Immunological Tolerance Flashcards
Clonality
(Specificity)
Two features of adaptive immunity:
1. Lymphocytes assembles antigen receptors, which ensures each lymphocytes has only one receptor specificity.
2. The rearrengment irreversibly changes in DNA.
Because the specificity is inherited, an individual lymphocyte forms a clonal response
Clonal expansion and deletion
Lymphocyte undergo a process like natural selection called Clonal Expansion
Lymphocytes that recognize antigen divide, producing identical progeny. Thus:
1. Each lymphocyte has a unique receptor
2. High affinity interaction with the receptor causes division of the lymphocyte
3. Differentiated effectors from the lymphocyte will have identical specificity.
4. Individual lymphocytes with receptors for self- or ubiquitous molecules need to be clonally deleted or removed at an early stage.
Main types of Tolerance
Immune System requires tolerance, and selective inactivation of harmful lymphocytes
- Central - Occurs in primary lymphoid organs
- Peripheral - Mature lymphocytes, many mechanism through the body.
Key Differences: Central tolerance happens in the primary lymphoid organs where as peripherial tolerance happens outside the lymphoid organ.
Central Tolerance
- Occurs during the development of immune cells in primary lymphoid organs, primarily in the thymus for T-cells and in the bone marrow for B-cells.
- Negative Selection ensures Self-Tolerance
- T-Cells learn to recognize MHC molecules but not with high affinity.
- Newly developing lymphocytes create receptors that determine fate.
- No Activity -> Apoptosis
- Mild Activiy -> Survival
- Strong Activity -> Apoptosis, receptor editing, or diversion
Peripherial Tolerance
Acts as checkpoint
- When self-reactive T-cells escape into the periphery, peripherial tolerance ensures that they are deleted or become anergic (functionally unresponsive to antigen).
- Peripherial tolerance mechanism operate in peripherial tissue after immune cells have matured and entered circulation (lymph node or circulation).
- Peripherial tolerance = collection of mechanisms that limit peripherial activation.
1. Treg mediates supression of autoreactive cells.
2. Clonal anergy of autoreactive cells
3. Peripherial Deletion
Types of Tolerance
Peripheral Tolerance
Immunological Ignorance
(Preventing autoimmunity)
Ignorance: Lymphocytes do not recognize abundant ligand and/or normally make no effector response. May have low affinity to the ligand, or antigen is not available.
Broken when:
- Infection or injury overcomes potentiates signaling.
- Autoantigen is a TLR ligand.
Peripheral Tolerance
Ignorance breach in systemic lupus flare
- Apoptotic cells are not cleared
- Nuclellar antigents accumulate
- B-cells receptors to anti-nuclear antigens (ANAs) crosslink
- ANA are internalized. DNA triggers TLR9, which acts like co-stimulation.
- ANA B-cells clones expand and may drive lupus-like disease.
Peripheral Tolerance
Anergy
(Monomeric Antigens)
Some antigens are available, but in a poorly immunologic form.
Monomeric antigens poorly crosslink BCRs.
Examples:
1. Rheumatoid factor : IgG is normally monomeric and does not crosslink BCRs well. Infection may cause IgG clustering, and anti-IgG complexes build in rheumatoid arthritis joints.
2. Soluble MHC-I: Pregnancy assocaited to induce toleracne to fetus.
3. Peptide hormones (e.g. Insulin):Insulin is normally monomeric and small. High levels of anti-insulin antibodies are seen in type 1 diabetes.
Peripheral Tolerance
Inhibition
(Privilege)
Auto-reactive T-cells may never encounter the appropiate antigen beacuse it is sequestered in innaccessible tissues.
Privileged tissues typically:
* Do not drain by normal lymphatics and have barrriers to prevent naive T-cells from entering
* Soluble factors promote tolerogenic immune responses
* Receptors may kill or alter immune cells.
Peripheral Tolerance
Inhibition
(Privilege)
Injury or infection may release privileged antigens
Example: Sympathetic ophthalmia
Peripheral Tolerance
Inhibition
(Privilege)
Together: Privilege is an active process with multiple redundancies, not merely exclusion
Other features of privileged tissues
Peripheral Tolerance
Regulatory T-cells
Suppress conventional T-cells
* Depend upon the transcription factor FOXP3
* Express high levels of CD25 and CTLA-4
* Very important lymphocytes because it limits autoimmunity, allergy, food allergy, tumor eradication, transplantation reject, and many more.
Peripherial Tolerance
Treg Development
Central Tregs
* Develop in the thymus from CD4+ SP cells.
* Differentiation is dependent on high affinity self-TCR and IL-2
* Bypassing negative selecition allows for diverse, high affinity-self TCRs
Inducible Tregs
* Generated in the periphery lymph tissues
* Differentiation is dependent on TGF-Beta, and other cytokines
Peripherial Tolerance
Treg Mechanism
- Suppress function of local immune cells, including T-Cells and APC
- Inhibitory cytokines such as IL-10 and TGF-beta can contribute to the suppressive capacity of Tregs, but are not neccessary for Treg function.
Review Peripherial Tolerance
Regulatory T-cells
* Depend upon Foxp3, express high levels of CD25
* Suppress APC and lymphocytes
* Can develop from the thymus due to self-reactivity, or in the periphery
Privileged Sites
* Sites in the body that actively suppress immune responses via above mechanisms.
Immunologica privileged refers to:
Some tissues actively surpass immune responses, and/or prevent lymphocytes from accessing tissues (ignorance)
Small monomeric molecules will not elicit a B-cell response because they cannot cross link BCRs. This is an example of:
Clonal ignorance or clonal anergy
Central Deletion and Tolerance
- Central Tolerance primary lymphoid organs
- T-Cell tolerance occurs in the thymus
- B-cell tolerance occurs in the bone marrow and the meninges for CNS immunity
- T-cell central tolerance occurs in the thymus, an organ dedicated to preventing autoimmunity.
T-cell Central Tolerance
- All peptides presented in the thymus are self-peptides
- So, negative selection (deletion) of T-cells that recognize self is important for preventing immune-mediated damage to tissues.
- If TCR has a high affinity for the MHC/peptide complex, the T-cell will die, leaving T-cells that have TCR that does not bind self, but may bind to peptides from foreign antigens.
Clonal Deletion
Mechanism by which developing T-cells and B-cells are rendered non-reactive to self in the primary lymphoid organs.
Clonal Deletion:Functionally immature clones that recognize antigen undergo a programmed cell death.
Affinity hypothesis: Low affinity interactions rescue death by neglect, high affinity interactions induce apoptosis.
Diversion
T-cell receptor self-affinity also determines if a cell will be clonally deleted or diverted.
Diversion - Clones with high self reactivity will develop into immune suppressive phenotype.
Some T-cell diversion fates:
* Regulatory T cell
* MAIT
* NKT
How can the thymus tolerize against non-thymic antigens?
- The thymus tolerizes against non-thymic antigens primarily through a mechanism involving AIRE (Autoimmune Regulator)-mediated expression of peripheral tissue antigens (PTAs). This process helps establish central tolerance to self-antigens not normally present in the thymus.
- Medullar Thymic Epithelia Cells (mTECs) express almost (85% of) all tissue specific antigen (TSA)
Tissue specific antigens (TSA) - Antigens not available in the circulation for tolerance induction by DCs and MACs
Meddullary Thymic Epithelial Cells (mTEC) - Displays most tissue specific antigens.
Medullar Thymic Epithelia Cells
(mTECs)
- Displays most tissue specific antigens
- mTECS depend on AIRE
- No AIRE = organ-specific autoimmunity
- Mutations in AIRE cause autoimmune polyendocrinopathycandidiases-ectodermal dystrophy (APECED) .
B-Cell Central Tolerance
(Part 1)
Fate of Insy- the insulin reactive B cell
* Receptor editing: Repeats V(D) J recombination on lught chain
* Transitional (IgD+) cell encounters self antigens. Becomes anergic, and undergoes apoptosis.
* When migrating to lymphatic, there is competition to enter follicle.
* Will be converted to a marginal zone B-cell, which makes low affinity IgM.
* If entering follicle, will not get T-cell help and will die.
* If activated, will become anergic or killed by resident NK cells.
* Encounters all peripheral tolerance above.
B-Cell Central Tolerance
(Part 2)
NO THYMUS:
- Bone marrow and meninges
- Central Tolerance is against circulating, and stromal (not TSA) antigens.
- Unlike T cells, against whole biomolecules not MHC-peptides.
B-Cell Central Tolerance
(Part 3)
- Receptor editing -Repeated V(D)J recombination when autoreactive
- Marginal Zone and B-1 diversion -Subsets that secrete large amounts of auto-antibodies with little somatic hypermutation.
- IgA -Tolerogenic antibody class secreted as a dimer through the intestine (most common Ab)
Review about Antibodies
Antibodies have a heavy and light chain
Specificity usually comes through heavy chain, which develops first.
The heavy chains evolved early (jawed vertebrates), but the light chain evolved much later (frogs-mammals) and usually alters heavy chain reactivity and autoreactivity.
Receptors Editing
- Highly self-reactive B-Cells will continue to rearrange their antibody light chain in process termed receptor editing.
- Highly autoreactive cells that cannot receptor edit will anergize and die by neglect.
Review
When functionally immature T-cell clones undergo mitocondrial apoptosis to eliminate self reactive cells it is:
Clonal deletion
T-cell central tolerance occurs in the
Thymus
Oral tolerance is when we do not mount immune responses against ingested food. B-cells in the instestine produce ____ that takes up antigen, passes through M cells, and is presented by resident dendritic cells to ____ + T-Cells know as Tregs.
IgA, FoxP3
What immune response(s) prevent a pathogen from evading immunity by evolving their outer membrane proteins to have the exact same structure as existing self-protein?
The immune responses most relevant to this scenario involve Regulatory T cells (Tregs) for suppressing inappropriate self-reactivity, and mechanisms like affinity maturation, PRR recognition, and epitope spreading for focusing immune responses on the pathogen rather than self-proteins.
