16: Tolerance, Autoimmunity, and Transplantation Flashcards
What is tolerance and self-tolerance?
Protection imposed by the immune system to prevent the reaction of its cells and Ab’s against host components.
Central vs peripheral
Evasion, elimination, and engagement.
What is evasion?
When tolerance is favored by the partial partitioning of tissue-specific Ag’s in sensitive or immune-privileged sites, away from most immune circulation and potentially harmful inflammatory mediators.
Location and sequestration.
What is central tolerance?
Occurs in the primary lymphoid organs (PLOs):
- Thymus for T cells
- Bone marrow for B cells
Mechanisms that foster the destruction of self-reactive lymphocytes
(elimination) before they can mature and selection/cultivation to engage in immune inhibitory responses targeting self-Ag’s at tissue sites, protecting against autoimmunity.
Outcomes for selected cells include apoptosis, anergy, or the capacity to later inhibit selected immune responses in the periphery.
What is peripheral tolerance?
- Not all self Ag’s are expressed in the central lymphoid organs where negative selection occur.
- There is a threshold requirement for affinity to self Ag’s before clonal deletion is triggered, allowing some weakly self-reactive clones to survive the weeding-out process.
In secondary lymphoid organs or at tissue site where the relevant self Ag is expressed.
Ag’s that induce tolerance = tolerogens
T cell engaged by a tolerogen have several fates in addition to apoptosis:
- Anergy (unresponsiveness)
- Regulation (engagement leading to suppression)
Name some factors that promote tolerance rather than stimulation of the immune system by a given Ag
- High doses of Ag
- Long-term persistence of Ag in the host
- Intravenous or oral introduction
- Absence of adjuvants (compounds that enhance the immune response to Ag)
- Low levels of costimulation.
- Presentation of Ag by immature or unactivated APCs.
What are regulatory T cells, T_REGs, and how do they function to inhibit anti-self responses?
Types: Natural (tT_REG), peripheral (induced)
Immunophenotype:
– CD4+, CD25++, FoxP3+ (master regulator TF),CTLA-4 (coinhibitory receptor)
Inhibition through:
– Immunosuppressive microenvironment
• Activation of IDO
– Suppressor cytokines:
• IL-10 and TGF-beta
– Absorbs IL-2
– Targeting DC
• Inhibitory molecules (i.e., CTLA-4)
– Effector cytoxicity
Inhibit, decommission, or kill other immune cells that respond to their cognate Ag, including T cells, B cells, and pAPCs.
What are regulatory B cells (B_REGs)?
Can, in addition to regulatory populations of macrophages (MDSCs), suppress inflammation.
Often by secreting compounds like IL-10 and by acting as immune-inhibiting APCs.
What is autoimmunity? Give examples on organ specific and systemic autoimmune diseases.
Autoimmune diseases are caused by immune-stimulatory lymphocytes or Ab’s that recognize self components, resulting in cellular lysis and/or in inflammatory response in the affected organ.
Organ specific:
- Type 1 diabetes
- Hashimoto’s thyroiditis
- Myasthenia gravis
Systemic:
- Rheumatoid arthritis
- Multiple sclerosis
- Systemic lupus erythematosus, (SLE/lupus)
What is the role of genes in autoimmunity?
Genetic variants of one or more immune-related genes are associated with predisposition to most autoimmune disorders, most notably certain MHC (class I and II, HLA) alleles and immune-regulatory genes (e.g., AIRE and FoxP3).
Which environmental factors can influence autoimmunity?
Diet, obesity, smoking, infection, and mucosal microflora.
What causes autoimmunity?
Sex/hormones, microflora,
infection (via polyclonal activation and
molecular mimicry), trauma, carcinogens
and plain old randomness.
- V(D)J recombination (random) => different sets of Ag-specific T cell and B cell receptors.
- Mutations in genes encoding Ag receptors, signaling molecules, costimulatory or inhibitory molecules, apoptosis regulators, or GFs.
- Activation of B cells reactive to self-Ab’s => auto-Ab’s
What is molecular mimicry?
Some pathogens express protein epitopes resembling self-components.
When these enter the body they accidently activate self-reactive cells in a proinflammatory microenvironment, bypassing immune regulation.
How can autoimmune diseases be treated?
Broad-spectrum:
Drugs that suppress systemic inflammation and/or preferentially kill certain leukocytes and their precursors, providing some relief from symptoms but with significant side effects.
Depending on cell/cytokine type:
Blocking of T/B cells, specific pathways, and subsets of cells or their products.
Blocking costimulation:
e.g., CTLA-4Ig fusion protein used in treatment of Rheumatoid arthritis (RA)
Induce tolerance to auto-antigen(s) or redirect the damaging effector response away from its target without impacting other immune processes.
Under investigation.
What is transplantation?
The act of transferring cells, tissues, or organs from one site to another, or from donor to recipient.
Can be needed because of birth defects, infection, burns, trauma, chronic disease…
Histocompatible:
Tissues that share sufficient antigenic similarity, allowing transfer without immunologic rejection.
Give a short description on the four types of transplants
Autograft:
- Self tissue from one body site to another in the same individual.
Isograft:
- Tissue transferred between genetically identical individuals, when the donor and recipient are syngeneic.
Allograft:
- Tissue transferred between genetically different individuals within the same species.
- Most common
Xenograft:
- Tissue transferred between different species.
