Tolerance and Autoimmunity Flashcards
What is immunological tolerance?
A specific unresponsiveness to an Ag
Autoimmunity results from what?
A breakdown in tolerance
Where is central tolerance induced?
In immature self reactive lymphocytes in the primary lymphoid organs
What does central tolerance ensure?
That mature lymphocytes are not reactive to self Ags
Immature lymphocytes specific for self Age may encounter these Ags in the generative (central) lymphoid organs and are either what?
Deleted by apoptosis, change BCR specificity (B cells only) or develop into Treg cells
When is peripheral tolerance induced?
In mature self reactive lymphocytes in LNs or peripheral sites such as submucosal tissue and is needed to prevent the activation of these potentially dangerous lymphocyte clones in the periphery
What can happen to mature self reactive lymphocytes in the peripheral tissues?
Can be inactivated (anergy), deleted by apoptosis or suppressed by Treg cells
Which cytokine is a critical factor for survival and functional competence of Treg cells?
IL-2
What are induced Treg cells (iTregs)?
Mature Th0 cells outside the thymus that have acquired Treg phenotype and function (in LNs and GI tract)
Ag recognition by a naive Th cell in the presence of TGF-beta, IL-2 and RA induces what?
FOXP3 expression if IL-6 is not present resulting in the cell developing into a iTreg cell
Ag recognition by a naive Th cell in the presence of TGF-beta and IL-6 prevents what?
FOXP3 expression leading to Th17 cell differentiation
Retinoic acid, produced by DCs, facilities the generation of what?
Of FOXP3+ induced Treg cells from naive CD4+CD25- T cells
Natural Treg cells are generated by what?
Self ag recognition in the thymus
All B cells with a BCR containing the lambda IgL chain undergo what?
BCR editing
Which cell plays a key role in peripheral tolerance?
Tregs
What happens to a T cell that recognizes an Ag without adequate CD80:CD28 costimulation?
Becomes anergic and incapable of responding to the Ag
Describe the death receptor (extrinsic) pathway for apoptosis
T cell expressing death receptor Fas(CD95) binds to FasL on another cell which causes activation of the initiator caspase in the cell expressing Fas
Cell dies by apoptosis
Describe the mitochondrial (intrinsic) pathway for apoptosis
Cytochrome c and other pro-apoptotic proteins leave the mitochondria and apoptosis pathway is triggered
What role does AIRE play in the breakdown of central tolerance?
Mutations in AIRE protein cause a breakdown of central tolerance and are associated with decreased expression of peripheral tissue self Ags in the thymus
It has been proposed to function as a TF
In the absence of AIRE self reactive T cells are not eliminated and can enter tissues where the Ags continue to be produced and cause injury
Which genes are associated with a breakdown in peripheral tolerance?
C4, CTLA4, Fas/FasL and FOXP3
Describe the cell intrinsic function of CTLA4
Engagement of CTLA4 on a T cell may deliver inhibitory signals that terminate further activation of that cell
Describe the cell extrinsic action of CTLA4
CLTA4 on Treg cells or responding T cells bind to B7 molecules on APCs to make it unavailable to CD28 and blocking T cell activation
Reduced B7 costimulation -> inhibition of T cell activation
What is immunological ignorance?
T cells that are physically separated from heir specific Ags cannot become activated
Which inhibitory cytokines are released by Treg cells?
IL-10 and TGF-beta
What does immune privileged site refer to?
Observation that tissue grafts placed in certain anatomical sites can survive for extended periods of time
Immune privileged sites include?
Eye, brain, pregnant uterus, ovary, testis, adrenal cortex and hair follicles
What is the cause of all autoimmune diseases?
Failure of T or B cell self tolerance
Which gene is strongly associated with autoimmune disorders?
MHC genes (mostly class II)
What are the three different mechanisms by which microbial Ags can initiate an autoimmune disorder?
Molecular mimicry, polyclonal (bystander) activation, and release of previously sequestered Ags
What is molecular mimicry?
Rheumatic fever is triggered by streptococcal infection and mediated by cross reactivity b/w streptococcal Ags and cardiac myosin
MS - T cells react with myelin basic protein and peptides from Epstein-Barr virus, influenza A and HPV
What is polyclonal (bystander) effect?
Microbial infection resulting in a robust inflammatory response can cause a polyclonal activation of auto reactive lymphocytes in the cytokine field
What is the mechanism of releasing previously sequestered Ags?
Microbes that kill cells and cause the release of sequestered Ags (DAMPs) lead to the development of autoimmunity
What are the principal clinical manifestations of SLE?
Rash, arthritis and glomerulonephritis
What is the most frequent Ab found in SLE?
Anti-DNA Abs which are responsible for glomerulonephritis, vasculitis and arthritis in these pts
What is the principal diagnostic test for SLE?
Presence of anti-nuclear (DNA) Abs
What is rheumatoid arthritis?
An inflammatory disease involving small and large joints associated with destruction of joint cartilage and bone
What are the cells involved with RA?
Th1 cells, Th17, activated B cells, plasma cells and macrophages
What is SLE mediated by?
Type III hypersensitivity reactions
What is RA mediated by?
Type IV hypersensitivity reactions in which Th17 cells play a key role
RA pts frequently have circulating what?
IgM or IgG called rheumatoid factor (RF) that react with the Fc portion of circulating IgG
What is the diagnostic test for RA?
Presence of circulating rheumatoid factor
