Flashcards in Tolerance and Autoimmunity Deck (69):
unresponsiveness to self antigens
results when immune system recognizes self antigens
takes place in central lymph organs
-B cells in bone marrow
-T cells in thymus
ex/ negative selection
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
negative selection if high affinity for MHC and self-antigens
signals to become a T reg cell
where are T reg cells formed?
when does selection for T reg cells occur?
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
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?
T reg cells?
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?
what could break anergy?
a very strong danger signal
cell death in T cells?
-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
usually in generative organs
long-lived exposure (bc its self)
in blood and periphery
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
-if self antigen recognition without T cell help
-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:
-pre-diabetes (loss of first phase insulin response)
beta cell death (type I diabetes)
types of autoimmune disease?
organ-specific and systemic
what sex has more autoimmune diseases?
-much more likely in women
-don't know why
factors contributing to autoimmunity
genes, infections, and environmental factors
Type I diabetes mellitus
gene that if we lose will result in autoimmune polyendocrine syndrome (APS-1)
responsible for expressing self antigens in the thymus (no negative selection)
defects in this gene lead to deficiency of regulatory T cells
can lead to X-linked polyendocrinopathy and enteropathy (IPEX)
defect leads to autoimmune hypoproliferative syndrome (ALPS)
defective apoptosis of self-reactive T and B cells in periphery
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
molecular mimicry for protein on heart muscle
activated T cells will attack cardiac muscle
what is pathogenic in lupus?
what is pathogenic in diabetes?
what is pathogenic in myasthenia gravis?
what is pathogenic in multiple sclerosis?
can be stimulatory or blocking
ex/ bind the TSH receptor and result in upregulation of thyroid hormones
ex/ bind the acetylcholine receptor (without activation)
-prevent the muscle activity
effect of corticosteroids?
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)