Immunological tolerance Flashcards
Tolerance
Mechanisms by which immunologically reactivity to specific antigens is induced and maintained.
Thymus and T cell development
- Migration
- Thymocytes
- No thymus?
T cell progenitor migrates from the bone marrow to the thymus where they develop into mature T cells.
- Site for somatic recombination for TCR.
- Thymocytes become associated with epithelial cells of the thymus. during development
Thymus is a necessary condition for T cell differentiation.
- Useless or harmful T cells are destroyed via apoptosis
Site for the development of central T cell tolerance.
Without thymus- no mature T cells (as in Di-George syndrome)
Thymus involution
Thymus progressively shrinks after puberty and the degeneration is complete by 30.
- Most active in young
Immunity is not impaired because T cell repertoire established is long-lived.
Purpose of receptor selection
Due to the random process of producing TCRs (to allow diversity), its specificity is also random.
TCRs of different affinities to self-antigens are produced.
- Harmful TcRs–> have high affinity to self-receptors= negatively selected.
- Useless TcRs; do not have affinity to any receptor= ignored.
- Useful TcRs; strong affinity to foreign antigens= positively selected
Thymus microenvironment
Immature T cells start off as double negative T cells (for CD4, CD8)
In the cortex: Positive selection
Medulla: negative selection
T cells become positive positive after positive selection.
- Cells with appropriate affinity for peptide presented on self-MHC complex are selected for.
Positive selection
Process that occurs in the thymic cortex.
Thymocytes TcR that recognise self-MHC on the surface of cortical epithelial cells are stimulated to survive.
- Those that do not undergo apoptosis (remainings removed by macrophages.)
Negative selection
Occurs in the thymic medulla.
APCs; dendritic cells and macrophages at cortico-medullary junction, present MHC I and II, containing self-peptides.
- T cells with TcR that bind strongly undergo apoptosis
- T cells with weak binding, live.
Promiscuous gene expression
Autoimmune regulator (AIRE) is highly expressed in medullary epithelial cells. - Expresses some self-antigens that is not specialised to the thymus.
Allows TcR to develop tolerance to some extrathymic antigens.
Autoimmune polyendocrine syndrome 1
Mutation of AIRE gene
Extrathymic self-antigens are not expressed for T cells to develop tolerance to.
Includes: Candidiasis, ectodermal dysplasia
Peripheral tolerance
When self-tolerance/ tolerance to harmless foreign antigens is induced and maintained outside the thymus.
- i.e lactose, insulin, antigens expressed at puberty.
Mechanisms:
- Ignorance
- Clonal anergy
- Clonal exhaustion
- Supression
Clonal ignorance
When self-reactive lymphocytes fail to recognise or respond to self-antigens in the periphery.
Certain antigens are anatomically sequestrated, so T cells never encounter them.
Anatomically sequestrated antigens
Antigens in immune-privilege sites
- Never encounter the immune system, so leads to clinical ignorance in T cells.
Sites include:
- eyes, testis, uterus, placenta.
Sympathetic opthalmia
Condition caused by disruption in clonal ingnorance.
Trauma to one eye can release intraocular protein antigens into lymph.
- This activates T cells in lymph node leading to attacks on self-antigens in both eyes.
Can cause blindness.
Clonal anergy
T cells encounter antigens but do not undergo co-stimulation (CD40L/ CD28) or its signalling is inhibited by CTLA-4.
CTLA-4
Receptor on T cells that bind to CD80/86/ B7 on B cells to block downstream signalling
- Induces anergy of T cells
- Limits immune response to tumours
Antibodies that block CTLA-4= tumour regression
