immune tolerance Flashcards
what is immune tolerance
state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune respone
what are the 3 types of immune tolerance
- self tolerance
- prevents damage to self by autoreactive T and B cells (central tolerance and peripheral tolerance) - neonatal (reproductive) tolerance
- necessary for the survival of foetus and placental within pregnant animal (peripheral tolerance) - oral tolerance
- essential that food is tolerated. failure leads to dietary hypersensitivity or IBD (peripheral tolerance in GALT)
what are the mechanisms of central tolerance
- potisive selection (survival of functional lymphocytes)
- negative selection ( deletion of self-reactive lymphocytes)
what are the mechanisms of peripheral tolerance
- apoptosis (B and T cells)
- anergy (B and T cells)
- inactivation by regulatory T cells, macrophages and dendritic cells (B and T cells)
- receptor revision (B cells)
outline the events that occur during the development of tolerance
- central tolerance starts in thymus and is supported by thymic epithelial cells, fibroblasts and dendritic cells
- positive selection of T cells = CD4+ and CD8+ double positive T cells maintain contacts with TEC, T cells interact with class 1 and 2 MHC on surrounding cells and those T cekks are retained (MHC1 binding leads to CD8+ cells and MHC2 = CD4+) this ensures T cells are functional
- negative selection = T cells undergo neg selection against self antigens. T cells which ignore self peptides are retained and those that dont are deleted and recycled. leads to self tolerance
- B cells basically do the same but with more receptor editing and are made in bone marrow (or bursa of fabricius in birds but who cares about birds)
- peripheral tolerance detects faulty T and B cells in secondary lymphoid tissues and delete them or make them anergic. (failure = hypersensitivity)
what 2 signals are required for the activation of naive T cells
- interaction of antigen in association with MHC molecules on the surface of antigen presenting cells
- interactions of co-stimulatory activating molecules such as CD28 on T cells with CD86
how does apoptosis occur
- lack of co-stimulatory signal 2 from antigen presenting cell
- downregulation of survivial factors such as IL-2 in the tissue
- binding of the death receptor
irreversible
how does anergy occur
- lack of co-stimulatory signal 2 from antigen presenting cell
- functional inactivation of lymphocytes that encounter antigen. the inhibitory receptor on antigen presenting cells
reversible
how is peripheral tolerance enforced
- anergy
- apoptosis
- receptor revision
what is oral tolerance
- occurs in the intestinal tract, therefore peripheral (GALT)
- can be antigen specific or inhibit lymphocytes of any specificity in the vicinity
- failure results in hypersensitivity disease
goal: shoudlnt respond to dietary antigens or commensals, but can respond to pathogens
how is oral tolerance developed
- microbiota plays key role in development through promotion of tolerogenic macrophages, dendritic cells and tregs secreting anti-inflammatory molecules like IL-10
- absence of microbiota is associated with a susceptibility to food allergy
- tolerogenic dendritic cells deliver antigen to the draining lymph node and induce od tregs and promote their homing to GALT
- tregs which home to the lamina propria where they interact with macrophages produce IL-10 and expand treg population in situ
- T and B cell anergy and apoptosis also contribute to oral tolerance
- the role of antibodies in iummune tolerance is poorly understood
failure of oral tolerance leads to
immune response to food items leading to food allergies which manifest as:
- atopic dermatitis
- otitis externa
- inflammatory bowel disease
- gluten sensitive eneropathy in irish setters
- protein loosing enteropathy and protein loosing nephropathy in the soft coated wheaten terrier
