L14 Autoimmunity Flashcards
What is immunological tolerance?
State of unresponsiveness to an antigen
What is central tolerance (clonal deletion)?
Education/selection of immature lymphocytes to distinguish self from non-self antigens. Occurs in primary lymphoid organs (thymus for T cells, bone marrow for B cells).
Explain how positive selection is done for T cells
(Checking to see if the receptor works and if it can bind to MHC)
Thymocytes (precursor T cells) migrate from bone marrow to thymus, and enter the cortex as double negative (not CD4 or CD8). Then, become double positive (both) and gain a re-arranged antigen receptor (TCR) on the cell surface.
If the cell is successful in binding (sufficient affinity) to self-MHC class 1 and 2 molecules, then they’re selected for. Those that don’t will undergo death by neglect from T cell repertoire
Explain the process of negative selection
(Checking to see if it binds strongly to self-cells)
In the cortex, negative selection occurs (single positive cells express CD8+). Thymic dendritic present cell peptides (self-MHC). If the T cell recognises and binds too strongly, apoptotic cell death occurs.
What percentage of thymocytes have TCR fail or weakly bind to self MHC, and thereby undergo death by neglect?
80%
What percentage of thymocytes are removed by negative selection?
20%
What percentage of thymocytes are preserved?
1-2%
Explain how negative selection occurs in B cells
Precursor B cells receive signals from stromal cells in the bone marrow to rearrange their immunoglobulin genes (which code for antigen receptors - BCRs). Later they are tested against self-antigens in the bone marrow, those that have a strong reaction undergo apoptosis (negative selection).
Later, B-cells migrate through circulatory system to lymphoid organs and are activated there (lymphnoid and spleen). When they recognise foreign antigens, activated B cells give rise to plasma cells and memory cells, leading to antibody secretion and memory cells in the bone marrow and lymphoid tissue.
Explain how anergy (peripheral tolerance) works.
Dendritic cells present antigens derived from host cells in the absence of pathogen attacks. In the absence of a pathogen attack, DC is inot activated due to no co-stimulatory signals which are needed to activate T cells that recognise self MHC: self peptide combination. Thus, when DC encounters an auto-reactive T cell, it inactivates the Th cell (anergised). Thus, there is no Th proliferation, activation, or effector cell generation.
What happens when an activated (presence of stimulatory molecule) dendritic cell with self-antigen is exposed to an anergized cell?
Th cell remains inactivated
What happens during suppression (peripheral tolerance)?
A small portion of T cells don’t undergo apoptosis is negative selection. With the transcription factor, FOXP3, T cell is instructed to become Treg cell. Treg cell inhibits surrounding autoreactive T cell by producing inhibitory cytokines: IL-10 and TGF-b
What do Treg cells do?
Treg cell inhibits surrounding autoreactive T cell by producing inhibitory cytokines
Which cytokines do Treg cells produce?
IL-10 and TGF-b
How does ignorance (peripheral tolerance) work?
There are sites which hold self-peptides (antigens) and are not exposed to the immune system.
What is sympathetic opthalmia?
Damage/trauma to immunologically privileged site (eye) causes release of sequestered eye antigens which is carried to lymph nodes and activate autoreactive T cells. T cells return to eye and encounter antigen in both eyes, thereby launching an immune response in both eyes. Can lead to blindness/visual loss for days-years.
What are the requirements for an autoimmune disease?
- Escape of autoreactive lymphocytes from central tolerance into periphery
- Autoreactive cells need to encounter self-antigens
- Failure of peripheral tolerance mechanisms
- Autoreactive/pathological tissue damage
What is organ-specific immunity? What diseases are correlated with it?
Tissue damage at a particular anatomical location, antibody mediated - type 2 hypersensitivity.
Good-pasture’s syndrome, Myasthenis Gravis, Pemphigus, Graves disease, Hashimoto’s disease
What is good pasture’s syndrome?
Type 2 hypersensitivity:
Autoimmunity against type 4 collagen in the basement membrane (glomeruli - kidney, alveoli - lung). Leads to kidney disfunction and bleeding in lungs.
What is myasthenia Gravis?
Type 2 hypersensitivity:
Antibodies that block Ach receptors, leading to muscle weakness. Leads to life-threatening breathing difficulties.
What is Pemphigus?
Type 2 hypersensitivity:
Auto-antibodies against molecular glue that holds your skin together.
Antibodies against intracellular adhesion molecules (desmogleins) between keratinocytes, causing blisters. Can lead to fatal injections.
What are the two tissue specific diseases affecting the thyroid?
Graves disease and Hashimoto’s disease
What happens in Graves disease?
Autoantibodies mimic the activity of a thyroid-stimulating hormone and bind to its receptor, acting as an agonist. Thus, causing hyperthyroidism.
Results in lots of thryoxin - helps regulate metabolic rate (primary hormone released from thyroid gland). Elevated thryoxin causes for a negative feedback loop, as anterior pituitary signals for lower thyroid-stimulating hormone.
Hence, less thyroid stimulating hormone is seen in people with Graves disease.
What happens in Hashimoto’s disease?
Auto-antibodies against proteins produced by thyroid cell - thryoglobulin and thryoid peroxidase. Antibodies recognise it and complement them. T cell receptors release perfurins and enzymes that drill a hole, causing thryoid cell to undergo apoptosis.
-> tissue destruction of thryoid cell.
What is systemic autoimmunity? Which diseases are associated with this?
Response is not restricted to a particular organ or tissue. Immune complex mediated.
SLE - systemic lupus erythematosus.
