Autoimmunity Flashcards
What is central tolerance
Autoreactive B and T cells are killed in the thymus to prevent auto-reactive lymphocytes from making it to the periphery (clonal deletion)
What is peripheral tolerance?
B and T cells that escape negative selection and encounter self-Ags in the periphery:
1) become overstimulated; undergo activation-induced apoptosis
2) enter a state of anergy (functional un-responsiveness), where lack of co-stimulation results in inability to activate
What are 4 mechanisms for autoimmunity
1) auto-reactive T cells escape thymic deletion
2) failure of peripheral tolerance
3) polyclonal/bystander activation
4) molecular mimicry
Sequestered antigens
1) Antigens normally hidden in the immune system (e.g., inside cells, or from cells of immune-privileged organs) can become exposed during infection
2) Since they are normally sequestered, they aren’t shown to T cells as self-Ags in the process of clonal deletion
3) Release and binding will thereby activate T/B cells
Molecular mimicry
1) In some cases, Ag from pathogens look like self-Ags (cross-reactivity)
2) Can lead to autoimmune response against self-Ags
Polyclonal/bystander activation
1) Typically, autoreactive T-cells do not receive the secondary signal to activate
2) During an infection, autoreactive T cells can receive the signal to activate
What methods are used to treat autoimmunity?
1) Carpet bombing
2) Focused attack
3) Precision guided weapons
4) Nuke (BM transplant)
Carpet bombing
Corticosteroids and cyclophosphamide
Cyclophosphamide
Alkylating agent that cross-links DNA and results in death of ALL proliferating immune cells
Focused attack
Cyclosporin A, FK506, plasmapheresis, anti-CD4
Cyclosporin A, FK506
Inhibits calcineurin/NFAT signaling which inhibits T cell activation
-non-T leukocytes are still functional but ALL T-cell activation is inhibited
Palsmapheresis
Remove either all Ab (total plasma exchange) or specifically remove the autoimmune Ab from blood (plasma absorption - traps antibodies such that they do not re-enter the patient)
Precision guided method
Anti-TCR clones
Anti-TCR clones
Anti-CD4 targets T-cells to stabilize disease
-Depletion of all CD4+ cells = immunocompromised
-Depletion must take place during the correct stage of disease development
Depletion of Ag-specific T cells
Generation of Ab against specific autoimmune TCRs (based on Valpha and Vbeta gene)
BM transplant
1) Deplete patients BM and peripheral leukocytes via chemotherapy and radiation
2) Autologous or allogenic transplant
Allogenic vs autologous BM transplant
Autologous - rejection less likely, but higher chance for autoimmune disease to return
Allogenic - risky due to graft failure, though less likely for autoimmunity to return
Autograft
Transplant self-tissue (e.g., bone reconstruction, burn victims)
Isograft (syngeneic graft)
Transplant tissue from genetically identical individual
Allograft
Tissue from a genetically different member of the same species (express non-self Ags and therefore can be rejected)
Xenograft
Transplant tissue between species
What are the 3 mechanisms of graft rejection?
1) Hyperacute - mediated by pre-existing Abs
2) Acute - mediated by T cells (treated via immunosuppresive drugs)
3) Chronic - unknown mediator
Process of BM transplants
1) Patients are placed on immunosuppressive drugs, radiation, or chemotherapy
2) Patients receive either donor BM or HSCT
3) Transplanted cells engraft in BM niches, proliferate and differentiate
4) T cell precursors traffic to recipient’s thymus where they are educated and tolerized to self-MHC
Graft vs Host disease (GVH)
-Mature T cells can be transferred from donor to recipient
-Recipient does not have an immune system
-Transplanted T cells recognize “foreign” MHC and attack recipient tissues
What is the GVH paradox?
In order to avoid GVH, mature T cells must be screened out prior to transplantation
However, mature T cells are required for successful engraftment
Mature T-cells may also be required to prevent malignancies from developing in the new BM
