Tolerance and Autoimmunity Flashcards
tolerance
unresponsiveness to self antigens
autoimmunity
results when immune system recognizes self antigens
anergy
functional unresponsiveness
central tolerance
takes place in central lymph organs
- B cells in bone marrow
- T cells in thymus
ex/ negative selection
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
ones that recognize MHC - selected for
central tolerance
negative selection if high affinity for MHC and self-antigens
Foxp3
transcription factor
signals to become a T reg cell
where are T reg cells formed?
thymus
when does selection for T reg cells occur?
intermediate affinity
-upregulate Foxp3
function of T reg cell
check on immune system to keep it from going out of control
also involved transplantation tolerance
peripheral T cell tolerance?
Regulatory T cells in the periphery
what do T reg cells express?
Foxp3 and CD25
CD25
on T reg cells
is the IL-2 receptor
what do T reg cells secrete?
IL-10 and TGF-beta
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 happens without co-stimulation in T cell activation?
leads to signaling block
-leads to anergy of T cell
what can lead to anergic T cell?
1 signal without co-stimulation
2 engagement of inhibitory receptors (CTLA-4)
co-stimulation in T cells?
B7:CD28 interaction
what could break anergy?
a very strong danger signal
cell death in T cells?
peripheral tolerance
- normally anti-apoptotic signals are higher
- absence of co-stimulation has more pro-apoptotic signals
Fas and FasL?
upregulated when T cell recognizes self antigen
results in apoptosis
what can mutations in Fas result in?
children with autoimmune diseases
tolerogenic antigens?
usually in generative organs
high concentrations
long-lived exposure (bc its self)
immunogenic antigens?
in blood and periphery
short lived
central B cell tolerance?
in bone marrow
if recognizes self antigen (T-independent antigen)
-can die (apoptosis)
-can undergo receptor editing
peripheral B cell tolerance
anergic
-if self antigen recognition without T cell help
apoptosis
-exclusion from the lymphoid follicle
immature B lymphocyte?
IgM+ and IgD-
tolerance-sensitive cell for T cells?
CD4+ CD8+ (double positive) T cells
effector mechanisms of autoimmunity?
circulating autoantibodies and autoreactive T lymphocytes
principle factors in development of autoimmunity?
susceptibility genes and environmental triggers
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 autoantibodies
goes through phases:
- genetic predisposition
- insulitis
- pre-diabetes (loss of first phase insulin response)
- diabetes
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 spondylitis
autoimmune disorder
HLA-DR4
rheumatoid arthritis
autoimmune disorder
HLA-DR3/DR4
Type I diabetes mellitus
HLA-DR4
pemphigus vulgaris
autoimmune disorder
AIRE
gene that if we lose will result in autoimmune polyendocrine syndrome (APS-1)
responsible for expressing self antigens in the thymus (no negative selection)
Foxp3
defects in this gene lead to deficiency of regulatory T cells
can lead to X-linked polyendocrinopathy and enteropathy (IPEX)
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 IL-10
suppress IgE production
action of TGF-beta
inhibit IgE prduction
what do T reg cells secrete?
IL-10 and TGF-beta
how does IL-4 and IL-13 induce IgE formation?
activate STAT6 to induce isotype switching
how does TGF-beta induce 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
streptococcus pyogenes?
rheumatic fever
molecular mimicry for protein on heart muscle
activated T cells will attack cardiac muscle
what is pathogenic in lupus?
antibody
what is pathogenic in diabetes?
T cells
what is pathogenic in myasthenia gravis?
antibody
what is pathogenic in multiple sclerosis?
T cells
autoantibodies
can be stimulatory or blocking
stimulatory autoantibodies?
ex/ bind the TSH receptor and result in upregulation of thyroid hormones
Graves disease
inhibitory autoantibodies?
ex/ bind the acetylcholine receptor (without activation)
-prevent the muscle activity
myasthenia gravis
effect of corticosteroids?
immunosuppression
cyclophosphamide
immunosuppression
multiple sclerosis
Th1 cell response against mylein
more likely in women HLA-DR2
oligoclonal immunoglobulins in central nervous system for MS?
never been exposed to all these new self antigens!
treatment of multiple sclerosis?
corticosteroid, cyclophosphamide, IFN-beta
treatment of MS with IFN-gamma not favorable?
because promoting Th1 cytokines (don’t want that)
why feed MBP (myelin basic protein) to mice to prevent EAE?
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
CTLA-4 mice would be really terrible EAE
