tolerance and autoimmunity (michels) Flashcards
tolerance
unresponsiveness to self antigens
anergy
functional unresponsiveness/inactivation that occurs when T cells recognize antigens without adequate levels of costimulators that are needed for full T cell activation
central tolerance
takes place in central lymph organs-B cells in bone marrow-T cells in thymus
when developing lymphocytes encounter these antigens
ex/ negative selection
principal mechanism is cell death (negative selection) and generation of CD4 regulatory T cells
peripheral tolerance
what mature lymphocytes undergo out in body-lymph nodes and spleen
ex/ T reg function, anergy, cell death
T cell development?
positive and negative selection
ons that recognize MHC - selected for central tolerance
Foxp3
transcription factor
signals to become a T reg cell
where are T reg cells formed?
thymus
formed when some immature CD4 t cells recognize self antigen with high affinity, and they do not undergo apopotosis but rather develop into T regs
when does selection for T reg cells occur?
intermediate affinity in thymus (central)
also can happen in periphery when t cells recognize self antigen
leads to upregulation of Foxp3
function of T reg cell
check on immune system to keep it from going out of control
prevent autoimmune diseases
Downmodulate immune response to allergens, pathogens, and cancer cells
also involved transplantation tolerance
T cell development
First step:
DP cells interact with MHC’s on TECs
those that interact are selected positively
Second step:
interact with macrophages, dendritic cells and TEC
sample with self antigen
negative selection–> die b/c bound with high affinity to self antigens
positive selection–> released into periphery as SP that either had weak affinity for Class I (CD8) or Class II (CD4)
intermediate/high affinity–> T regs
what do T reg cells express?
Foxp3 and CD25
CTLA-4–> blocks/depletes B7 from APC’s
CD25
on T reg cells
is the IL-2 receptor
purpose of having this is to bind IL-2 which is the essential T cell growth factor, reducing its availability for responding t cells
what do T reg cells secrete?
IL-10 and TGF-beta
these inhibit the activation of lymphocytes, dendritic cells and macrophages
autoimmunity
results when immune system recognizes self antigens
T reg cells depend on what for survival?
IL-2
T reg cells?
CD4+
anergy?
peripheral T cell tolerance-occurs when T cells activated without co-stimulation**
what can lead to anergic T cell?
1 signal without co-stimulation
2 engagement of inhibitory receptors (CTLA-4)
what happens without co-stimulation in T cell activation?
leads to signaling block-leads to anergy of T cell
co-stimulation in T cells?
B7:CD28 interaction
cell death in mature T cells?
peripheral tolerance-
1- self antigen recognition induces production of pro-apoptotic proteins that induce cell death by the mitochondrial pathway (leak out, activate caspases, etc) normally with costimulation anti-apoptotic signals couteract pro-apoptotic but without costimulation this doesn’t happen
2- recongition of self antigens may lead to coexpression of death receptors and their ligands Fas and FasL
Fas and FasL?
upregulated when T cell recognizes self antigen results in apoptosis
what could break anergy?
a very strong danger signal
tolerogenic antigens? (self)
usually in generative organs
high concentrations
long-lived exposure (bc its self) which means prolonged TCR engagement inducing anergy and apoptosis
immunogenic antigens? (microbes)
in blood and periphery
expression of costimulators typically seen with microbes, which promotes lymphocyte survival and activation
short lived
central B cell tolerance?
in bone marrow
if recognizes self antigen (T-independent antigen)-can die (apoptosis)-can undergo receptor editing
self polysaccharides, lipids, and nucleic acids are t-independent antigens that are not recognized by T cells –> these must induce B cell tolerance to prevent autoantibody production
peripheral B cell tolerance
anergic-if self antigen recognition without T cell help
apoptosis
exclusion from the lymphoid follicle so b cell does not receive survival stimuli
what can mutations in Fas result in?
children with autoimmune diseases
immature B lymphocyte?
IgM+ and IgD-
effector mechanisms of autoimmunity?
circulating autoantibodies
immune complexes
autoreactive T lymphocytes
principle factors in development of autoimmunity?
susceptibility genes and environmental triggers (such as infections)
Type I diabetes
autoimmune destruction of beta cells in pancreas-genetic predisposition - Dq8-thought to be an environmental trigger
can predict the onset based on presence of certain autoantibodies
goes through phases:-genetic predisposition-insulitis-pre-diabetes (loss of first phase insulin response)-diabetes
tolerance-sensitive cell for T cells?
CD4+ CD8+ (double positive) T cells
insulitis
beta cell death (type I diabetes)
types of autoimmune disease?
organ-specific and systemic
what sex has more autoimmune diseases?
female-much more likely in women-don’t know why
factors contributing to autoimmunity
genes, infections, and environmental factors
HLA-B27
ankylosing spondylitisautoimmune disorder
HLA-DR4
rheumatoid arthritisautoimmune disorder
HLA-DR3/DR4
Type I diabetes mellitus
AIRE
gene that if we lose will result in autoimmune polyendocrine syndrome (APS-1)
in this disorder several tissue antigens are not expressed in the thymus so immature T cells specific for these antigens are not eliminated. therefore T cells specific for these antigens are released into the periphery and attack the
Foxp3
defects in this gene lead to deficiency of regulatory T cellscan lead to X-linked polyendocrinopathy and enteropathy (IPEX)
Foxp3 plays a role in the gut
HLA-DR4
pemphigus vulgarisautoimmune disorder
Fas
defect leads to autoimmune hypoproliferative syndrome (ALPS)defective apoptosis of self-reactive T and B cells in periphery
IPEX
from loss of Foxp3 gene
what would cue you to think a single gene defect?
multiple autoimmune disease at early age
action of TGF-beta
inhibit IgE prduction
sooo…. someone with Foxp3 knockout would have decreased Tregs which means they wouldn’t be secreting alot of IL-10 (which normally suppresses IgE production) so their IgE would be very increased (too much TH2 response)
what does finding autoantibodies to GD65 or to pancreatic islets tell you?
it means the person probably has type I DM
action of IL-10
suppress IgE production
how does TGF-beta inhibit IgE formation?
inhibit Id2-repressor of IgE isotype switching
treatment of IPEX
bone marrow transplant-to restore Foxp3 expressing cells
poor prognosis for IPEX
triggers of autoimmunity?
presence of microbe induces co-stimulators on the APC presenting self antigen
molecular mimicry - microbe antigen resembles the self tissue–> leads to self-reactive T cell that recognizes microbial peptide (that is mimicing a self antigen) leading to activation of T cells–> autoimmunity
streptococcus pyogenes?
causes strep throat and rheumatic fever
molecular mimicry for protein on heart muscleactivated T cells will attack cardiac muscle
what is pathogenic in lupus?
auto-antibody
what is pathogenic in diabetes?
T cells
what is pathogenic in myasthenia gravis?
antibody
autoantibodies against acetylcholine receptor
what is pathogenic in multiple sclerosis?
T cells (Th1 cells)
how does IL-4 and IL-13 induce IgE formation?
activate STAT6 to induce isotype switching
stimulatory autoantibodies?
ex/ autoantibodies against TSH receptor bind the TSH receptor and result in upregulation of thyroid hormones (antibody looks like TSH)
Graves disease
inhibitory autoantibodies?
ex/ autoantibody bind the acetylcholine receptor (without activation)–> prevent the muscle activity
by blocking it
myasthenia gravis
autoantibodies
can be stimulatory or blocking
effect of corticosteroids?
immunosuppression
multiple sclerosis
Th1 cell response against myelin –> lymphocytes are releasing cytokines (TH1 cytokines–TNF-alpha and IFN-gamma) leading to vascular permeability (makes it easier for lymphocytes to get into the CNS)
linked to class II alleles
more likely in women with HLA-DR2
characterized by lymphocytes in the CNS (not supposed to be there)
relapsing–> remitting–> this is typical of autoimmune condition
oligoclonal immunoglobulins in central nervous system for MS?
never been exposed to all these new self antigens!
B cells got into the CNS–> now producing a bunch of oligoclonal Ig’s b/c they have never been exposed to those antigens
treatment of multiple sclerosis?
corticosteroid, cyclophosphamide, IFN-beta
trying to dampen immune response
these people are then more susceptible to infections
treatment of MS with IFN-gamma not favorable?
because promoting Th1 cytokines (don’t want that)
since MS is already caused by TH1 response
why feed MBP (myelin basic protein) to mice to prevent EAE?
fed prior to immunizing them with MBP they are protected from EAE
give this protein that has no co-stimulatory molecules/danger signal present causing anergy–>
because this would place self-antigen in their bodies (induce peripheral tolerance)
can you induce EAE in CD28 knockout mice?
no because no co-stimulation
CD28 is the costimulatory signal and is the second signal for activation of T cells
CTLA-4 mice would be really terrible EAE
wouldn’t be a mechanism to shut off t cell activation/responses, so propagation of immune response
cyclophosphamide
immunosuppression
negative selection
negative selection happens if an immature lymphocyte (in thymus) interacts strongly with a self antigen, dsiplayed as a peptide bound to a self MHC. which then leads to that lymphocyte going through apoptosis
CTL4
on recognition of self antigens T cells may also engage this CTL4, which functions to terminate T cell activation
CTL4 recognizes B7 and removes it from the surface of APC’s, reducing costimulation
CTL4 has higher affinity for B7 molecules than CD28, so when B7 levels are low (as normally expected when APC’s are displaying self antigens) then CTL4 is preferentially engaged
TGFbeta
plays a role in the generation of T regs perhaps by stimulating expression of the FoxP3 transcription factor
why is peripheral tolerance necessary?
b/c central tolerance is not absolute
some T cells escape from thymus and are self reactive
what induces co-stimulatory signals
LPS through toll like receptors
chronic inflammation also puts B7 onto APC’s
HLA alleles in autoimmunity
HLA-B27 -Ankylosing spondylitis
HLA-DR4
- RA
- pemphigus vulgaris
HLADQ8- DM type I
usually expressed later on in life
Non-HLA alleles in autoimmunity
Usually these genes are developed early on in life
so children show symptoms ***
single gene defects:
AIRE–> leads to APS-1
FOXP3–> leads to IPEX
FAS–> leads to ALPS
genes that contribute
CD25
CD25 mutation
similar presentation as Foxp3 mutation
CD25 induces transcription of Foxp3 so without this it would look like a Foxp3 deficiency
IL-2
secreted by T cells after they are activated
causes proliferation and differentation of T cells
