L: 19 Immunological Tolerance and Autoimmunity

Question 1

Where is Central Tolerance induced?

Answer 1

In immature self-reactive lymphocytes in the primary lymphoid organs (thymus, bone marrow)

Question 2

Where is peripheral tolerance induced?

Answer 2

Mature self reactive lymphocytes in peripheral sites

Question 3

Why is peripheral tolerance needed?

Answer 3

To prevent activation of these potentially dangerous lymphocytes in the tissue

Question 4

What does central tolerance ensure?

Answer 4

That mature lymphocytes are not reactive to self Ags.

Question 5

Unlike “nonspecific” immunosuppression tolerance is ?

Answer 5

Ag specific

Question 6

Immunological Tolerance is specific ___________ to an Ag

Answer 6

Unresponsiveness

Question 7

What is the result of autoimmunity?

Answer 7

Breakdown of self-tolerance

Question 8

Immature lymphocytes specific for self Ags may encounter these Ags in the generative lymphoid organs and are either?
What type of tolerance?

Answer 8

• Deleted
• Change BCR specificity(B cells only)
• Developed into Treg cells

Central Tolerance

Question 9

Mature self-reactive lymphocytes in peripheral tissues may be either?

What type of tolerance?

Answer 9

• Inactivated (anergy)
• Deleted (apoptosis)
• Suppressed by the Treg cells

Peripheral tolerance

Question 10

The thymus has a special mechanism for expressing many protein Ags that are?

Answer 10

Present only in certain peripheral tissues

Question 11

TCR signaling in T cells triggers what?

Answer 11

Mitochondrial pathway of apoptosis- negative selection

Question 12

What 2 things does recognition of self Ags by immature T cells in the thymus lead to?

Answer 12

1. Death of the cell by negative selection

2. Development of Treg cells that enter peripheral tissue

Question 13

Where does Central Tolerance take place?

Answer 13

Thymus

Question 14

What happens to nonfunctioning thymocytes showing no affinity?

Answer 14

Apoptosis

Question 15

What happens to strongly self-reactive thymocytes, and where is this determined?

Answer 15

Determined my interaction with MHC self peptide complexes

They are deleted

Question 16

Thymocytes that are activated by MHC-self peptide complexes below a certain threshold are what?

Answer 16

positively selected and migrate into the periphery as mature T-cells

Question 17

Most of the thymocytes that migrate into the periphery develop into what?

Answer 17

Effector CD4+ and CD8+ T cells and mediate both cell- mediated and humoral immune response

Question 18

What happens to only a small percentage of T cells that emigrate from the thymus?

Answer 18

Express FOXP3 and develop into natural CD4+ CD25+ CTLA4+ Treg cells

Question 19

What happens to immature B cells that recognize self Ags in the bone marrow with high avidity?

Answer 19

Die by apoptosis or undergo receptor editing and change specificity of BCRs

Question 20

Define receptor editing

Answer 20

Rearrangement and replacement of the IgL-chain genes that occur until non-self recognizing receptors are produced or the cell dies

Question 21

What may lead to anergy of the B cells?

Answer 21

Weak recognition of self Ags in bone marrow

Question 22

What are two major mechanisms mediating central tolerance?

Answer 22

Clonal deletion

Anergy

Question 23

What happens when an immature B-cell reacts with high avidity?

Answer 23

Apoptosis within 2-3 days

Question 24

What happens when an immature B-cell reacts with low avidity?

Answer 24

induced unresponsiveness or anergy but allowed for migration into peripheral compartment

Question 25

There is one other mode of selection against autoreactive immature B cells called receptor editing. Describe receptor editing

Answer 25

rearrangement program at the Ig light chain resulting i expression of a new light chain with the existing H chain to form a non-autoreactive BCR

Question 26

What is the ration of kappa/lambda in peripheral B cells?

Answer 26

3:2

Question 27

Receptor editing of the IgL chain generates cell-surface immunoglobulin that lack?

Answer 27

Self-reactivity

Question 28

Deletion of self-reactive lymphocytes occur via what two pathways?

Answer 28

``` Mitochondrial (intrinsic) pathway Death receptor (extrinsic) pathway ```

Question 29

Key mediator of peripheral tolerance?

Answer 29

Treg cells

Question 30

Treg cells may inhibit T cell activation by _____ and inhibit T-cell differentiation into ____.

Answer 30

APCs | CTLs

Question 31

Treg cells may prevent T-cells from providing what?

Answer 31

Help to B cells in the production of Abs

Question 32

What are induced Treg cells?

Answer 32

FOXP3+ Treg cells generated from peripheral mature T cells OUTSIDE the thymus

Question 33

What cells can also acquire Treg phenotype and function?

Answer 33

iTreg cells (induced) OUTSIDE THE THYMUS

Question 34

Theree is a close relationship between iTreg and what cells?

Answer 34

Th17

Question 35

What needs to be present for FoxP3 expression in naive CD4+ cells in vitro?

Answer 35

TGF-Beta

Question 36

What prevents FoxP3 expression

Answer 36

IL-6

Question 37

What sparks Th17 cell differentiation?

Answer 37

TGF-B + IL-6 prevents FoxP3 expression and induces retinoic acid receptors (RAR) and related orphan nuclear receptors therefore activating Th17 differentiation

Question 38

What do Treg cell suppress in peripheral tissues

Answer 38

Activation of self-reactive lymphocytes

Question 39

Development and survival of regulatory Tcell requires?

Answer 39

IL-2 and FoxP3

Question 40

Natural Treg cells are generated by?

Answer 40

self Ag recognition in the thymus

Question 41

Inducible Treg cells are produced by Ag recognition where?

Answer 41

Lymph nodes and GI tract

Question 42

What attenuates BCR signaling?

Answer 42

CD22 inhibitory receptor is phosphorylated by Lyn and then recruits SHP-1 tyrosine phosphatase

Question 43

Defects in what Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and CD22 inhibitory receptor leads to what?

Answer 43

Autoimmunity

Question 44

The balance of what controls the outcome of peripheral tolerance

Answer 44

BCR vs BAFF signaling controls

Question 45

AIRE deficiency causes?

Answer 45

Failure of central tolerance causing Autoimmune polyendocrine syndrome (APS)

Question 46

FoxP3 deficiency causes?

Answer 46

Impaired production of regulatory T calls causing IPEX syndrome

Question 47

C1q and C4 deficiency causes?

Answer 47

Decreased clearance and impaired tolerance induction by apoptotic cells

Question 48

CTLA-4 polymorphisms causes?

Answer 48

Failure of anergy in CD4+ T cells causing Altered Immune Signaling thresholds

Question 49

Loss of self tolerance leads to what?

Answer 49

Autoimmunity

Question 50

What does AIRE stand for?

Answer 50

AutoImmune REgulator

Question 51

What has a key function as APCs and express large numbers of self-Ags that are presented to developing T-cells

Answer 51

Medullary Thymic Epithelial Cells

Question 52

Mutations in AIRE proteins cause?

Answer 52

breakdown of central tolerance by decreased expression of Self-Ags in the thymus

Question 53

AIRE regulates the expression of?

Answer 53

Tissue-restricted Ags (TRAs)

Question 54

Peptide from what are displayed on the Medullary Thymic Epithelial cells

Answer 54

Tissue restricted Ags (TRAs)

Question 55

The recognition of TRAs by T-cells leads to?

Answer 55

Deletion of self-reactive T cells

Question 56

What happens in the absence of AIRE

Answer 56

Self-reactive T-cells are not eliminated and can enter tissue and cause injury

Question 57

What is outcome of normal T-cell response?

Answer 57

An Effector and Memory T cell

Question 58

T cell responses are induced when?

Answer 58

1. TCR recognizes an Ag presented by APC (signal 1) | 2. CD28 recognizes B7 costimulators on the APCs (signal 2)

Question 59

If the T cell recognizes a self Ag without costimulation, the T cell becomes unresponsive to the Ag because of a block in signal from the TCR complex. What are three possible causes of the block?

Answer 59

1. Recruitment of phosphatase to TCR complex 2. Activation of Ubiquitin Ligase that degrades signaling protein 3. Engagement of inhibitory receptors CTLA-4

Question 60

What happens with an Anergic T-cell?

Answer 60

Remains viable but unable to respond to the self Ag

Question 61

T cell activation is regulated by members what family of costimulatory molecules

Answer 61

B7-CD28

Question 62

Homolog of CD28?

Answer 62

CTLA4

Question 63

what does CTLA-4 do?

Answer 63

Inhibitory receptor that terminates immune responses and maintains self tolerance

Question 64

What two autoimmune diseases is caused by polymorphisms in CTLA-4?

Answer 64

Type 1 diabetes and Graves disease

Question 65

Two important properties of CTLA-4

Answer 65

1. Expression is low on resting T-cell until cell is activated by Ag 2. CTLA-4 terminates continuing activation of responding Regulatory T cells

Question 66

Explain CTLA-4 cell intrinsic inhibitory signal?

Answer 66

Engagement of CTLA-4 on T cell delivers inhibitory signal that terminates further activation

Question 67

Explain Cell-extrinsic Action of CTLA-4

Answer 67

CTLA-4 on Treg cell or responding T-cell binds to B7 on APC or makes unavailable to CD28 blocking T cell activation

Question 68

Where is CTLA-4 expressed?

Answer 68

Regulatory T-cell and mediates the suppressive function of these cells by inhibiting the activation of naive T cells

Question 69

Natural Treg cells are ______ selected in the Thymus

Answer 69

Positively

Question 70

Are Natural Treg cells eliminated by Apoptosis?

Answer 70

No they produce an Anti-apoptotic molecule which protects them from negative selection in the thymus

Question 71

All Treg cells express______ transcriptional factor and are _____ _____ positive

Answer 71

FoxP3 | CD4+ CD25+

Question 72

All Treg cell express high levels of _______

Answer 72

CTLA-4

Question 73

What cytokine is critical for the survival and competence of all Treg cells

Answer 73

IL-2

Question 74

Treg cells are endogenous ________ population of ________ T-cells

Answer 74

Long Lived | Self-Ag-specific

Question 75

What does growth factor-B inhibit?

Answer 75

Inhibits development of Th1 and Th2 subsets Inhibits M1 macrophages Inhibits proliferation of effector function of T-cell

Question 76

What does growth factor-B Promote?

Answer 76

* Th17 in cooperation with IL-1 and IL-6 * Tissue repair/collogen synthesis * Stimulates production of IgA by inducing B cells to switch to this isotype

Question 77

What does Growth Factor-B regulate?

Answer 77

Differentiation of induced FoxP3+Treg cells

Question 78

What is Autoimmunity essentially caused by?

Answer 78

* Activation of T cells and/or B-cells in the absence of an ongoing infection or discernible cause * Hypersensetive Immune System that causes one's own immune system to attack itself

Question 79

What is immunologic ignorance?

Answer 79

T cells are physically separated from their specific Ag and cannot become activated

Question 80

Describe the process known as deletion

Answer 80

T-cells that express Fas (CD95) can recieve signal from cells that express FasL and undergo apoptosis

Question 81

Describe T-cell inhibition

Answer 81

CTLA4 binds CD80 on APC inhibiting T cell activation

Question 82

Describe T-cell Suppression

Answer 82

Regulatory T cells can inhibit through the production of inhibitory cytokines such as IL-10 and TGFbeta

Question 83

What is the underlying cause of all autoimmune disease?

Answer 83

Failure of self-tolerance mechanism

Question 84

What is the first step in autoimmune development?

Answer 84

Inflammation

Question 85

Genetically most autoimmune diseases are?

Answer 85

Complex polygenic traits. The individual typically inherits multiple genetic polymorphisms that contribute to disease susceptibility

Question 86

What genes have strongest association to autoimmunity?

Answer 86

****MCH genes***** | Polymorphism in NON_HLA genes is also associated

Question 87

Microbial Ags can initiate autoimmune disorders through?

Answer 87

* molecular mimicry * polyclonal activation * release of previous sequestered Ag

Question 88

Who is more common to autoimmune disorders men or woman?

Answer 88

Women. Estrogen exacerbates systemic lupus erythematous by altering B-cell repertoire