Lecture 1 Flashcards
Define Autoimmunity
This is where the immune system malfunctions and produces an immune response which is detrimental to healthy cells, organs and tissues
Pathogenic mechanisms of autoantibodies to acetylcholine receptor (AChR) (Condition: Myasthenia Gravis)
Autoantibody binding to the AChR on the surface of postsynaptic muscle membrane
activates the complement cascade resulting in the formation of membrane attack complex (MAC) and localized destruction of the postsynaptic membrane.
The immune assault releases shedding of membrane fragments containing AChRs into the synaptic cleft which leads to altered morphology of the postsynaptic membrane.
Autoantibodies cross-link AChR molecules on the postsynaptic muscle membrane, causing endocytosis of the cross-linked AChR molecules and their degradation (antigenic modulation).
This leads to a reduced number of AChR molecules on the postsynaptic membrane
Process of T cell Development (Pos and Neg Selection)
During T cell development: T cell receptors (TCR) are generated randomly but undergo a positive & negative selection process
Selection depends on the strength and duration of the TCR interaction with and the “self-peptide-MHC-complex presented by thymic cells (thymus)
T cells that have low or no self MHC reactivity are neglected
T cells that make the positive selection threshold go on to the next stage
T cells with very high affinity towards self-MHC and past the negative threshold are deleted
The selected T cells may then move into circulation where they undergo another round of checks
2 problems with selection process
TCR’s may theoretically have infinite affinity generated, the mechanisms of selection is thus prone to error and thus development of autoreactive T cells – especially T cells with affinity closer to the negative threshold (as not all antigens are present in the thymus and therefore might be TCR with high affintity to self antigen but cant be deleted as antigen isnt in thmyus)
Another issue is the presence of tissue specific genes that are not expressed in the thymus and are poorly regulated by the autoimmune regulator (AIRE) – autoreactive T cells are therefore not depleted during thymic selection.
Define immune tolerance
an active state of unresponsiveness to specific antigens in an effort to prevent destructive over-reactivity of the immune system. It prevents an immune response to antigens produced by the body itself or recognized from a prior encounter
What are the mechanisms of central tolerance in T cells
+ diagram
and the two factors that will cause the negative selection of self reactive T cell
Pos and Neg Selection - deletion
During their maturation in the thymus, many immature T cells that recognize antigens with high avidity are deleted, and some of the surviving cells in the CD4+ lineage develop into regulatory T cells. This process is called T cell deletion, ornegative selection.
The two main factors that determine if a particular self-antigen will induce negative selection of self-reactive thymocytes are
1. the presence of that antigen in the thymus
2. The affinity of the thymocyte T cell receptors (TCRs) that recognize the antigen.
How are antigens only expressed in peripheral tissues expressed in central tolerance
+ diargram
Antigens present in thymus include many circulating and cell-associated proteins that are widely distributed in tissues.
The thymus also has a special mechanism for expressing many protein antigens that are typically present only in certain peripheral tissues, so that immature T cells specific for these antigens can be deleted from the developing T cell repertoire.
These peripheral tissue antigens are expressed in thymic medullary epithelial cells under the control of the autoimmune regulator (AIRE) protein
How does AIRE work?
When AIRE is present, there is production of TRA’s (tissue restricted antigens) from the medullary thymic epithelial cell which are expressed on the MHC which the T cell can bind to (if strongly then deleted)
However, if AIRE is not present then there is no formation of tissue restricted antigens, so a potentially self reactive T cell is not deleted and goes to periphery where it binds to the self antigen causing autoimmunity.
Mechanisms of peripheral T cell tolerance
anergy, suppression by regulatory T cells, and deletion
What must a TCR bind to?
What are the co-stimualtion molecules?
TCR to MCHII antigen
B7 on APC to CD80/86 on T cell
Peripheral Tolerance (T cells): How does anergy and suppression occur?
Diagrams
- when there is disruption in the signal of the co-stimulation of B7-CD28 either by..
- B7 is not expressed on APC
- Blockage of signal via free CTLA-4 binding to the B7 before the T cell can causing the T cell unable to become activated and thus anergy
Suppression:
Blockage of the co-stimulating signal via cell to cell contact by T-reg cell moving the B7 on APC and binding to it via its CTLA-4 receptor
Peripheral Tolerance (T cells): How does deletion occur?
Diagrams
T lymphocytes that recognize self-antigens with high affinity or are repeatedly stimulated by antigens may die by apoptosis.
Where does peripheral tolerance occur?
Spleen and lymph nodes
Central Tolerance (B cells) mechanisms (list)
Explain anergy
Deletion, receptor editing and anergy
If immature B cells do not bind or bind weakly to Monovalent antigens on cells in the BM, they successfully leave the BM and migrate to secondary lymphoid organs
Immature B cells that react to monovalent antigens have a weak reaction and do not cross link BCR’s. They become functionally unresponsive (anergic) and exit the BM and eventually die by apoptosis in the periphery organs
Central Tolerance (B cells): Receptor Editing
Receptor editing: When BCR’s bind too strongly to self antigens, B cells reactivate their RAG1 and RAG2 genes and initiate a new round of VJ recombination (old light chain is deleted and a new one is generated)
If receptor editing is still not successful these autoreactive B cells will undergo apoptosis (clonal deletion)
BCR binds strongly to multivalent self-antigen / self-antigen present in high concentrations
Development arrested
BCR of autoreactive immature B cell is modified self reactive light chain deleted and replaced with new one
If new BCR no longer self-reactive it continues to develop
If new BCR still self-reactive further light chain rearrangement may occur
If does not resolve = deletion
