Lecture 19 Flashcards
Define central tolerance
Ensures that mature lymphocytes are NOT REACTIVE to self antigens in primary lymphoid organs
Define peripheral tolerance
Needed to prevent activation of these potentially dangerous lymphocytes in the tissues (peripheral sites)
What are the fates of lymphocytes that recognize self antigens in both central and peripheral tolerance?
Central: deleted (apoptosis), change BCR (B cells only), develop into Treg cells
Peripheral: inactivated (anergy), deleted (apoptosis), suppressed by the Treg cells
What happens when there is TCR signaling in immature T cells in the thymus?
Mitochondrial pathway of apoptosis is triggered; negative selection
What kind of cell does this describe? CD4+, CD25+, CTLA4+
Treg cells that express FOXP3 transcription factor
What is the process of receptor editing in B cells?
Rearrangement and replacement of the IgL-chain (lamda) genes; occurs until non-self-recognizing receptors are produced or the cell dies; this process changes the specificity of their BCRs when immature B cells recognize self Ags
What is the result of weak recognition of self Ags by B cells in the bone marrow?
Anergy (functional inactivation); these cells have a reduced lifespan and fail to enter the follicle, but are allowed to migrate into peripheral compartment
What are the 2 pathways for apoptosis of self-reactive lymphocytes? What initiates each pathway?
Mitochondrial (intrinsic) Pathway: initiated by cell injury, deficiency of growth factors/survival signals, DNA damage, and protein misfolding
Death Receptor (extrinsic) Pathway: Fas receptor/Fas ligand, TNF receptor/TNF
What are the ways Treg cells can mediate peripheral resistance?
May inhibit T cell activation by APCs, inhibit T cell differentiation into CTLs, prevent T cells from providing help to B cells in the production of Abs
Where can FOXP3+ Treg cells be generated from?
Thymus from immature lymphocytes and peripheral T cells (induced Treg cells; iTreg cells)
How are iTreg cells generated?
FOXP3 expression is induced by TGF-beta in naive CD4+ cells; Ag recognition in the presence of TGF-beta induces FOXP3 if IL-6 is NOT present; Ag recognition in the presence of both TGF-beta and IL-6 prevents FOXP3 expression and instead induces the expression of the retinoic acid receptor (RAR), related orphan nuclear receptor ROR-gamma-t expression, and Th17 differentiation
Discuss the CD22 inhibitory receptor in B cells
It is phosphorylated by Lyn and recruits SHP-1 tyrosine phosphatase, attenuating BCR signaling; defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and CD22 receptor leads to autoimmunity
If you have high expression of BAFF and low BCR signaling, what happens to the B cell in peripheral tolerance?
B cell matures; low BAFF and high BCR signaling results in apoptosis
What does a AIRE deficiency cause?
Autoimmune Polyendocrine Syndrome; failure of central tolerance; decreased expression of self-Ags by medullary thymic epithelial cells (function as APCs in thymus) needed for selection of T cells
What does a FOXP3 deficiency cause?
IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) Syndrome; impaired production of Treg cells
What does complement deficiency of C1q and C4 cause?
Decreased clearance and impaired tolerance induction by apoptotic cells
What do CTLA-4 polymorphisms cause?
Altered immune signaling, failure of anergy in CD4+ T cells; polymorphisms associated with several autoimmune diseases such as type 1 diabetes and Grave’s disease
What deficiencies are associated with breaking central tolerance?
AIRE
What deficiencies are associated with breaking peripheral tolerance?
C1q, C4, CTLA-4, Fas/FasL, FOXP3, IL-2/IL-2R alpha/beta, SHP-1
What does Fas/FasL deficiency cause?
Defective deletion of anergic self-reactive B cells, reduced deletion of mature CD4+ T cells; autoimmune lympho-proliferative syndrome (ALPS)
What does IL-2/IL-2R alpha/beta deficiency cause?
Defective development, survival or function of Treg cells
What does SHP-1 deficiency cause?
Failure of negative regulation of B cells
What could blocking of signaling in the TCR complex be the cause of?
Recruitment of phosphatases to TCR complex, activation of ubiquitin ligases that degrade signaling proteins, engagement of inhibitory receptors CTLA-4
When T cells recognize self Ags, what is responsible for terminating the T cell responses?
Inhibitory receptors of the CD28 family; main one is CTLA-4
What is the cell-intrinsic mode of CTLA-4 action?
Engagement of CTLA-4 on a T cell may deliver inhibitory signals that terminate further activation of that cell
What is the cell-extrinsic mode of CTLA-4 action?
CTLA-4 on Treg cells or responding T cells bind to B7 molecules on APCs or makes unavailable to CD28 and blocking T cell activation
What is the function of immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO)?
Suppresses T-cell responses and promotes immune tolerance by mechanisms of tryptophan starvation
What is the function of TGF-beta?
Inhibits proliferation and effector functions of T cells, inhibits activation of M1 macrophages, stimulates production of IgA, promotes tissue repair by stimulating collagen synthesis after immune/inflammatory responses
What is the first step in the development of autoimmunity?
Inflammation or an initial innate immune response
What are ways microbial Ags can initiate autoimmune disorder?
Molecular mimicry, polyclonal (bystander) activation, release of previously sequestered Ags
Specific examples on slide 49
T/F: Autoimmune diseases are much more common in men than in women
False; much more common in women than men
