Immunologic tolerance Lecture 1 Flashcards
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
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
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
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
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
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)
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
Anergy
A state of immune unresponsiveness after antigen encounters: lack of co stimulation or inhibitory receptors
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.
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.
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
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
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
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
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.
