What is allorecognition?
- The ability of an organism to distinguish its own tissues from those of another
- It manifests itself in the recognition of antigens expressed on the surface of cells of non-self origin
= transplant rejection
What are the cellular processes behind allorecognition?
- MHC dramatically different for each individual
- → ALLORECOGNITION
- Random, instant activation of 10% of all CD4 and CD8 T cells in the body
- Many are memory and effector cells already programmed to defend against pathogens
What is the major histocompatibility complex (MHC)?
- Set of cell surface proteins essential for the adaptive immune system
- Contains large number of immune-related genes
- MHC molecule (class I & II) binds to epitope from antigen and presents it to T-cell receptor
How is MHC expressed?
- MHC expression is co-dominant for each MHC gene
- ∴ both sets of inherited alleles are in each cell
- Total 14 MHC genes
How is diversity in MHC achieved?
- An organism’s MHC repertoire is polygenic (works with other genes to have an effect)
- MHC expression is co-dominant (from both sets of inherited alleles);
- MHC gene variants are highly polymorphic - greatly varying from organism to organism within a species, many different alleles for each MHC gene
Why is MHC diverse?
- Driven by the need to be able to present as many different peptide antigens as possible (to T-cells)
- Each different MHC allele can present a select set of peptides
- To be same from all viruses, need a set of different MHC alleles
→ ∴ infectious diseases are driving the evolution of MHC
List 3 mechanisms of rejection
Adaptive immune response
Depends on type of organ and the type of antigenic mismatch:
- Antibody-mediated cell killing (like type II hypersensitivity)
- T cell-mediated cell killing
- T cell-mediated inflammation (like Type IV hypersensitivity)
What is an allogeneic transplant?
- Patient receives bone marrow or peripheral blood stem cells from another person
- Usually a sibling but can be an unrelated donor
- Usually required following high dose whole body radiotherapy = kills bone marrow cells = loss of blood cell replacement
What is Graft vs Host Disease? (GvHD)
Condition that can occur after an allogeneic transplant
- Allorecognition → The donated bone marrow/peripheral blood stem cells view the recipient’s body as foreign
- Donor’s lymphocytes become activated
- The transplanted lymphocytes attack the body
What is the only way to avoid transplant rejection/GvHD?
Remove antigen:
The perfect MHC match of donor and recipient
Why is it difficult to get a good MHC match?
- Have to match up 7 different genes
- And 2 different types (alleles) of each gene = 14 genes
What are the sources of the 2 best possible MHC matches?
- Genetically identical twins = syngeneic
- Self = autograft
List the 3 classes of immunosuppressant drugs which block alloantigen-specific/adaptive immune priming
By blocking signals or killing lymphocytes:
- Calcineurin inhibitors
- Proliferation blockers
- Monoclonal antibodies
Therefore alloantigen-specific effector functions cannot occur
Name the class of drugs used to block alloantigen-specific effector functions
Glucocorticoids
List the 3 classes of drugs which inhibit the adaptive immune system
Block all lymphocyte activity = inhibit ongoing and new adaptive immune system
- Anti-proliferative drugs - e.g. methotrexate
- Inhibitors of lymphocyte signalling - e.g. ciclosporin
- Biologic inhibtors of lymphocyte signalling
What are the major differences in therapy between transplantation and autoimmunity?
- Different types of immunosuppressant used in the 2 situations
- Can provide blanket immunosuppression from 1st day of transplant, unlike autoimmunity
- Standard best treatment known for transplantation, unlike autoimmunity where a series of drugs are tried to see what works
What is the major consequence of immunosuppression (adaptive IS) after transplantation?
Increased sensitivity to infection
However adults have already encountered many important pathogens which immune system has created memory cells for and antibodies are long-lived
What is AIDS?
- Acquired Immune Deficiency Syndrome
- Caused by HIV
- The final stage of HIV infection
- Body can no longer fight infections
How does HIV develop in the body?
- Virus infects CD4 T lymphocytes
- Increased viral load as decreased CD4 cell count
What causes a patient to reach the AIDS stage of HIV infection?
- AIDS results from catastrophic killing of all CD4 T lymphocytes
- As CD8 killer cells recognise all CD4 cells as virally infected
- Leaves patient highly sensitive to fungal, viral and bacterial infections
What is the first opportunistic infection that many AIDS patients may present with?
- Oral thrush
= infection with Candida fungal infection
- Also Mycobacterium tuberculosis that may have been latent (dormant)
List 3 other opportunistic infections that AIDS patients may present with
- Shingles (Varicella zoster virus)
- Herpes infection (Herpes virus)
- Pneumonia (from fungal Pneumocystis carinii)
List 2 cancer-causing opportunistic infections which AIDS patients may present with
- Karposi’s sarcoma (Human herpes virus 8)
- B-cell lymphoma (uncontrolled Epstein-Barr virus)
In summary, outline the profile of Autoimmunity
- What: Inflammatory damage or specific interference
- When: Chronic or acute
- Where: Systemic or organ-specific
- How: Immune response to self-antigens
- Why: Often genetic
In summary, outline the immune response to Allergy
- What: Inflammation on allergen encounter
- When: Immunopathology, acute
- Where: Organ specific (systemic can be fatal)
- How: Priming to antigens encountered in the environment
- Why: Possibly genetic
In summary, outline the immune response to Transplantation
- What: Killing or inflammatory damage to transplanted organ
- When: Acute or chronic
- Where: Transplanted organ
- How: Immune response to non-self MHC and antigens
- WHy: MHC diversity