Tolerance And Regulation Of Lymphocyte Responses (16) Flashcards
What is the importance of immune regulation?
- to avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
- to prevent inappropriate reactions against self antigens
What is autoimmunity?
- immune response against self antigen–> imbalance between immune activation and control
- disorders classified as “immune-mediated inflammatory diseases”
- systemic e.g. lupus or organ-specific e.g. Grave’s disease
- must have susceptibility genes and environmental trigger
What are immune-mediated inflammatory diseases?
- chronic disease w/ prominent inflammation, often caused by failure of tolerance or regulation
- e.g. rheumatoid arthritis, IBS, MS etc…
- may result from immune responses against self antigens or microbial antigens in gut (Crohn’s?)
- systemic or organ specific
- may be caused by T cells or antibodies
What is allergy?
- harmful immune response to non-infectious antigens that causes tissue damage and disease
- can be mediated by antibody (IgE) and mast cells–> acute anaphylactic shock
- or by T cells–> delayed type hypersensitivity
What is hypercytokinemia and sepsis?
- too much immune response (systemic)
- often in a positive feedback loop
- triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate the response correctly
What is the 3 signal model of licensing a response?
- antigen recognition: cell sees antigen
- co-stimulation: cell to cell contact–> molecules on APC clear a space called ‘immune synapse’ on T cell membrane, bringing all TCRs together, enabling them to crosstalk and activate cascade
- cytokine release
Why are immune responses self-limiting?
principal mechanism: immune response eliminates antigen that initiated the response, so the first signal for lymphocyte activation is eliminated
What are the 3 phases of cell mediated immunity?
- induction: MHC w/epitope on DC recognised by TCR and T cell activated
- naive T cell becomes effector cell–> performs function and proliferates
- memory: effector pool contracts to memory
What is a resolution of an infection?
- no tissue damage- returns to normal
- phagocytosis of debris by macrophages
What is repair?
healing w/ scar tissue and regeneration
- fibroblasts and collagen synthesis
What is chronic inflammation?
active inflammation and attempts to repair damage are ongoing
What molecule is a marker that makes immune cells inert/tolerant to persistent antigens (active control mechanism)?
PD-L1
T cells become harder to activate
What is immunological tolerance?
specific unresponsiveness to an antigen, induced by exposure of lymphocytes to that antigen
N.B. all individuals are tolerant of their own antigens (self-tolerance)–> breakdown in self-tolerance leads to autoimmunity
What is central tolerance?
- self-reactive T or B cells in lymphoid organs destroyed before they enter circulation
- if B cell recognises a (self) antigen in bone marrow, it dies by apoptosis
- T cell needs to be able to bind to self-MHC, but not too strongly (otherwise apoptosis is triggered)
What is peripheral tolerance?
self-reactive T or B cells in the circulation are destroyed or controlled by the way that antigen is presented to them
N.B. some B cells change their specificity and some T cells develop into Tregs (suppress immune response and prevent autoimmunity)
What is autoimmune regulator protein (AIRE)?
- a specialised transcription factor that produces the entire repertoire of human proteins by thymus cells–> and all loaded up onto self MHC
- promotes self tolerance
- mutations in AIRE lead to multi-organ autoimmunity, but better at responding to infections (as similar to self)
What is anergy?
- mechanism of peripheral tolerance
- when a naive T cell sees its MHC/peptide ligand without appropriate co-stimulatory protein–> becomes anergic/tolerised
What is ignorance?
- mechanism of peripheral tolerance
- antigen conc. too low or not enough T cells to get activated
- immunologically privileged sites (T cells cannot access) e.g. eye
What is antigen-induced cell death?
- mechanism of peripheral tolerance
- death ligand, Fas induces apoptosis
- anergy but DEATH instead
What are the subsets of CD4 Th cells?
- Th1: produce interferon gamma–> boosts intracellular immune response (anti-viral)
- Th2: produce IL4, IL5, IL13–> boosts anti-multicellular organism response e.g. against parasite
- Tfh (follicular helper T cells): produce IL21, activate B cells
- Th17: secrete IL17 in autoimmune disease e.g. arthritis; important for control of bacteria
- regulatory T cells (Treg): necessary to maintain tolerance to self antigens
What is cross regulation by T cell cytokines?
one type of cytokine shuts down other pathways and boosts own, so no 2 type of CD4 helper response at same time
What are T regulatory cells?
- subset of Th cells
- inhibit other T cells by producing IL10 (anti-inflammatory cytokine)
- make transcription factor Foxp3 that drives IL10 production (absence leads to broad systemic autoimmunity- IPEX syndrome)
What are the different types of Tregs?
- nTreg (natural)
- iTreg (inducible) induced during immune response
How can you lose tolerance?
- exposure to environmental antigens or self-antigens in the context of infections can alter tolerance–> e.g. bacteria Streptococcus pyogenes antigen looks like antigen on heart muscle
- exposure in the wrong place
What is class switching under T cell influence?
- keep variable region the same, but antibody type changes
- cytokine production by T cell leads to different constant immunoglobulin genes being linked to variable region
- cytokine depends on type of Th cell
