Lecture 19 Flashcards
Autoimmunity results from the breakdown of ___-____. The Negative selection of T lymphocytes is not perfect, therefore there is a ____level of physiological auto-reactivity that is crucial to normal immune function.
Self-tolerance
low
(this is because the self antigens can mutate to become pathologic to the body, such as the formation of cancer. The body needs to draw a fine line between self and non-self and therefore needs to be slightly self reactive in order to stand guard at all times)
Compare Central and Peripheral Tolerance in terms of the age of lymphocyte, where they occur, and their purpose
Central Tolerance: induced in immature self-reactive lymphocytes in the primary lymphoid organs
Ensures that mature lymphocytes are not reactive to self-Ags
Peripheral Tolerance: induced in mature self-reactive lymphocytes in peripheral sites
Prevents activation of dangerous lymphocytes in the tissues
Arrange the following processes as either a part of central tolerance of peripheral tolerance
Deleted (apoptosis) Develop into T reg cells Deleted Inactivated (anergy) "Tolerated" (not suppressed) by T reg Cells Change in BCR specificity
Central Tolerance:
Deleted
Change in BCR specificity
Develop into T reg cells
Peripheral Tolerance:
Inactivated (anergy)
Deleted (apoptosis)
“Tolerated” (not suppressed) by T reg Cells
Immunosuppression is ____, while Tolerance is __-_______.
Nonspecific
Ag-Specific
T cells induce tolerance for a specific Ag, unlike the less specific process of suppression
When it comes to T cell central tolerance, which cells present Soluble plasma proteins (circulating) to T cells and which present Tissue proteins (Tissue restricted Ags)? Which of these processes is AIRE involved in and what is its role?
Soluble/Circulating Ags (proteins) are presented to thymocytes in the Thymus by DCs
Tissue Ags (proteins) are presented in the thymus by mTECs (Medullary Thymic Epithelial Cells)
AIRE is a transcription factor that allows mTECs to present a variety of tissue types Ags to Thymocytes
If a thymocyte (immature T cell in the thymus) recognized a self Ag, what are the 2 steps that can occur?
- the thymocyte is killed via negative selection
- or the thymocyte is developed into a T reg cell (CD25+ cell) that enters the peripheral tissues
(these are the “borderline reactive to self Ags” cells)
Compare where in the body T cell and B cell central tolerance occurs
T cell central tolerance occurs in the thymus
B cell central tolerance occurs in the Bone Marrow
Explain what the following levels of avidity in a thymus thymocyte will eventually lead to.
Low avidity:
Medium Avidity:
The brink of Medium and High Avidity:
High Avidity:
Low avidity: programmed cell death (not reactive enough to be useful)
Medium Avidity: Positive selection (will develop into effector CD4+ or CD8+ T cell)
The brink of Medium and High Avidity: Selected to become a CD25+ T reg cell (will express FOXP3 and develop CD4+CD25+CTLA4 on it’s surface)
High Avidity: Negative selection (these are too reactive and are destroyed to prevent autoimmunity)
During the process of B cell development in the bone marrow, RAG induces the heavy chain formation to form a Pre-B cell (with a surrogate light chain). Then RAG induces the light chain formation in an attempt to form an immature B cell. Explain what will happen from the following outcomes after an attempt at the formation of a B cell light chain.
The immature B cell BCR recognizes self Ags:
The immature B cell forms a non-self recognizing BCR:
The immature B cell BCR has weak recognition of self Ags:
The immature B cell BCR recognizes self Ags: either dies by apoptosis or undergoes light chain “receptor editing” to change the BCR specificity (“try again”)
The immature B cell forms a BCR with no affinity for self Ags: The immature B cell goes to the spleen to become a mature B cell (good to go)
The immature B cell BCR has weak recognition of self Ags: Anergy will occur (not useful)
Which chain forms first during the development of a B cell? what are the 2 types of chains that are potentially formed second on a B cell and what is their significance?
The Heavy chain is formed first
The 2 types of light chains are Kappa and Lambda
Kappa is the first to form so the B cell is on it’s first attempt at forming a satisfactory light chain
Lambda light chains on a B cell means that the B cell is on it’s second attempt at forming a satisfactory light chain (Lambda = last chance before apoptosis)
During BCR editing, what is the ratio of Kappa to Lambda light chains on B cells that have made it into the periphery? What 2 transcription factors conduct the BCR editing and are turned off when a satisfactory BCR is formed?
3 : 2
RAG1 and RAG2
True or False:
All cells express Fas, which is the receptor for FasL (ligand) that cytotoxic T cells use to induce the death receptor (extrinsic) pathway of apoptosis. explain.
True
All cells express Fas, however they will only be signalled into apoptosis if an immunological synapse is formed between it and a cytotoxic T cell. Forming the immunological synapse is an antigen specific process, so most cells will not form the synapse.
State the 2 apoptotic deletion pathways that are used to delete self-reactive lymphocytes. Compare these 2 in terms of what they are activated by.(include which is intrinsic and which is extrinsic)
Mitochondrial (intrinsic) pathway: activated by “everything but Fas-FasL interaction”
(Cell injury, Deficiency of growth factors/survival signals, DNA damage, Protein misfolding)
Death Receptor (extrinsic) pathway: activated by Fas-FasL interaction (Fas and TNF receptor)
Which specific type of cells are considered to be key mediators of peripheral tolerance? For these cells state whether they are CD4+/CD8+/CD25+, state their characteristic co-signalling molecule, and state the transcription factor that is responsible for inducing the development of this specific type of cell.
T reg cells
T reg cells = CD4+, CD25+, CTLA4+ , FOXP3+
Explain what 2 processes T reg cells inhibit. What effect do they have on antibody production?
T reg cells inhibit T cell activation by APCs
T reg cells inhibit T-cell differentiation into CTLs
T reg cells may prevent T cells from providing help to B cells in the production of antibodies
For iTreg cells, where in the body are they generated?
iTreg cells are FOXP3+ Treg cells that are generated from peripheral T cells
(Periphery means “outside of the thymus” in LNs or GI tract)
(iTreg cells = Induced T reg cells)
Which cell type are iTreg cells closely “related” to? What is the common Cytokine that affects both of these cells? For both of these cell types, state the cytokines they are exposed to beginning from the naive Th cell stage that both begin at.
iTreg cells are closely related to Th17 cells
Both iTreg and Th17 cells are exposed to TGF-Beta from DC
iTreg cells: TGF-Beta and IL-2 from DC
Th17 cells: TGF-Beta, IL-6, and Retinoic Acid from DC
Describe in detail the process by which FOXP3 is either expressed to form an iTreg cell from a naive Th cell or NOT expressed to form a Th17 cell from a naive Th cell.
Ag recognition in the presence of TGF-Beta induces FOXP3 expression if IL-6 is NOT present (iTreg cell forms)
Ag recognition in the presence of TGF-Beta and IL-6 PREVENTS FOXP3 expression and induces the expression of a RAR (retinoic acid receptor) instead
(RAR stimulated be retinoic acid expresses RORgammat and forms a Th17 cell)
Both Natural Treg cells (from the thymus) and iTreg cells (from LN’s or GI tract) require which cytokine to survive and which transcription factor to develop? What is the function of both of these types of Treg cells?
IL-2 and FOXP3
Both function to suppress the activation of self-reactive lymphocytes
When it comes to B cell tolerance, B cells that recognize self Ags in peripheral tissues in the absence of Th cells will be deleted via apoptosis or exhibit anergy. Explain the other process that can regulate self reactive BCRs (begin with receptor and state the steps)
The CD22 inhibitory receptor is phosphorylated by Lyn, which recruits SHP-1 tyrosine phosphatase
SHP-1 tyrosine phosphatase then attenuates the BCR signaling
What type of issues can arise from defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, or the CD22 inhibitory receptor? briefly explain why.
Autoimmunity
This occurs because Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and CD22 inhibitory receptor all work together to signal for the attenuation of a BCR that is signaling to attack self Ags
The balance of ____ vs ______ signaling controls the outcome of peripheral tolerance. Where in the body and what stage of B cell is peripheral tolerance normally exhibited?
BCR vs. BAFF
(the outcome meaning the formation of a mature B cell or signaling for cell death)
Peripheral tolerance is primarily found in splenic transitional B cells (B cells arrive to the spleen as immature B cells that recognized an antigen and either leave as a mature B cell or die)
Place the following stages of B cell development into the category of central tolerance in the bone marrow, peripheral tolerance in the LN’s, GI tract, or Spleen OR “in between”.
Pro-B cell
Pre-B cell
Immature B cell
T1/2/3 B cell
Mature B cell
Anergic B cell
Central tolerance in bone marrow:
Pro-B cell
Pre-B cell
Immature B cell
“In between”:
T1/2/3 B cell
Anergic B cell
Peripheral tolerance in spleen/LN/GI tract:
Mature B cell
For the following gene, state the role it is supposed to play and what disease occurs when this gene is defective.
AIRE
Role: involved in T cell central tolerance to occur by allowing mTECs (medullary thymic epithelial cells) to present a variety of “tissue Ags” to T lymphocytes
Disease: APS (Autoimmune Polyendocrine Syndrome)
(this autoimmune disease develops bc T cell central tolerance is not conducted properly, creating self reactive T cells)
