Immune Regulation and Tolerance Flashcards Preview

IAHI Block 1 > Immune Regulation and Tolerance > Flashcards

Flashcards in Immune Regulation and Tolerance Deck (37):
1

Immunologic tolerance

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

2

Difference between T cell tolerance and B cell tolerance

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

3

Activation: Immunogenic antigens

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

4

Tolerance: Tolerogenic antigens

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

5

Ignorance: Non Immunogenic

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

6

Whether an antigen will induce tolerance is largely determined by

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

7

Significance of immunologic toleranc

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

8

Central tolerance

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

9

Peripheral tolerance

Tolerance obtained by mature cells in peripheral lymphoid tissues

10

3rd checkpoint in lymphocyte maturation

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

11

Thymocytes

Immature T-cells before expression of TCRβ and TCRα chains

12

Positive selection

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

13

Negative Selection

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

14

Death by neglect

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

15

Double positive thymocytes

Thymocytes that express both CD8+ and CD4+

16

Aire Transcription factor gene

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

17

Avidity and Selection

Positive Selection = Low avidity
Negative selection = High avidity

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Loss of Aire

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

19

APECED

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

20

Treg

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

21

Peripheral tolerance mechanisms

Anergy, Suppression, Deletion

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Treg development

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

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Anergy: Unresponsiveness

APCs lack costimulatory molecules (B7)
T cells express the CTLA-4 molecule which sends an inhibition to the T cells upon binding APC B7

24

CD28 vs. CTLA-4

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

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Supression Mechanisms

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

26

CTLA-4-IG biologic immunotherapy

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

27

IPEX syndrome

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

28

T-cell deletion

1) Cell death caused by deficiency of survival genes
2) Cell death caused by engagement of death receptors

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

location, abundance, persistance

30

Central B tolerance: Strong avidity and Low avidity

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

31

Receptor editing

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

32

Peripheral B cell tolerance mechanisms

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

33

Autoimmunity (1-2% of individuals)

An immune response against self antigens; failure of tolerance

34

Principle factors in the development of autoimmune disease

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

35

Autoimmunity is a mixture of...

Genetic susceptibility
Environmental Triggers
Uncontrolled immune response

36

Mutations in MHC may contribute to autoimmune disease through:

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

37

Autoimmunity: Environment (Mechanisms)

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