B3 Immunotolerance Flashcards
Intro
Specific non responsiveness to atg (tolerogen). Most frequently seen when young animals are born and shed certain microorganisms without producing any atb.
• Bacteria + viruses can enter the primary lymphoid organs during the foetal development, and they may affect the cells developing cells receptors, inducing an immune tolerance —> no receptors for the atg will be produced. It will never be able to respond with a new response against the pathogens, e.g. BVD
• Dose, quality and route of entry of the atg is also important.
• Immunotolerance is atg specific - do not confuse with immune suppression of immune deficiency (immune is not good or strong enough)
• Immune tolerance can also be induced after birth for a few weeks. This can be used to reduce problems with diseases later in life - allergies in humans rarely develop when there are pathogens around in the environment. The allergen itself is not harmful but the reaction might be.
• Can also be utilised when the immune system is developed —> immune paralysis with high doses of atg treatment with monomeric atg can block certain TCR binding sites, but is not a full tolerance. As long as the molecules are provided the b cells will not produce IgE. o Oral introduction will induce a local tolerance.
Mechanisms of immune tolerance
• Clonal deletion: those cells that can react with the atg are deleted. Irreversible.
• Receptor editing: BCR will increase their affinity, TCR will not. Limited number of point mutations will decrease the affinity
• Clonal ignorance: low affinity to Ag, it will be tolerated.
• Clonal Anergy: immune paralysis that is reversible, based on the high cc of the atg, cells were not killed during foetal life. As the animal grow older certain production of proteins will decrease and the B cells will get out of the paralysis and start to react with the atg again —> they have a receptor for the atg but they are paralysed.
o Second source of autoimmune disease in old animals (other source is when natural immunity goes wrong)
• Immunosuppression: complete tolerance, there are no receptors anymore. Can be induced during foetal life or shortly after birth in the primary lymphoid organs.
o Induced later if atg is combined with immunosuppression.
o Some of the immunosuppressive medicines can target Th or macrophages
o Th —> together with the atg they may leave compete tolerance (T independent Ag)
Forms of immune tolerance:
Central/peripheral, innate/acquired, real/pseudo, long-lasting/transient, humoral/cellular.
• Central immune tolerance - always primary lymphoid organs.
o Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.
o It is the age of the lymphocyte that defines whether an atg that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive.
o Self-tolerance is ‘learned’ during lymphocyte development.
o Central tolerance is distinct from peripheral tolerance in that it occurs while developing immune cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery.
• Peripheral tolerance is immunological tolerance developed after T and B cells mature and enter the periphery.
o These include the suppression of autoreactive cells by ‘regulatory’ T cells (Tregs) and the generation of hypo-responsiveness (anergy) in lymphocytes which encounter antigen in the absence of the co-stimulatory signals that accompany inflammation, or in the presence of coinhibitory signals.
B cell tolerance
• Recognition of atg by the immature B cells in the bone marrow is critical to the development of immunological tolerance to self. This process produces a population of B cells that tolerates self-atgs but may recognise non self atgs.
• Immature B cells expressing only surface IgM molecules undergo negative selection by recognising self- molecules present in the bone marrow.
-Atg induced loss of cells is known as clonal deletion. The cells undergo apoptosis if no receptor editing takes place - the self atg recognising receptor is replaced with a foreign atg recognition receptor.
• Immature B cells that bind soluble self-antigens (i.e. low valence) don’t die but their ability to express IgM on their surfaces is lost ( a result of the downregulation in receptor synthesis due to the development of receptor tolerance - similar to the process of drug tolerance - through constant exposure to self-atg).
• Thus, they migrate to the periphery only expressing IgD (pushed by the division of more B cells) and are unable to respond to Atgs. These B cells are said to be anergic. Only B cells that do not encounter antigens whilst they are maturing in the BM can be activated after they enter the periphery. These cells bear both IgM & IgD receptors and constitute the repertoire of B cells that recognize foreign Atgs.
- B cells may encounter 2 types of antigen,
(1) multivalent cell surface antigens or (2) low valence soluble antigens:
• When immature B cells express surface IgM that recognises ubiquitous self-cell-surface (i.e. multivalent) antigens (such as those of the MHC) they are eliminated by a process known as clonal deletion. These B cells are believed to undergo apoptosis.
-However, there’s an interval before apoptosis during which the self-reactive B cell may be rescued by further gene rearrangements (receptor editing) that may replace the self-reactive receptor with a new, not auto-reactive, receptor.
• Even if mature self-reacting B cells survive intact, they would very rarely be activated as B cells need co-stimulatory signals from T cells & the presence of its recognised atg to proliferate + produce antibodies (Peripheral tolerance). If mature peripheral B cells encounter multivalent Atg (e.g. cell surfaces) they are eliminated via apoptosis. If mature B cells recognise soluble Atg in the periphery in the absence of T cell help, they lose surface IgM receptors and become anergic.
T cell tolerance
T cells are selected with both positive and negative selection - they have to be able to recognise the self MHC and at the same time not recognise the self peptides. The T cell tolerance is induced in the thymus. Positive selection takes place in the thymus cortex which is rich in MHC molecules. If the maturating T cell manage to bind to the surface MHC molecule in the thymus it is saved from apoptosis - the cells that fail to recognise the MHC will die. The process of positive selection also determines if it becomes a CD4 or CD8. Prior to selection all T cells are double CD4/CD8. Depending on which MHC (I or II) they recognise, they will require the one or the other. The negative selection is the same same as the self tolerance of the B cells. It occurs in the cortico-medullary junction of the thymus. The epithelial cells in the junction will signal all T cells recognising self proteins to undergo apoptosis. This clonal selection cannot eliminate every potentially self reactive T cell —> some cells may self recognise proteins found at other sites in the body or only during certain times of development of the individual. These cells must be inactivate din the periphery. Also, many self reactive T ells may not have sufficient affinity for the self atg to be deleted in the thymus.
