(L29) Immunological Tolerance and Autoimmunity Flashcards
Self tolerance
tolerant to self IG
autoimmunity
breakdown of self tolerance
Centeral tolerance
induced in immature self reactive lympocytes at the primary lympoid organs: ensures that mature lymps are not reactive to self antigens.
peripheral tolerance
induced in mature self reactive lymphocytes in the lymph nodes or submucosal tissue. It is needed to prevent activation of potential dangerous lymphocyte clones in the periphery.
What is negative reaction
They way you kill T lymphocytes that react to self ag.
Describe the regulation of centeral and peripheral tolerance
CT: if reactive to self antigens they are deleted by apoptosis, change BCR specificity, or develop into T regs
PT: inactivated (anergy), deleted (apoptosis), supressed by t regs
Central T cell tolerance
- takes place in thymus
- if t cell is strong binding to self ag will be deleted by apoptosis
- if has no affinity at all will also be deleted
- if t cells that bind self are below a threshold but still have some avidity then will migrate into the blood as mature Naieve t cells
T reg cells are what?
Positivley selected in the thymus via strong TCR interactions with self antigens.
T reg cells
- develop in thymus
- positevly selected in thymus via strong TCR interactions with self antigens
- not elimitated by apoptosis after self ag recognition and produce anti apoptotic molecules which protect them from negative selection in thymus.
- T regs express foxp3 trascription factor, cd4 and cd25+, CTLA-4
______ is a critical factor for surival and functional competence for treg cells
Cytokine IL-2
T regs do what? What do they represent?
- serve and prevent potential auto immune rxns in various tissues.
- Represent a long lived population of self antigen specific T cells.
describe induced Tregs
- t regs normally diff inisde the thymus
- mature naieve Th0 cells CAN AQUIRE T regs by being induced (outside the thymus)
- when a naieve CD4+ cell recognizes a self antigen in the precense of TGF-B, foxP3 expression can be induced in naieve cd4+ t cells.
- retinoic acid produced by DC faciliates the generation of fox p3 from naieve t cells
TLDR: YOU NEED TGF-B, IL2 and retinoic acid to make a iTreg
What is made if TGF beta, IL-6 and retinonic acid is present to a Tho cell (naieve)?
TH17
-ag recognition in presense of TFG B, IL-6 prevents foxP3 expression and induces the expression of retinoic acid receptor (rar), orphan nuclear receptor (roryt) leading to th17 cell diff.
Where are Itregs made and where are natrual t regs made
- natrual: thymus
- inducible: Lymph nodes and GI tract
T reg mechanism
binds to TCR on APC with cell to cell contact and pumps out cytokines IL4, 10 and TGF beta which will inhibit the APC which will loose ability to induce effectors.
What do T regs need to survive
IL 2 and fox p3
T regs effect what
Tregs inhibit T cell responses and inhibiton of other cells.
T cell peripheral anergy
- (naieve mature cells in lymphnodes) if AG does not recognize the cd80/cd28 co stimulation will become anergic
- (effector cells in periphery) T cells may engage inhibitory receptors of CTLA 4 and PD1 that cause suppression of T cell responses as these are expressed on CD4 and 8 after AG stimulation
Decribe the check point blockade
-used in cancer patients where you treat them with anti CTLA 4 and PD1 so they are still active
Checkpoint blockade can result in what?
Auto immune rxs
T cell deleteion by apoptosis
This is caused when there is no co stimulation apoptosis is stimulated and apoptotic bodies are made
If death receptor is expressed what happens?
Will die -fas on t cell -fasL on something else (known as the extrinisc apoptic pathway)
Centeral B cell tolerance
- immature B cells that recognize self antigents in BM with high avidity will die by apoptosis or undergo receptor editing and change specificity of their BCR
- weak recognition of self antigens in the BM may lead to anergy of B cells
BCR editing occurs when?
- pre b cells that express the k light chain will yeild a autoreactive BCR
- the self reaction promotes developmental arrest and continued recomination
- receptor editing of IGL chain leads to lampda light chain which lacks self reactivity
Peripheral B cell tolerance (anergy/ apoptosis)
mature b cells that recognize self antigens in peripheral tissues in the abssence of Th cells may be rendered functionally unresponsive or die
How is BCR signaling attenuated?
-cd22 inhibitory receptor is phosporylated by lyn and then recuits SHP 1 tyrosine phosphatase attenuating BCR signaling. A defect in Lyn tyrosine kinase, or shp 1 tyrosne phosphatase, and CD22 inhibitory receptor lead to autoimmunity.
A defect in lyn tyrosine kinase, SHP 1 tyrosne phospoatase and CD22 inhibit receptor will lead to what?
autoimmunity
what can T regs inhibit?
B cells, CTL cells after proliferation and differntation from APC, or effector T cells
What are commensal microbes and what do they do?
found in intesine, respiratory tracts and skin
- inhibit pathogen coloization by inducing t reg cells and IL 10
- help with digestion and have antifflamatiory properties
How to break self tolerance
1) susceptiblity of gene interefe with pathways of self tolerance and lead to persistance of reactive t and b lympocytes
2) enviromental triggers and promote lympocytes to come to the tissues and activation of APCs
3) apcs may activate these self reactive lympocytes generating of effector T cells and auto antibodies that are responsible for auto immune dz
What is the one way to break central tolerance
mutiation on AIRE (Auto immune regulator)
AIRE function
express large number of peripheral tissue restrecive self antigens on medulary thymic epithelial cells.
It is a TF
mutations in it decrase expression of peripheral tissue self antigens in thymus.
It is necessary to show T cells self antigens to do negative selection.m
Mutation in AIRE leads to what
AUTOIMMUNITY AND FAILURE OF NEGATIVE EXPRESSION OF T CELLS
ways to break peripheral tolerance
mutation in genes coding:
- C4
- CTLA
- fas/fastL
- fox p3
- IL-2
- SHIP 1
Role of CTLA-4
Found on T Cells -provides signals that terminate immune reponses and maintain self tolerance. Produced AFTER ag presented to cell.
CTLA 4 activation
- it is low on all t resting cells until activated by an Ag
- ONCE expressed, CTLA 4 terminates activation of T cells
- CTLA 4 is also found on regulatory T cells that mediate supressive activations
CTLA 4 is a ______
homolog of CD28.
It is an inhibotyr receptor.
Intrinsic vs extrinic CTLA action
- intrisnic function of CTLA 4: engagement of CTLA 4 on a T cell will inhibit the action of the T cell
- extrinisc action of CTLA 4: T reg cells with it will bind to B7 on APC blocking B7 and CD28 activation
T cells that are seperated from Ag by the BBB can not be active due to what
immune ingorance/ priviledged sites
Ways to prevent autoimmunity (deletion)
T cells that express fas (CD59) and other cells that have FASL can undergo apoptosis (deletion)
Ways to prevent autoimmunity (inhibition)
CTLA 4 can bind to CD80 on APC which inhibits T cell acivation
Ways to prevent autoimmunity (supression)
Regulatory T cells can inhibit rhough the productions of IL10 and TGF-B
List immune privleged sites
eyes, brain, testis, overies, uters, hair follices
Failure of T or B cell self tolerance leads to
autoimmune dz
What is the gene that is associated with autoimmunity?
MHC genes
Suceptibility genes interact with _______ to cause what?
enviromental factors
etiology of auto immunity
genetic suceptibility –> failure of self tolerance –> funcitonal self reactive lymphocytes and enviromental triggers will lead to activation of self reactive lymphocytes and immune repsonses against self tissues.
Systemic lupus erythematous
type 3 hypersentivity -immune complexes formed
- make susceptible genes of b and t cells for self nuclear antigens
- apoptosis/uv causes increased burden of nuclear antigens
- anti nuclear antibody and antigen complexes form
- this causes a high level of anit nulcera I g production that cause rashes glomerulophitis and arthirits.
RA
- inflamatory disease invloving small and large joints
- inflamation of the synovium associated with distruction of the joint and cartalage and bone
- TH1, 17, B and plasma cells, and MO WILL ENTER THE JOINTS and cause immune complexes to form, cytokne production, and inflamation which will distroy cartlinge abd bone
- also pateints have IGM and IGG circulating called rheumatoid factor taht reacts with the FC portion to IGG.
Most auto immune diseases are ________.
Affected individual inherit _________ that contribute to disease suceptibility.
among the genes that are associated with autoimmunity the strongest are ____ but also polymorphysims in _______ are also associated with auto immunity.
Suseptibilty genes _____ with enviromental factors to cause the disease.
- complex polygenic traits
- multiple genetic polymor[hism
- MHC genes
- non mhc genes (such as ctla4)
- interact with
Ankylosing sondylitis
HLA-B27
Role of enviromental triggers
molecular mimicry examples
- Rheumatic fever is triggered by strep infection and mediated cross ractivity between streptococal ag and cardiac myosin.
- MS: T cells interact with mylein basic protein and peptides from EBV, influenzaz and human papilloma virus.
Polyclonal bystandard activation
robust inflamatory response can cause polyclonal activation of autoractive lyhocytes in the cytokine field.
