L: 19 Immunological Tolerance and Autoimmunity Flashcards
Where is Central Tolerance induced?
In immature self-reactive lymphocytes in the primary lymphoid organs (thymus, bone marrow)
Where is peripheral tolerance induced?
Mature self reactive lymphocytes in peripheral sites
Why is peripheral tolerance needed?
To prevent activation of these potentially dangerous lymphocytes in the tissue
What does central tolerance ensure?
That mature lymphocytes are not reactive to self Ags.
Unlike “nonspecific” immunosuppression tolerance is ?
Ag specific
Immunological Tolerance is specific ___________ to an Ag
Unresponsiveness
What is the result of autoimmunity?
Breakdown of self-tolerance
Immature lymphocytes specific for self Ags may encounter these Ags in the generative lymphoid organs and are either?
What type of tolerance?
- Deleted
- Change BCR specificity(B cells only)
- Developed into Treg cells
Central Tolerance
Mature self-reactive lymphocytes in peripheral tissues may be either?
What type of tolerance?
- Inactivated (anergy)
- Deleted (apoptosis)
- Suppressed by the Treg cells
Peripheral tolerance
The thymus has a special mechanism for expressing many protein Ags that are?
Present only in certain peripheral tissues
TCR signaling in T cells triggers what?
Mitochondrial pathway of apoptosis- negative selection
What 2 things does recognition of self Ags by immature T cells in the thymus lead to?
- Death of the cell by negative selection
2. Development of Treg cells that enter peripheral tissue
Where does Central Tolerance take place?
Thymus
What happens to nonfunctioning thymocytes showing no affinity?
Apoptosis
What happens to strongly self-reactive thymocytes, and where is this determined?
Determined my interaction with MHC self peptide complexes
They are deleted
Thymocytes that are activated by MHC-self peptide complexes below a certain threshold are what?
positively selected and migrate into the periphery as mature T-cells
Most of the thymocytes that migrate into the periphery develop into what?
Effector CD4+ and CD8+ T cells and mediate both cell- mediated and humoral immune response
What happens to only a small percentage of T cells that emigrate from the thymus?
Express FOXP3 and develop into natural CD4+ CD25+ CTLA4+ Treg cells
What happens to immature B cells that recognize self Ags in the bone marrow with high avidity?
Die by apoptosis or undergo receptor editing and change specificity of BCRs
Define receptor editing
Rearrangement and replacement of the IgL-chain genes that occur until non-self recognizing receptors are produced or the cell dies
What may lead to anergy of the B cells?
Weak recognition of self Ags in bone marrow
What are two major mechanisms mediating central tolerance?
Clonal deletion
Anergy
What happens when an immature B-cell reacts with high avidity?
Apoptosis within 2-3 days
What happens when an immature B-cell reacts with low avidity?
induced unresponsiveness or anergy but allowed for migration into peripheral compartment
There is one other mode of selection against autoreactive immature B cells called receptor editing. Describe receptor editing
rearrangement program at the Ig light chain resulting i expression of a new light chain with the existing H chain to form a non-autoreactive BCR
What is the ration of kappa/lambda in peripheral B cells?
3:2
Receptor editing of the IgL chain generates cell-surface immunoglobulin that lack?
Self-reactivity
Deletion of self-reactive lymphocytes occur via what two pathways?
Mitochondrial (intrinsic) pathway Death receptor (extrinsic) pathway
Key mediator of peripheral tolerance?
Treg cells
Treg cells may inhibit T cell activation by _____ and inhibit T-cell differentiation into ____.
APCs
CTLs
Treg cells may prevent T-cells from providing what?
Help to B cells in the production of Abs
What are induced Treg cells?
FOXP3+ Treg cells generated from peripheral mature T cells OUTSIDE the thymus
What cells can also acquire Treg phenotype and function?
iTreg cells (induced) OUTSIDE THE THYMUS
Theree is a close relationship between iTreg and what cells?
Th17
What needs to be present for FoxP3 expression in naive CD4+ cells in vitro?
TGF-Beta
What prevents FoxP3 expression
IL-6
What sparks Th17 cell differentiation?
TGF-B + IL-6 prevents FoxP3 expression and induces retinoic acid receptors (RAR) and related orphan nuclear receptors therefore activating Th17 differentiation
What do Treg cell suppress in peripheral tissues
Activation of self-reactive lymphocytes
Development and survival of regulatory Tcell requires?
IL-2 and FoxP3
Natural Treg cells are generated by?
self Ag recognition in the thymus
Inducible Treg cells are produced by Ag recognition where?
Lymph nodes and GI tract
What attenuates BCR signaling?
CD22 inhibitory receptor is phosphorylated by Lyn and then recruits SHP-1 tyrosine phosphatase
Defects in what Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and CD22 inhibitory receptor leads to what?
Autoimmunity
The balance of what controls the outcome of peripheral tolerance
BCR vs BAFF signaling controls
AIRE deficiency causes?
Failure of central tolerance causing Autoimmune polyendocrine syndrome (APS)
FoxP3 deficiency causes?
Impaired production of regulatory T calls causing IPEX syndrome
C1q and C4 deficiency causes?
Decreased clearance and impaired tolerance induction by apoptotic cells
CTLA-4 polymorphisms causes?
Failure of anergy in CD4+ T cells causing Altered Immune Signaling thresholds
Loss of self tolerance leads to what?
Autoimmunity
What does AIRE stand for?
AutoImmune REgulator
What has a key function as APCs and express large numbers of self-Ags that are presented to developing T-cells
Medullary Thymic Epithelial Cells
Mutations in AIRE proteins cause?
breakdown of central tolerance by decreased expression of Self-Ags in the thymus
AIRE regulates the expression of?
Tissue-restricted Ags (TRAs)
Peptide from what are displayed on the Medullary Thymic Epithelial cells
Tissue restricted Ags (TRAs)
The recognition of TRAs by T-cells leads to?
Deletion of self-reactive T cells
What happens in the absence of AIRE
Self-reactive T-cells are not eliminated and can enter tissue and cause injury
What is outcome of normal T-cell response?
An Effector and Memory T cell
T cell responses are induced when?
- TCR recognizes an Ag presented by APC (signal 1)
2. CD28 recognizes B7 costimulators on the APCs (signal 2)
If the T cell recognizes a self Ag without costimulation, the T cell becomes unresponsive to the Ag because of a block in signal from the TCR complex. What are three possible causes of the block?
- Recruitment of phosphatase to TCR complex
- Activation of Ubiquitin Ligase that degrades signaling protein
- Engagement of inhibitory receptors CTLA-4
What happens with an Anergic T-cell?
Remains viable but unable to respond to the self Ag
T cell activation is regulated by members what family of costimulatory molecules
B7-CD28
Homolog of CD28?
CTLA4
what does CTLA-4 do?
Inhibitory receptor that terminates immune responses and maintains self tolerance
What two autoimmune diseases is caused by polymorphisms in CTLA-4?
Type 1 diabetes and Graves disease
Two important properties of CTLA-4
- Expression is low on resting T-cell until cell is activated by Ag
- CTLA-4 terminates continuing activation of responding Regulatory T cells
Explain CTLA-4 cell intrinsic inhibitory signal?
Engagement of CTLA-4 on T cell delivers inhibitory signal that terminates further activation
Explain Cell-extrinsic Action of CTLA-4
CTLA-4 on Treg cell or responding T-cell binds to B7 on APC or makes unavailable to CD28 blocking T cell activation
Where is CTLA-4 expressed?
Regulatory T-cell and mediates the suppressive function of these cells by inhibiting the activation of naive T cells
Natural Treg cells are ______ selected in the Thymus
Positively
Are Natural Treg cells eliminated by Apoptosis?
No they produce an Anti-apoptotic molecule which protects them from negative selection in the thymus
All Treg cells express______ transcriptional factor and are _____ _____ positive
FoxP3
CD4+ CD25+
All Treg cell express high levels of _______
CTLA-4
What cytokine is critical for the survival and competence of all Treg cells
IL-2
Treg cells are endogenous ________ population of ________ T-cells
Long Lived
Self-Ag-specific
What does growth factor-B inhibit?
Inhibits development of Th1 and Th2 subsets
Inhibits M1 macrophages
Inhibits proliferation of effector function of T-cell
What does growth factor-B Promote?
- Th17 in cooperation with IL-1 and IL-6
- Tissue repair/collogen synthesis
- Stimulates production of IgA by inducing B cells to switch to this isotype
What does Growth Factor-B regulate?
Differentiation of induced FoxP3+Treg cells
What is Autoimmunity essentially caused by?
- Activation of T cells and/or B-cells in the absence of an ongoing infection or discernible cause
- Hypersensetive Immune System that causes one’s own immune system to attack itself
What is immunologic ignorance?
T cells are physically separated from their specific Ag and cannot become activated
Describe the process known as deletion
T-cells that express Fas (CD95) can recieve signal from cells that express FasL and undergo apoptosis
Describe T-cell inhibition
CTLA4 binds CD80 on APC inhibiting T cell activation
Describe T-cell Suppression
Regulatory T cells can inhibit through the production of inhibitory cytokines such as IL-10 and TGFbeta
What is the underlying cause of all autoimmune disease?
Failure of self-tolerance mechanism
What is the first step in autoimmune development?
Inflammation
Genetically most autoimmune diseases are?
Complex polygenic traits. The individual typically inherits multiple genetic polymorphisms that contribute to disease susceptibility
What genes have strongest association to autoimmunity?
MCH genes*
Polymorphism in NON_HLA genes is also associated
Microbial Ags can initiate autoimmune disorders through?
- molecular mimicry
- polyclonal activation
- release of previous sequestered Ag
Who is more common to autoimmune disorders men or woman?
Women. Estrogen exacerbates systemic lupus erythematous by altering B-cell repertoire