Tolerance

Question 1

What is central tolerance?

Answer 1

Induced in immature self-reactive lymphocytes in primary lymphoid organs
Ensures mature lymphocytes are not reactive to self-Ags

Question 2

What is peripheral tolerance?

Answer 2

Induced in mature self reactive lymphocytes in lymph nodes or peripheral tissue (submucosal)
Prevent activation of dangerous lymphocyte clones in periphery

Question 3

What are the 3 outcomes of central tolerance?

Answer 3

Deletion by apoptosis
Change of BCR specificity
Development of Treg cells
All happening in central lymphoid organs

Question 4

What are the 3 outcomes of peripheral tolerance?

Answer 4

Inactivated (anergy)
Deleted (apoptosis)
Suppression by the Treg cells

Question 5

How does Central T Cell Tolerance occur?

Answer 5

Thymus able to express Ags that are present only in certain peripheral tissues
- recognize self Ags –> death by negative selection or development into Treg
- no affinity –> apoptosis because TCR not functional
Window of selection/threshold for positively selected that are allowed to migrate into the blood

Question 6

What are natural Treg cells? What cell markers do they express?

Answer 6

Positively selected in the thymus via strong TCR interactions with self-Ags

High levels of CD25 allow them to bind IL-2 for survival
Express high levels of CTLA-4
Expression of FoxP3 allows production of anti apop molecules and synthesis of anti inflammatory molecules

Highest avidity so get first Ag recognition

CD4+ FoxP3+ CD25high

Question 7

What are induced Treg cells?

Answer 7

Differentiate in periphery (lymph nodes and GI tract)

• FoxP3 induced in presence of TGF-B and IL2
• only happens if IL-6 is not present

Question 8

How do Treg cells work?

Answer 8

Anti-inflammtory cytokines: IL-4, IL-10, and TGF-B

Activation happens in Ag specific matter
Outcompetes tReg because don’t need to up-regulate Il-2 (already have it, higher avidity)
Binding with APC causes lower production of co-stimulators (CD40, CD80/86, IL-12) and increase in IL-10 (anti-inflam)

Question 9

What is the mechanism of peripheral T cell tolerance?

Answer 9

Regulatory cytokines produced by dendritic cells
- Ag recgonition without adequate CD80:CD28=
anergy through engagemnt of inhibitory receptor CTLA-4 (homolog of CD28 but has higher affinity) or PD-1
or
apoptosis via Fas receptor which is expressed on every Cytotoxic T or by release of apoptotic proteins from mitochondria

Question 10

What is the mechanism of central B Cell Tolerance?

Answer 10

Immature B cells that recognize self ags in the bone marrow with high avidity die by apoptosis or undergo receptor editing of their BCR so they express new Ig light chain (know happens if have lambda)
Low avidity leads to reduced receptor signaling and become anergic

Question 11

What is the mechanism of peripheral B cell tolerance?

Answer 11

Mature B cells that recognize Ag in peripheral in absence of Th cells become anergic or die by apoptosis
- become anergic via CD22 inhibitory receptor which is phosphorylated by Lyn and recruits SHP-1 tyr phosphatase

Question 12

What are Treg cells role in peripheral tolerance?

Answer 12

key mediator
Directly tregs release anti inflammatory cytokines inhibiting CD4+ T cell activation by APCS and T-cell differentiation in CD8+ CTLs
Indirectly= precent T cells from providing help to B cells in production of Abs
Deficiency causes IPEX

Question 13

What mutation is the only one that breaks central tolerance? What is its mechanism?

Answer 13

Mutation of AIRE which controls expression of Ag in thymus –> failure of central tolerance because you can’t test immature T cells, instead self-reactive T cells are not eliminated an can enter tissue and cause injury in response to self Ag
Disease= Autoimmune polyendocrine syndrome (APS)

Question 14

How does a mutation in C4 break peripheral tolerance?

Answer 14

Defective clearance of immune complexes leading to increase chance of autoimmunity
Disease= SLE

Question 15

How does a mutation in CTLA-4 break peripheral tolerance?

Answer 15

Failure of anergy in CD4+ T cells leading to lymphoproliferation

Question 16

How does a mutation in Fas/FasL break peripheral tolerance?

Answer 16

Defective deletion of anergic self reactive B cells and reduced deletion of mature CD4+
disease= ALPS, autoimmuno lympho-proliferative syndrome

Question 17

How does a mutation in IL-2:IL2Ralphabeta break peripheral tolerance?

Answer 17

Defective development because Treg heavily relies upon

Effects survival and function of Tregs

Question 18

How are immune complexes cleared?

Answer 18

Activation of complement leads to deposition of C3b on immune complexes
CR1 on erythrocytes binds the immune complexes and take to the spleen and liver so phagocytes (specifically Macrophages with CR1 and FcR) cane remove complexes from surface of erythrocytes

Question 19

What are the 2 important properties of CTLA-4?

Answer 19

Expression is low on resting T cells until the cells are activated by Ag
When expressed terminates continuing activation of responding T cells
On Tregs mediates suppressive function by inhibiting activation of naive T cells

Question 20

What is autoimmunity?

Answer 20

activation of T cells and or B cells in absence of ongoing infection –> activation of types 2, 3, and 4 hypersensitivity reactions

Disorders can be system or organ specific
All are chronic, progressive and self-perpetuating

Question 21

How is autoimmunity prevented?

Answer 21

Immunological tolerance= T cells physically seperated from their specific Ag via BBB
Deletion= T cells express Fas (CD95) and can undergo apoptosis when come in contact of cell with FasL
Inhibition= CTLA4 (CD152) bind CD80 on APC and inhibit costim signal
Suppression= Tregs produce inhibitory cytokines such as IL-10 and TGFb

Question 22

What role does genetics and environmental factors play in autoimmunity?

Answer 22

Genetic polymorphism increase susceptibility, many associated with MHC gene
These susceptibility genes interact with environmental factors to cause disease

Question 23

How can microbial Ags intiate autoimmune disorder?

Answer 23

Molecular mimicry=

• rehumatic fever: cross reactivity between strep Ags and cardiac myosin
• MS: T cells react with myelin basic protein from HPV, flu, etc.

Polyclonal (bystander) activation= robust inflammatory response resulting in activation of auto reactive lymphocytes in cytokine field

Release of previously sequestered Ags
- microbes that kill cells cause DAMPs to be release –> autoimmunity

Question 24

What is systemic lupus erythematosus (SLE)?

Answer 24

Immune complex mediated disease, type II
responsible for glomerulopehritis, arthritis, and vasculitis
diagnose by presence of anti-nuclear Abs because external trigger is exposure to light (cause butterfly redness= erythematous rash)
Antibodies to chromosomal proteins

Question 25

What is rheumatoid arthritis?

Answer 25

Local inflammatory disease of small and large joints Type IV
Usual players of type IV invovled: Th1, TH17, activated B cells and plasma cells, macrophages
Have circulating IgM or G with rheumatoid factor that reacts with Fc portion of IgG

Question 26

What autoimmune disease is caused by a single genetic defect?

Answer 26

ALPS has been shown to arise as a direct consequence of a mutated Fas gene, which leads to impaired Fas-mediated apoptosis of lymphocytes

Question 27

What cells contribute to the pathology of Type I diabetes?

Answer 27

TH1 CD4+ cells and cytotoxic CD8+ T cells

Question 28

What is the best treatment for Chrohn’s disease?

Answer 28

Anti-tumor necrosis factor (TNF)-α because chronic inflammation is maintained by the activation of a Th1 type of cytokineproduction, including IL-12, IFN-gamma, and TNF-α.