Immunotolerance Flashcards
Describe immunologic tolerance.
-unresponsiveness to antigen induced by exposure to that antigen
-animals had encountered an antigen & would tolerate (not respond) to subsequent exposures of the same antigen
-when lymphocytes encounter antigens the lymphocytes may be:
>activated = immune resp
>inactivated = tolerance
*same antigen may induce immune resp or tolerance depending on conditions of exposure & presence/absences of costimulators
Describe autoimmunity.
-self tolerance = tolerance to self antigens
>normal immune system
>failure of self tolerance = immune resp against self (autologous) antigens -> ‘auto immunity / auto immune diseases’
-self non self discrimination = immune system recog & resp to foreign antigen not self antigens
Describe tolerogens VS immunogens.
-tolerogens = antigens that induce tolerance
-immunogens = generate immunity
Describe the mechanisms of tolerance.
-elim & inactivate lymphocytes that express high affinity receptors for self antigens
-all individuals inherit same antigen receptor gene seg = recombine & expressed in lymphocytes as cells arise from precursor cells
-T & B cells express receptors capable of recog self antigens
-mechanisms of immunologic tolerance prevent reactions
Describe central & peripheral tolerance.
-tolerance is antigen specific resulting from recog of antigens by clones of lymphocytes
-therapeutic immunosuppression = affects lymphocytes
-self tolerance induced in immature self reactive lymphocytes in generative lymphoid organs (central tolerance) or in mature lymphocytes in peripheral tolerance
Describe central tolerance.
-ensures that mature naive lymphocytes are incapable of resp to self antigen expressed in generative lymphoid organs (thymus for T cells & bone marrow for B lymphocytes) = ‘primary/central lymphoid organs’
-occurs during stage in maturation of lymphocytes when encountering antigen leads to cell death/replacement of a self reactive antigen receptor w one that’s not self reactive
-some self reactive lymphocytes complete maturation & in healthy individuals = mechanisms of peripheral tolerance needed to prevent activation
Describe peripheral tolerance.
-mature lymphocyte recog self antigen in peripheral tissue & become incapable of activation by re-exposure to that antigen or die (apoptosis)
-imp to maintain unresponsiveness to self antigens in peripheral tissue & not in generative lymphoid organs
-imp for tolerance to antigens expressed after mature lymphocytes specific for these antigens have already been generated
-maintained by Treg = suppress activation of lymphocytes specific for self
Describe central T cell tolerance.
-during maturation in thymus immature T cells that recog antigen w high affinity die & some surviving cells in CD4 become Tregs
-death of immature T cells as a result of recog of antigen in thymus = deletion / neg selection
>resp for mature T cells leaving thymus & populate peripheral lymphoid tissue that are unresp to self antigens in thymus
>neg selection in double pos T cells in thymic cortex & single pos T cells in medulla
-process affects MHC I & II (IMP for tolerance in CD8 & CD4 lymphocytes
Describe AIRE.
-peripheral tissue antigens made in medullary thymic epi cells (MTECs) under control of AIRE protein
-autoimmune disease = antibody & lymphocyte mediated injury to endocrine organs
Describe the mechanisms of peripheral tolerance.
- Anergy = functional unresp
- Suppression by Tregs
- Deletion (cell death)
Describe anergy.
-mature CD4 T cell exposure to antigen in absence of costim or innate immunity = cells are made incapable of resp to that antigen
-anergy = self reactive cells not killed but are unresp to antigen
-full activation of T cells requires the recog of antigen by TCR (signal 1) & recog of costim by B7-1 & B7-2 by CD28 (signal 2)
-prolonged signal 1 may lead to anergy
Describe the mechanisms that function to induce & maintain anergic state.
- TCR induced signal transduction blocked
- Self antigen recog without costim may activate cellular ubiquitin ligases (ubiquitinate TCR associated proteins) & target them for proteolytic degradation in proteasomes or lysosomes
- T cells recog self antigen in absence of innate immune resp = express inhibitory receptors of CD28 (terminate T cell resp)
Describe suppression by Treg cells.
-suppress immune resp
-CD4 Treg express high levels of IL2 receptor a chain (CD25) & transcription factor FOXP3
-Treg generated by self antigen recog in thymus & recog of self & foreign antigen in peripheral tissues
-Treg develop after inflammatory reaction
-majority of Treg in lymphoid tissue derived from thymus due to self antigen expression
-IL2 = gen, survival, functional Treg
-TGFB = generation of Treg requirement
Describe the deletion of T cells by apoptotic cell death.
-T lymphocytes recog self antigen w high affinity or repeatedly stim by antigens die by apoptosis
*2 pathways of apoptosis:
1. Mitochondrial (intrinsic) pathway
2. Death receptor (extrinsic) pathway
