Adaptive immunity Flashcards
What are the clinical outcomes of adaptive immunity?
Fight infection/ immunity to reinfection- vaccination/ kill mutated or tumour cells
Allergy/ autoimmunity/ transplant rejection
What are the adaptive immune cells?
T and B cells- types of lymphocyte found in lymph, secondary lymphoid organs (spleen and nodes), recirculate through lymph and blood
Antigen specificity, naïve- inactivated, memory- activated, effector- during immune response
What are the types of T cells?
CD8+ Cytotoxic T Lymphocyte- kills infected/mutated cells
CD4+ T helper cells- organise immune response by producing different cytokines, TH1, 2, 17, Treg
Describe the process of clonal selection
T and B cells express receptors of random specificity
When bins to specific antigen, activates and proliferates
Daughter cell expresses same receptor
Expanded population mediates immune response, maintained at higher precursor frequency
What are the structures of B cell and T cell receptors?
Both have variable regions at tip (bind to antigen) and constant region
BcR is membrane bound version of antibody with identical specificity, TcR- alpha and beta straight chains
Where are lymphocytes developed?
Arise from hematopoietic stem cells in bone marrow
B- bone marrow
T- matures in thymus from lymphoid progenitor
How is BcR and TcR diversity generated?
- Variable regions are encoded by Variable, Diversity and Joining gene segments
- Multiple copies of V D and J gene segments present in series in genome
- VDJ segments rearranged by somatic recombination to form variable region
- Imprecise and random events occur when DNA breaks and re-joined allowing new nucleotides to be inserted or lost- wasteful
What is combinatorial diversity in BcR and TcR?
Different VDJ combinations
Different heavy and light chains (BcR)
Different alpha/ beta chains (TcR)
What is junctional diversity in BcR and TcR?
Extra/ fewer nucleotides at VDJ junctions
How are antigens recognised?
BcR and antibody recognise soluble antigen in native form- sugar, lipid, chemical or protein
TcR has antigen presented to it on MHC (Major Histocompatibility Complex) molecules on another cell
Protein chopped up into short chain amino acids, loaded onto MHC and presented at surface
What are the types of MHC molecules?
Class 1 and Class 2
CD8+ and CTLs only bind antigen on Class 1
CD4+ T helper cells only bind antigen on Class 2
Describe Class 1 MHC molecules?
On all nucleated cells apart from neurons
Presents only endogenous antigens- proteins from within cell- self proteins, mutated proteins, intracellular pathogen proteins
Describe Class 2 MHC molecules?
Only on specialised Antigen Presenting Cells (APC)
Dendritic cells
Exogenous proteins (outside)- extracellular pathogens, environmental and food proteins and self proteins
What is the structure of a MHC molecule?
Groove/ peptide-binding cleft for loading
CD8- 8-10 amino acids long
CD4- 13-25 amino acids long (larger)
Presents a restricted range of peptides, peptides bind anchor pockets via anchor amino acids, interact with limited range of biochemically similar AA, presents peptide with common motif/ sequence
How is diversity generated in MHC molecules
alleles inherited from mother and father- co-expression
polygeny- multiple independent genes for each MHC type
Polymorphisms- multiple variants of each gene within the human population- mainly in peptide bonding domain
How can MHC molecules cause transplant rejection?
MHC mismatch main cause- tissue compatibility
Virtually impossible for two unrelated individuals to express the same combination of MHC variants
Polymorphisms- MHC foreign
How do we avoid self-reactive immune responses while maintaining sensitivity and specificity to different pathogens?
Central tolerance- deletion of self-reactive T cells in thymus/ B cells in bone marrow
Peripheral tolerance- activation of lymphocytes requires multiple signals or cells become anergic (never respond again), immune regulation by T-regulatory cells
What is the process of T cell selection in the thymus (central tolerance)?
Positive- ability to bind to MHC, signalling allows survival
Negative- strength of binding to MHC presenting self-peptide; strong signalling causes death
95% deleted
What clones are useful in central tolerance?
- Clones with low affinity fail selection and die by neglect
- clones with intermediate selection are positively selected and survive
- Clones with high affinity are negatively selected and deleted
- Some self-specific T cells escape death and become Tregs
Describe peripheral tolerance
Signal 1- MHC antigen presentation between dendritic cell and CD4+ T helper cell
Costimulation signal 2- B7 upregulated by dendritic cell
1 and no 2- activation , anergy/ Treg differentiation- needs danger
What is the role of T regulatory cells in peripheral tolerance?
Natural Tregs recognise self antigens- thymus
Inducible Tregs recognise self or environmental antigens- periphery
When activated, CD4+ Tregs switch off adaptive and innate immune response- produce cytokines that dampen immune responses- IL10, suppresses
