from the thymus

Answer 8

Regulatory T cells (Tregs), CD4s, or CD8s

Question 9

What is death by neglect?

Answer 9

In the thymus when T cells do not recognize MHC at all and undergo apoptosis

Question 10

How are Tregs selected for? What must they express?

Answer 10

They recognize MHC with strong affinity, and survive, they contribute to peripheral tolerance

-must express FoxP3 genes

Question 11

What is the fate, and how is it done, of a T cell specific for antigen that is not expressed in the thymus?

Answer 11

They are negatively selected by the AIRE gene (autoimmune regulator)

-AIRE induces the expression of peripheral tissue antigens by cells in the thymus. That way if a maturing T cell has afffinity for these antigens, it can be negatively selected against.

Question 12

What happens if there is a mutation in AIRE?

Answer 12

APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrohpy syndrome)

-this is a multi-organ autoimmunity

Question 13

In peripheral tolerance, what are the 4 options for dealing with autoreactive T cells?

Answer 13

1. Anergy (functional inactivation)
2. Treg- mediated suppression
3. Death (apoptosis)
4. Ignorance (this is most dangerous)

Question 14

What induces anergy, and how long does it last? (for T cells)

Answer 14

Anery is long-lived functional inactivation

• Induced in two ways.
  1. Lack of costimulation by CD28 to B7 (also known as CD80/84)
  2. Stimulation of an inhibitory signal like CTLA-4 with B7 or PD-1 with PDL
  note: CTLA-4 is expressed in high levels on activated T cells making it a good off switch.

Question 15

What are the targets of Ipilimumab and Nivolumab?

Answer 15

Ipilimumab is a anti-CTLA-4 antibody

Nivolumab is a anti-PD-1 antibody

• both work to prevent T cell anergy or inactivation
• this is dangerous and can lead to autoimmunity

Question 16

What transcription factor is required for Tregs, and what would a mutation in this cause?

Answer 16

FoxP3, a mutation in FoxP3 leads to IPEX (multiorgan autoimmunity)

• FoxP3 is a transcription factor
• Tregs suppress the function of other T cells specific for self-antigens that did not get negatively selected

Question 17

What interaction is responsible for lymphocyte activation induced cell death (AICD)?

Answer 17

Fas-FasL interaction

• make effector T cells short lived
• helps to return to homeostasis after infection

Question 18

What is induced upon on effector T cell upon activation?

Answer 18

Fas is induced

FasL is always expressed

Question 19

What causes Autoimmune Lymphoproliferative Syndrome?

Answer 19

Mutation in genes involved in FAS signaling

-leads to autoimmunity, and lymphocyte accumulation

Question 20

What is receptor editing?

Answer 20

Immature B cells (that mature in the BM) that recognize self antigens, they will reexpress RAG genes, resume Ig light chain recombination and rexpress a new Ig light chain to avoid self recognition

-25-50% of B cells undergo receptor editing

Question 21

How is Ig concentration related to Ig Half-life?

Answer 21

Inverse. The higher the Ig conc, the shorter the half life

Question 22

What receptor interaction is required for B cell stimulation by T cells and what happends without it?

Answer 22

CD40L (on T cell) with CD40 (on B cell) is required for B cell stimulation.

-without you get anergy, this is an example of B cell peripheral tolerance

Question 23

What is the main inhibitory receptor of both B cells and machrophages?

Answer 23

Fc receptors

-although there are both stimulatory and inhibitory Fc receptors

Question 24

What is the main inhibitory signal for B cells?

Answer 24

Co-cross linking of BCR and Fc-gamma-Receptor II turns off the B cell.

-this co-cross linking is more likely to happen at high Ig concentrations.

Question 25

What is Rhogam and what is it used for?

Answer 25

Rhogam is immune gammaglobulin to Rh antigens (IgG ab) - given to Rh neg mothers with an Rh+ fetus during pregnancy. - elimantes fetal Rh pos RBCs from maternal circulation - turns off maternal B cells by cross-linking BCR and FcgammaRII - Rh- mom would have Rh antibodies that would attack the Rh antigens of the Rh+ fetus.

Question 26

Which three cytokines are secreted by macrophages to aid in the return to homeostasis after infection? What does each inhibit?

Answer 26

**IL-10** inhibits Th1 cells **TNF-beta** inhibits macrophage and T cell activation **PRGe2** inhibits lymphocyte proliferation

Question 27

What Ab is present in Graves disease, what does it cause? and what type of hypersensitivity is it?

Answer 27

Graves disease has agonistic TSH antibodies that over stimulate the Thryoid stimulating hormone receptor. - leads to hyperthyroidism, also Goiter (thyroid hyperplasia) - leads to B and T cell infiltration type II hypersen. b/c ab mediated

Question 28

What causes Goodpasture's disease?

Answer 28

Ab against non-collagenous domains of type IV collagen of glomerular basement membrane (GBM) - leads to linera IgG in kidney GBM and anti-GBM antibodies - neutrophil mediated cytotoxicity - Bleeding in the lungs and progressive kidney failure - type II hypersen.

Question 29

What causes Systemic Lupus Eryhtematosus?

Answer 29

- Ab against nuclear contents; dsDNA, snRNPs - leads to skin, kidney, joint symptoms reflect immune complex deposition - type III hypersen, ab-ag-immune complex - prevalent immune-complex mediated diease in developed countries among women - fever, arthritis, myalgia, skin involvement, photosensitivity, anemia

Question 30

What is a ANA test?

Answer 30

Cells fixed on slide, add patient serum, anti-nuclear ab bind, secondary antiody against human ab taged with a fluorescent dye - 95% of SLE patients test postivie - up to 15% of healthy patients have anti-ANA ab and would also test positive, this would be false positive

Question 31

What causes MS?

Answer 31

Immune attack of myelin sheath that cover nerve fibers -type IV hypersens (cell mediated)

Question 32

What causes DM type I?

Answer 32

Descrution of insulin-producing Beta cell in pancreatic islets - type IV hypersen (cell mediated) - CD4 and CD8 T cells specific for Beta cell antigens responsible for islet cell desrtuction

Question 33

What does infection have to do with risk of autoimmunity?

Answer 33

Hypothesis that infection increases risk of autoimmune disease because it increases co-stimulation. So you have a higher risk of co-stimulating cells that recognize self that would normally be anergetic. - **also molecular mimicry: peptide antigens from a microbe is very similar to a self antigen** : like rheumatic fever, where antibodies against streptococci cross-react with myocardial antigen - remember though in some cases infection can be protective from autoimmunity

Question 34

What set of genes has a strong association with AI dz?

Answer 34

HLA genes HLA-B27 is 90 relative risk in developing AI -important is HLA does not cause disease, and vast majority of peopple with HLA allele do not develop disease -

Question 35

What are 5 polymorphisms that affect a person's genetic susceptibility to an AI dz? What dz's are they associated with?

Answer 35

**PTPN22:** involved in B and T cell signaling -- RA, SLE, TIDM **NOD-2**: involved in NLR (innate) -- 25% of Crohn's dz **high affinity chain of IL-2 receptor (CD25)**: effector Treg balance -- multiple AI dz **IL-23R**: involved in Th17 differentiation -- multiple AI dz **CTLA-4**: multiple AI dz

Question 36

What is Abatcept?

Answer 36

CTLA-4-Ig biologic - fusion or protein composed of Fc region of IgG fused to CTLA-4 - trigger off switch, treat autoimmune

Question 37

Name an anti-CD20 antibody?

Answer 37

Rituximab

Question 38

What are the 3 anti-TNF abs?

Answer 38

Infliximab Adalimumab Certolizumab Pergol

Question 39

What is the Anti-IL-6 Ab?

Answer 39

Toclizumab