Lecture 36 Flashcards
What does tolerance ensure
That the immune system avoids destroying host tissue
Helps keep self-reactive recognition molecules/cells (BCRs and TCRs) from circulating in the blood stream
Where do T cells develop
Initially in bone marrow (early stages) but then migrate to thymus (reach maturity)
Name of developing T cells
Thymocytes
Parts of the Thymus
Cortex–>top/superficial
Medulla–>bottom/deep
Which cells are in the cortex of the thymus
Cortical epithelial cells and thymocytes
Which cells are in the medulla of the Thymus
Medullary epithelial cells, macrophages, and conventional dendritic cells
How do T cell precursors enter the thymus from bone marrow
As double negative (DN) cells
Don’t express CD4 OR CD8
Pathway of receptor expression during T cell development
Double negative (DN), no expression of CD4 OR CD8–>Double positive (DP), expresses BOTH CD4 AND CD8–> Single positive (SP), expresses EITHER CD4 OR CD8
Outcome of Positive selection in T cells
MHC restriction
Selecting thymocytes with receptors capable of binding self-MHC molecules
Outcome of Negative selection in T cells
Self-tolerance
Selecting AGAINST thymocytes with high affinity receptors for self/MHC/self peptide complexes
What do cortical epithelial cells express high levels of
MHC 1 and 2
Outcome of TCR not binding to self-MHC molecules (positive selection)
Death by neglect
Outcome of TCR binding too strongly to self-MHC molecules
Cell death/apoptosis
Outcome of TCR binding with low affinity-just right to self-MHC molecules
Positive selection occurs, proceed to single-positive stage
Outcome of positive selection to MHC II
T cell becomes a SP CD4+ T cell
Outcome of Positive selection to MHC 1
T cell becomes a SP CD8+ T cell
Which cells express Autoimmune regulator (AIRE, transcription factor) (negative selection)
Medullary epithelial cells
Main action of AIRE (autoimmune regulator) (negative selection)
Induce expression of many tissue-specific proteins in thymic epithelial cells (allows many peptides in to then be presented on MHC 1 and 2)
What does AIRE permit (negative selection)
Allows T cells to be screened against self-antigens safely in thymus
Outcome of TCR NOT binding to self-MHC molecules (negative selection)
Cells survive
Outcomes of TCR binding to pMHC (negative selection)
1) Clonal deletion leading to death of self-reactive T cells
2) Clonal anergy (inactivation of autoreactive T cells)
3) Clonal editing (second or third chances at rearranging a non-self-reactive TCR gene)
Where does Peripheral tolerance take place
In periphery
Circulation and secondary lymphoid organs
Main action of Peripheral tolerance
Helps protect against autoreactive thymocytes that have escapes negative selection in thymus (induce anergy)
Which cells help maintain peripheral tolerance
Regulatory T cells (Tregs)
Where does B cell development occur
Starts and majority is in bone marrow, but completed in periphery (including spleen)
Type of selection required for B cells
Negative selection (self-tolerance), no need for MHC restriction/positive selection
Outcomes of Negative selection in B cells (binding to pMHC)
1) Clonal deletion of strongly autoreactive cells (apoptosis)
2) Receptor editing (reactivation of recombination machinery)
3) Anergy (induction of nonresponsiveness to further stimuli)
How are self-antigens presented
Present on stromal cells and other cells or just soluble proteins in circulation
Where do B cells migrate for further maturation
The Spleen
Characteristics of Mature B cells
1) Express high levels of IgM/IgD on their surfaces
2) Negative selection (peripheral tolerance)
3) Recirculate between blood and lymphoid organs
4) Half life ~4.5 months in periphery
Where does receptor editing of potential autoreactive receptors happen
In light chains
What is central tolerance (negative selection)
Induction of immune tolerance IN primary lymphoid organs (bone marrow, thymus) through;
Clonal deletion
Receptor editing
Clonal anergy
What is Peripheral tolerance
Induction of tolerance OUTSIDE primary lymphoid organs through;
Anergy
Deletion
Immune regulation (Tregs)
Mechanisms of Central tolerance
1) Clonal deletion
2) Receptor editing
3) Clonal anergy
Mechanisms of Peripheral tolerance
1) Anergy
2) Deletion
3) Immune regulation (Tregs)
What is autoimmunity
A defect in tolerance
What is organ-specific autoimmunity
Predominant injury of AN (singular) organ or tissue
What is systemic autoimmunity
Injury of MANY (plural) different tissues
Types of mechanism of autoimmunity
1) Cell-mediated autoimmunity (T cells)
2) Antibody-mediated autoimmunity (antibodies)
Malfunction of Cell-mediated autoimmunity results in
Multiple sclerosis, Type 1 diabetes, etc
Malfunction of antibody-mediated autoimmunity results in
Lupus
How are the mechanisms of autoimmunity transferred
Cell-mediated autoimmunity–> T cell transfer
Antibody-mediated autoimmunity–>Serum transfer
