Self Non-Self Discrimination Flashcards
What is tolerance?
mechanism by which lymphocytes with self-antigens are either removed or controlled
Where are central tolerance mechanisms active?
Where the lymphocyte is devloping: thymus for T cells and bone marrow for B cells
Where are peripheral tolerance mechanisms active?
secondary lymphoid tissue (nodes; adaptive response) or peripheral tissues (reaction or trigger)
What are the two types of tolerance?
central and peripheral
What are the mechanisms used to induce tolerance?
delete: eliminate the cell
anergize: turn off the cell
ignore: ignore the trigger
regulate: contain the problem (Tregs)
Tregs are a subset of
T helper/CD4+ T cells
What are the mechanisms of central B cell tolerance?
Deletion and anergy
What are the mechanisms of peripheral B cell tolerance?
Ignorance, anergy, death (lack of co-stimulation/T cell help)
T/F B cell tolerance is less efficient than T cell tolerance
True
Why is B cell tolerance less efficient than T cell tolerance?
it’s common to identify self-Ag Abs in normal healthy people - ie in diagnosing viral infections; they tend to be transient
B cell tolerance occurs
in the bone marrow during development
Normal mature B cells are produced from
non-self-reacting immature B cells that appropriately express Ag receptors on the cell surface (ie no cross-linking)
Clonally ignorant B cells result from
Immature B cells with low-affinity binding for self-antigens that is not strong enough to initiate cross-linking that activates the molecule tf it matures but does not react to its Ags
Anergic B cells result from
soluble self-molecules (eg serum proteins) with inefficient cross linking that is still able to trigger the cell; this inappropriate activation turns the cell off (anergy)
B cell apoptosis occurs in tolerance when
Multivalent self-molecules (eg membrane associated ones) cross link extensively with self antigens, inducing cell death by clonal deletion or receptor editing
The major peripheral tolerance mechanism for B cells is
survival signals
What are the 2 survival signals for mature B cell response and survival?
Signals via the surface Ig-Ag interaction (cross-linking) and T cell help (CD40L and some cytokines)
Affinity maturation and isotype switching are dependent on
T cell help, esp CD4+T cells with CD40L
Peripheral B cell tolerance is dependent on
T cell tolerance functioning, because CD4+ T cell help is required for affinity maturation and isotype switching
B cells see
whole proteins or components or whole proteins or pathogens
T cells see
peptide fragments that are processed and presented at the cell surface by MHC
T/F TCR only recognises peptide fragments
False; it also recognizes the MHC - it interacts with the complex of protein fragment and MHC
Why is there a ‘fine balance’ between auto-reactivity and pathogen-specific reactivity in T cells?
because TCRs recognize MHCs, they are self-reactive to a degree - they see self-antigen (MHC)
What is positive selection?
Thymocytes that express TCRs that recognize self-MHC are selected to survive
What is negative selection?
Removal of immature lymphocytes that have strong reactivity to self-peptide
Which lymphocytes survive positive selection?
thymocytes with TCRs that can recognize self-MHC
Negative selection terminates
immature lymphocytes with TCRs that see self-MHC w/self-peptide too well
AIRE
autoimmune regulator of expression
What is the function of AIRE?
it non-specifically turns on gene expression in the thymus of peripheral tissues and their antigens (eg insulin/pancreas) such that immature T cells get exposure to these self-Ags and can be deleted
Where is AIRE expressed?
medullary epithelial cells of the thymus
What is the consequence of defects in AIRE?
failure of negative selection for some self-Ags resulting in autoimmunity
What are the central tolerance mechanisms for T cells?
Deletion (main); selection of Tregs (type of CD4+T cell)
What are the peripheral tolerance mechanisms for T cells?
Deletion, anergy, ignorance, and regulation
T/F Positive selection = tolerance
False; it is more a mechanism of self restriction that is part of tolerance
What are the 2 signals required for T cell activation?
recognition of MHC-peptide by the TCR; costimulation eg CD28 (T cell) ligating CD80/86 on DCs (upregulated by DC ligation of PAMPs - NOD, TLR, etc.)
How does anergy arise in peripheral T cell tolerance?
Failure of Signal 2: costimulation (CD28 on T cell w/ CD80/86 on DC)
What happens without Signal 2 in T cell activation?
failure to proliferate, inactivation (anergy), and tolerance
Treg cells can suppress
all T helper cell and CD8+ T cell responses
nTregs
natural Tregs - derived from thymus during T cell development
iTregs
induced Tregs - derived following activation of naïve CD4 T cells in the presence of TGFb
How do iTregs suppress autoreactivity?
expression of immunosuppressive cytokines IL-10 and TGFb; expression of CTLA4, an inhibitory receptor; release of suppressive molecules
How does CTLA4 (iTregs) work?
CTLA4 also binds CD86 on DCs with higher affinity than CD28; this inhibits co-stimulation (signal 2) and tf activation of naïve T cells
Autoimmune disease is defined by
loss of tolerance
How is tolerance lost?
Self-reactive T or B cells escape regulatory mechanisms (they are deficient)
What are the 3 key components necessary in pathogenesis of immune disease?
genetic susceptibility
environmental factors
loss of self-tolerance
How can ignorance (tolerance) be lost?
Ag becomes available or something that looks like it that is a self-Ag that triggers the response causing these quiescent cells to become self-reactive
How can anergy be lost?
if signal 2 somehow becomes supplied, autoreactive T and B cells can be activated and trigger autoimmunity
How can peripheral B cell tolerance be lost?
CD4+ T cell help is provided from elsewhere, eg co-infection with viruses etc - thought to be why these trigger some autoimmune diseases
T/F Autoimmune responses always result in autoimmune disease
False; they do not always result in AI disease
T/F All autoimmune diseases involve autoimmune responses
True
Autoimmunity results from
a chronic/ongoing autoimmune response with ongoing tissue damage
What are the 2 classes of autoimmune disease?
Organ specific
Systemic
Organ-specific autoimmune diseases are
confined to particular organs or cell types and the Ags recognized are organ specific
Examples of organ specific autoimmunity are
thyroid, ovarian, islet cells, gastric parietal cells (pernicious anaemia); neurological: MS, MG
Systemic autoimmune diseases
affect multiple tissues of the body and the Ags recognized are more ubiquitous
Examples of systemic autoimmune disease are
rheumatoid arthritis, systemic lupus erythematosus (SLE)
B cells are involved in which hypersensitivities?
II (ligand-mediated reactions) and III (IC deposition)
T cells are involved in which hypersensitivities?
IV delayed type
Loss of central tolerance is linked to defects in which gene?
AIRE
Loss of peripheral tolerance is linked to defects in which gene?
FOXP3 (X-linked) leading to loss of Tregs and peripheral tolerance mechanisms
What are examples of B cell mediated autoimmunity?
Graves disease (stimulatory Ab; II); Myasthenia Gravis (inhibitory Ab); SLE (III/IC deposition)
Examples of T-cell mediated autoimmunity are
Type 1 insulin-dependent diabetes mellitus; MS
T1 IDDM occurs more frequently in which HLA types?
HLA DR3-DQ2 and HLA DR4-DQ8
How are T cells implicated in Type 1 IDDM?
destruction of pancreatic B cells by T cell reactivity to islet proteins
How are the particular MHCs for Type 1 IDDM related to its pathogenesis?
thought that these MHCs promote or help present self-antigens more readily
How are T cells implicated in MS?
T cells specific for myelin antigens promote an inflammatory response that degrades the myelin sheath of nerve axons
Which Th cells are predominant in MS destruction?
Th1 and Th17 - pro-inflammatory w/IFNy
Which Th cells are associated with MS remission?
Th2
Dysregulation of what cell type is associated with MS?
Tregs
Which HLA types are more associated with MS?
HLA-DR15 and HLA-DQ6
What is thought to initiate autoimmune diseases?
self-Ags released from injured cells are recognized by B cells; T cells specific for that self peptide activate B cells to differentiate into plasma cells; plasma cells secrete self-Ag Abs that cause inflammation at the injury site, perpetuating the cycle
What is the bystander role in autoimmune disease?
infection of tissue releases self Ags and infects DCs at the same time; get a B cell with self-Ag reacting with a DC with same Ags; T cell can activate B cell or become self-reactive
What is the role of molecular mimicry in autoimmune disease?
Ags from a pathogen are similar to those of self-Ags causing cross-reactivity reactions when the immune system is activated of B cells (eg rheumatic fever) and T cells
