Immune Regulation and Tolerance

Question 1

Immunologic tolerance

Answer 1

The specific unresponsiveness of the normal adaptive immune system to an individuals own SELF antigens

Question 2

Difference between T cell tolerance and B cell tolerance

Answer 2

T cell tolerance is long lived

B cell tolerance is short lived, less complete than in T cells, and is quiescent in the absence of T cell help

Question 3

Activation: Immunogenic antigens

Answer 3

Elicit the functional ACTIVATION of lymphocytes bearing specific receptors (require co-stimulation) of T-cells by activated APCs

Question 4

Tolerance: Tolerogenic antigens

Answer 4

Elicit functional INACTIVATION or KILLING of lymphocytes bearing specific receptors for those antigens (without co-stimulation or T cell help) - deletion of lymphocytes that recognize SELF antigens

Question 5

Ignorance: Non Immunogenic

Answer 5

Antigens that are ignored by lymphocytes bearing specific receptors for those antigens

Question 6

Whether an antigen will induce tolerance is largely determined by

Answer 6

1) Immunologic maturity
2) Antigenic structure and dose
3) Immunosuppressive therapy

Question 7

Significance of immunologic toleranc

Answer 7

Abnormal immune responses to self-antigens can lead to autoimmune and other diseases

Question 8

Central tolerance

Answer 8

Tolerance obtained by immature cells in the generative lymphoid organs - the B-cells or T-cells encounter SELF antigen

Question 9

Peripheral tolerance

Answer 9

Tolerance obtained by mature cells in peripheral lymphoid tissues

Question 10

3rd checkpoint in lymphocyte maturation

Answer 10

Positive and Negative selection: Does the antigen receptor recognize SELF - the strength of this interaction is called avidity

Question 11

Thymocytes

Answer 11

Immature T-cells before expression of TCRβ and TCRα chains

Question 12

Positive selection

Answer 12

Occurs in the thymic cortex - selection of T cells expressing functional T cell receptors that can recognize either Class I MHC or Class II MHC molecules

Question 13

Negative Selection

Answer 13

Occurs in the thymic medulla - Cells that recgonize high avidity self antigens presented on MHCs are killed through apoptosis
- Exception is T-regulatory cells

Question 14

Death by neglect

Answer 14

No recognition of MHC + self-peptide by TCR and co-receptor

Question 15

Double positive thymocytes

Answer 15

Thymocytes that express both CD8+ and CD4+

Question 16

Aire Transcription factor gene

Answer 16

Drives expression of numerous tissue-specific self-peptides of peripheral organs - T-cells that respond to these are eliminated

Question 17

Avidity and Selection

Answer 17

Positive Selection = Low avidity

Negative selection = High avidity

Question 18

Loss of Aire

Answer 18

Results in lack of NEGATIVE SELECETION OF SELF-REACTIVE T CELLS in thymus

Question 19

APECED

Answer 19

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: Patients make auto-antibodies to immune proteins important in the control of fungal infections

Question 20

Treg

Answer 20

T-regulatory cell: Some self reactive CD4+ cells are not deleted but become regulatory Treg
Express Foxp3
When activated in the periphery these cells suppress immune responses

Question 21

Peripheral tolerance mechanisms

Answer 21

Anergy, Suppression, Deletion

Question 22

Treg development

Answer 22

Develop in the thymus following recognition of self-antigen by immature double positive thymocytes - activated in periphery by self antigen and IL-2

Question 23

Anergy: Unresponsiveness

Answer 23

APCs lack costimulatory molecules (B7)

T cells express the CTLA-4 molecule which sends an inhibition to the T cells upon binding APC B7

Question 24

CD28 vs. CTLA-4

Answer 24

T cells express CD28 (ITAM - Activating - high levels of B7) or CTLA-4 (ITIM - Inhibiting - low levels of B7)

Question 25

Supression Mechanisms

Answer 25

Contact dependent: Tregs directly bind to mature T cells to induce inhibitory signaling via CTLA-r surface bound TGFβ killing of targets thorugh perforin
Contact independent: Treg cells secrete high levels of TGFβ and IL-10 that inhibit T-cell activation

Question 26

CTLA-4-IG biologic immunotherapy

Answer 26

Binding domain of CTLA-4 molecule works by binding CD80 and CD86 on antigen presenting cells - prevents those co-stimulatory molecules from binding to CD28 expresed on T cells - Removes 2nd signal, limits T cell activation

Question 27

IPEX syndrome

Answer 27

Due to mutation in Foxp3 and loss of T regulatory cells
Affects boys in infance
Broad regional hyper-inflammatory responses in the mucosa, skin, pancreas and thyroid

Question 28

T-cell deletion

Answer 28

1) Cell death caused by deficiency of survival genes

2) Cell death caused by engagement of death receptors

Question 29

The _______, _______ and ________ of self-antigen recognition may contribute to tolerance or breakdown in tolerance

Answer 29

location, abundance, persistance

Question 30

Central B tolerance: Strong avidity and Low avidity

Answer 30

Strong avidity:
- Receptor editing - rearrangement of IgL chains
- Deletion - negative selection by apoptosis
Low avidity
- Anergy

Question 31

Receptor editing

Answer 31

Generation of new light chains after additional VJ recombination events
Re-expression of BCR - non-self

Question 32

Peripheral B cell tolerance mechanisms

Answer 32

1) Occurs in germinal centers during immune response
2) Differ from normal Naive B cells
- Short lifespan
- Reversible
3) Constitute 1-4% of B cells in blood

Question 33

Autoimmunity (1-2% of individuals)

Answer 33

An immune response against self antigens; failure of tolerance

Question 34

Principle factors in the development of autoimmune disease

Answer 34

1) Inheritance of susceptibility genes which may contribute to FAILURE of SELF-TOLERANCE
2) Environmental triggers which may activate self-reactive lymphocytes

Question 35

Autoimmunity is a mixture of…

Answer 35

Genetic susceptibility
Environmental Triggers
Uncontrolled immune response

Question 36

Mutations in MHC may contribute to autoimmune disease through:

Answer 36

Defect in Central Tolerance - Inefficient display of self-antigens
Defect in Peripheral Tolerance - Mutant MHC may not stimulate Tregs

Question 37

Autoimmunity: Environment (Mechanisms)

Answer 37

1) Microbes induce co-stimulatory molecule expression - self reactive T cells become activated
2) Molecular mimcry - microbial peptide is similar to self peptide