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
Clonal exhaustion
Elimination of T cells specific for abundant peripheral antigens
- Due to persistent stimulation of antigens (as seen with chronic infections)
Apoptosis is stimulated by expression of inhibitory receptors of T cells
- CTLA-4
- PD-1
Suppression
Treg cells suppress the activation of effector responses
-Regulates homeostasis and tolerance to self-antigens.
Therapeutic potential
Exploitation of Treg cells in promoting tolerance
- Can be used to promote self-tolerance in autoimmune disease
Can induce tolerance to non-self antigens in : transplantation, Graft vs host disease and allergy.
Can Induce Tumour immunity in cancer patients
IPEX
X-linked syndrome causing a deficiency of Treg cells
Leads to Systemic autoimmunity in 1st year of life
Regulating responses of specific lymphocytes to antigens.
The same antigen can be immunogenic or tolerogneic, depending on its interaction with lymphocytes.
Factors that influence this:
- How antigen is presented
- How the responses of specific lymphocytes to the antigens are regulated.
- Molecular weight of antigen
- Dosage of antigen
- Routes of administration
Molecular weight of antigen and immunological response.
Smaller, soluble, not-aggregated molecules–> favors tolerance.
Large, aggregated, complex molecules–> favors immunogenicity
Dosage of antigen and immunological response.
Very small or large doses–> favors tolerance.
Intermediate doses–> favors immunogenicity
Routes of administration and immunological response.
Following routes can activate T cells to secrete TGF–> stimulate Tree cells - Oral (Treg cells most important in inducing oral tolerance)
- Intratracheal
- Orbital exposure
GALT
Gut-associated lymphoid tissue (i.e Peyer’s patch)
Interactions of food proteins with GALT= essential for oral tolerance.
