Immunologic tolerance Lecture 1 Flashcards Preview

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1

Tolerance

Lack of an imune response when immune cells are exposed to antigen.

Lymphocyte receptors are generated no regard to whetther they are specific for host tissue antigens

normally, we do not mount immune responses to our own tissues. This is called self tolerance

Autoimmune occurs when it fails

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Central tolerance

refers to elimination of self reactive T and B cells during development in the thymus or bone marrow. Some of them can escape this and get into the body

They can be apoptosised, the B cels can change receptrs, and T cells can develop into regulatory T lymphocytes

3

peripheral tolerance

refers to mechanisms after the lymphocyte has left bone marrow or thymus and encounters self antigen

Anergy or apoptosis or get suppressed by the Treg cells

4

T cell tolerance Central

T cells develop in the thymus

T cell receptors develop with sepcificity for both self and foreign antigen

Can be deleted or turned into Treg cells

T cells are exposed to Theymic antigens as they develop in the thymus. However, they also see many antigens not present in thymic tissue

Transcription factor encoded by autoimmune regulatory gene (AIRE) regulates the expression of these peripheral proteins.

Negative selection in the thymus is not perfect and some self reactive T cells will escape and enter the periphery

5

AIRE

Autoimmune regulatory gene encodes a transcription factor that is expressed in the thymic medulla

controls the expression of the thymic tissue restricted antigens

when defective, autoimmune polyendocrine syndrome. T cells with receptors that interact with self antigen escape into the circulation

APS can present with mucocutaneous candidasis, hypoparathydrodism and adrenal insufficiency

6

TREG

CD4 T cells

inhibit the activation fo conventional CD4 and CD8 T cells, and thus can prevent autoimmune and allergic disease

Produce cytokines IL10 and CTLA-4 (blocks B7 molecules on antigen presenting cells)

Expresss CD 25 and the transcription factor Foxp3

FOxp3 mutations cause IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome)

7

T cell tolerance Peripheral

Occurs when self reactive T cells in the periphery reocgnize their self antigen

when a self reactive T cell in the periphery encounters its self antigen it can do one of three things

Anergy, deletion through apoptosis or suppression by TREg cells

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Anergy

A state of immune unresponsiveness after antigen encounters: lack of co stimulation or inhibitory receptors

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Anergy: Lack of costim

T cells need 2 signals to become activated CD4 helper T cell need the MHC and antigen as well as B7 from the antigen presenting cell binding CDC28.

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Anergy: Lack of co-stimulatory

T cells need 2 signals to become activated CD4 helper T cell need the MHC and antigen as well as B7 from the antigen presenting cell binding CDC28.

11

CTLA4 more

always expressed on Tregs and is expressed on cytotoxic T cells after their activation, serving as an "off switch"

Higher affinity for B7 than does CD 28

Mutations in the CTLA4 genes leads to autoimmune disease

Antibodies against CTLA 4 are being developed as cancer immunotherapy drugs to increase the activity of cytotoxic t cells which can recognize and destroy cancer cell.

Ipilimumab blocks negative signaling from CTLA 4

12

CTLA4 more

always expressed on Tregs and is expressed on cytotoxic T cells after their activation, serving as an "off switch"

Higher affinity for B7 than does CD 28

Mutations in the CTLA4 genes leads to autoimmune disease

Antibodies against CTLA 4 are being developed as cancer immunotherapy drugs to increase the activity of cytotoxic t cells which can recognize and destroy cancer cell.

Ipilimumab blocks negative signaling from CTLA 4

13

Deletion through apoptosis

Two pathways can be tirggered by peripheral engagement of T cells with self antigen

Self antigen recognition with poor costimulation can cause the leak of mitochondrial proteins which will activate caspases, enzymes that induce apoptosis

self antigen recognition with poor costimulation can elad to the stimulation of the FAS-FAS L apoptosis pathway

Mutations in FAs and FasL, caspases or mitochondrial pathway of apoptosis result in autoimmune disease

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Suppression by Treg ells

made mostly in the thymus and fox p3 and CD25

grow in response to IL2 so do effector T cells

Inhibit immune system by: producing cytokines like il10 and TGf beta, express CTLA 4 which block B7 and APCs, therefore the APC cannot present to and activate T cells, and consume IL2 so that it is unavailable for effector T cells

15

B cell tolerance Central

Developing B cells encounter self antigen in the bone marrow, they can do one of two things

They can edit their receptors (receptor editing)

Deltion through apoptosis (similar to T cell negative selection) Immature (IgM B cells) deleted when they bind self antigen.

16

B cell receptor Editing

An immature B cell in the bone marrow can interact with self antigen and instead of dying, can reactivate the RAG genes

resume Ig light chain recombination and make new light chain

the same heavy chain is expressed

receptor editing is strictly a b cell phenomenon

17

B cell tolerance Peripheral

Self reactive B cells int he periphery can die or become anergic

B cells that recognize an antigen need help from Helper T cells. The helper T cells might not be available as they themselves could have been deleted or tolerant. Therefore, the B cells do not have the T cell stimulation (CD40 L to CD40). B cells become anergic

B cells in the periphery can recognize the self antigen and die.

Mitoo pathway and Fas FasL pathway

18

Toelrance to commensal microbes

Physical barrier of mucus and epithelium helps to limit the response

T reg cells ceontrol the effector T cell response to commensals

special CD103+ dendritic cells promote Treg cell

IL 10 secretion

19

Maternal tolerance to fetus

The fetus expresses antigens from the father. These are foreign to the mother. Fortunately the mother rarely mounts an immune response towards the fetus. There are a number of proposed mechanisms.

Placental barrier

Treg cells

Exclusion of inflammatory ells from the uterus

poor antigen presentation in the uterus