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.
