Lecture 19: Immunologic Tolerance and Autoimmunity Flashcards
Central tolerance is induced in ____, and where
Immature self reactive lymphocytes in the primary lymphoid organs
Peripheral tolerance is induced in ___ and where
Mature self reactive lymphocytes in peripheral sites
Outcomes of immature lymphocytes in generative lymphoid organs that react with self Ag
Deleted
Change BCR specificity
Develop into Treg cells
Outcomes of mature lymphocytes self reactive lymphocytes in peripheral tissues
Inactivated (anergy)
Apoptosis
Suppressed by Treg cells
Which thymocytes are positively selected
Only those that are activated by MHC self peptide complexes below a certain threshold (affinity cant be too high, but it there has to be some affinity)
What happens to B cells with no/weak/strong recognition of self Ag
None- survive
Weak- May lead to anergy
Strong- Apoptosis or receptor editing
Kappa/lambda light chain ratio in peripheral B cells is
3:2
Treg cells effect on T cells and B cells
May inhibit T cell activation by APC and differentiation
May prevent T cells from helping B cells produce Abs
FoxP3 expression can be induced in naïve CD4 T cells by
Ag recognition in the presence of TGF-b, if IL-6 is NOT present
Ag recognition in the presence of TGF-b and IL-6 does what
Prevents FoxP3 expression and induces expression of retinoic acid receptor (RAR) and then RORyt, causing Th17 cell differentiation
Development and survival of Treg cells requires
IL-2 and FoxP3
CD22 is a BCR inhibitory receptor phosphorylated by Lyn and recruits SHP-1 tyrosine phosphatase, attenuating (weakening) BCR signaling- defects in this cascade can cause what, and why
Autoimmunity, because BCR is not inhibited and may allow reaction to self Ag
Peripheral B cell tolerance depends on
The balance of BCR signaling and BAFF signaling
Which cells would be effected most if IL-2 was depleted and what may occur
Treg cells, autoimmunity
What causes IPEX syndrome
FoxP3 deficiency- impaired production of Treg cells
What is the effect of complement deficiency of C1q and C4
Decreased clearance of immune complexes and impaired tolerance of B cells
What causes Autoimmune polyendocrine syndrome (APS) and what mechanism fails
Defects in AIRE gene- failure of central tolerance
What is the function of medullary thymic epithelial cells, and what role does AIRE play
They have a key function as APCs
They express a large number of self Ags that are presented to developing T cells
Mutations in AIRE is associated with decreased expression of self Ag in thymus- leading to more self reactive T-cells being able to leave undetected
Natural Treg cells are positively selected where via ___ TCR interactions with self Ags
In the thymus via strong TCR interactions
Treg cells express ___ and ___ and are ___/___ positive
Express FoxP3 and CTLA-4
CD4+ CD25+
CD25 is actually what
IL-2 receptor Alpha chain
TGF-b promotes Th17 differentiation in cooperation with what cytokines
IL-1 and IL-6
TGF-b inhibits development of what and activation of what
Differentiation of Th1/Th2 and activation of M1 macrophages
TGF-b stimulates production of what
IgA, by inducing B cells to switch to that isotype
What is typically the first step in autoimmunity development (besides the genetic susceptibility)
Inflammation or an initial innate immune response
What genes are most strongly associated with autoimmunity
MHC
Molecular mimicry
Method of microbial Ag initiating autoimmune disorder
Rheumatic fever is triggered by streptococcal infection and mediated by cross reactivity between streptococcal Ags and cardiac myosin
Polyclonal (bystander) activation
Method of microbial Ag initiation autoimmune disorder
-Can cause polyclonal activation of autoreactive lymphocytes due to massive activation of naïve cells and release of cytokines
Release of previously sequestered Ag
Microbes that kill cells can cause inflammation, the release of sequestered Ags (Ags that are not presented well in the primary lymphoid organs) causing autoimmunity
Autoimmune disease are more common in women because
Estrogens exacerbate SLE (systemic lupus erythematosus) by altering the B cell repertoire in the absence of inflammation
How can drugs alter immune repertoire
Penicillins and cephalosporins can bind to RBC membrane and generate neoantigen that elicits an Auto-Ag causing hemolytic anemia
Blockade of TNF-a and autoimmunity
TNF-a has inhibitory effects on activated T cells
It induces autoimmunity
