Autoimmunity and immunologic tolerance Flashcards
what is the mechanism of T cell central tolerance
formation of Treg cells increased by TGF-B and IL2
death of self-reactive T cell by negative selection
what is the function of AIRE
autoimmune regulator of periphery tissue Ag and responsible for thymic expression of peripheral tissue ag
what will lack of AIRE cause?
Autoimmune polyendocrine syndrome,
which is no central tolerance so T cell attack peripheral tissue
and it will cause chronic mucocutaneous candidiasis
hypoparathyroidism
adrenal insufficiency ( addisons disease)
autoimmune hepatitis, DM1 and vitiligo
what are the mechanism of Peripheral T cell tolerance
1- anergy
2- apoptosis
3- supression by Treg
due to no costimulation
what is the mechnaism of anergy in periphral T cell tolerance?
1- Tc bind to DC without costimulation, causing actiation of ubiqutin ligase causing intraceullar destruction
2- Tc Bind to Dc but with inhibitor R ( CTLA4 or PD1) causing naergy
how CTLA4 inhibit T cell
blocks B7 and removes it from APC so blocking costimulation by CD28
and it has higher affnity for B7 than CD28
how PD1 inhibit T cell
it is expressed on CD8 T cell and CD4 T cell, it has cytoplasmic tail with inhibitory motif with tyrosine and th etyrosine get phopshorylated when binding to PDL1 or PDL2 and it inhibiton activation from CD28 and TCR by binding tyrosine phasphatase kinase
what will happen in mutation in CTLA4 gene
mulitorgan inflammation
how do Treg suppress T cells
CD25 secretion the Alpha chian of IL2R
secertion of FoxP3
what will mutation of FoxP3 cause
immune dysregulation polyendocrinopathy enteropathy Xlinked syndrome ( IPEX)
loss of tolerance
autoimmune damage to endocrine glands causing DM1 and thryoditis with early onset
chornci diarrhea and severe ecze,a
Death of T cell by by sAg
T cell recognize sAg and produce apoptoic protiens wihich will cause mitochondria portiens like cytochrome C to leak out and cause activation of caspase will will cause apoptosis of cell
T cell will recgonize sAg and coexpression of Death Receptor and ligands which will increase caspase synthesis
what will mutation in capsase 8 or 10 cause
Autoimmune lymphoproliferative syndrome
accumlation of lymphocytes
chornic lymphadenopathy
spleenomegaly
hemolytic anemia and thrombocytopenia
mechanism of B cell central tolerance
1- Receptor editing
2- Apoptisis
3- Anergy
what is the mechanism of receptor editing?
immaute B cell will recognize sAg which will acitvate RAG which was inhibtied and i willa ctivate recombinase which will make New Ig Light chian and new ag R
what is the mechanism of Deletion in B cell central tolerance?
B cell recgonize soluble sAg with high affnity and recive death signals apoptosis
what is the mechansim of Anergy in B cell central tolerance
some sAg are recongize with low avidity and just decrease AgR secretion causing anergy
Peripheral B cell tolerance mechanism
basicall no Th cell singaling so apoptosis inhibitng R signling and anergy
why are commensal microbes tolerated
high Treg –> IL10Inc
TLR of DC send inhibitory signals
physical sepration
how is fetal Ag are tolerated
1- peripheral FoxP3 Treg specific for paternal Ag
2- exclusion of inflammatory cell in uterus
poor ag presention
inability to generate Th1 response
Mut in HLA-B27 disease
Ankylosing spondilytis where Tc cells attack joints, cartilage destruction, Bone remodeling and systemic infalmmation
Tc cells attack cell presenting peptides by HLA-B27
HLA-DRB1 mutation
Rheumatoid arthritis and DM1
HLA-DR4 mutation
pemphigus vulgaris, which is blisters on skin and mucus membrane
autoantibody against adhesion molecules in desmosomes causing loss of cell adhesion
Polymorphism of PTPN2
uncontrolled activated of T and B cell casuign RA, SLE and DM1
mutation in NOD2
crohns disease
Mutation in IL23R
IL23 promote proINF Th17
inflammatory bowel disease, psoriasis, and ankylosing spondilyits
Mutation in CTLA4
DM1 and RA and multiorgan inflammation
Mut in FcR2B
SLE due to defective feedback inhibiton
single gene defect in CTLA4
autosome dominant immune dysregulation synddrome
which causes impaired Treg function and loss of T and B cell homeostasis
