Zusammenfassung der Ressource
Adaptive Immune System
- Humoral
- Antibodies
- Functions
- Bind very specifically to an antigen
- Neutralisaiton
- Mark for phagocytosis
- Activates complement system
- Structure
- 5 isotypes: IgA, IgD, IgE, IgG and IgM
- IgG most common
- Y shaped
- 4 polypeptides
- Heavy chains help together by
covalent intermolecular-disulphide
bonds
- Heavy chain and light chain held together by
covalent intermolecular-disulphide bonds
- Antigen binding sites found at teh N-terminus of polypeptides
- Variability found in the amino acids of the antigen binding sites
- HV = hypervariable
- CDR = complementarity determining regions
- Epitope = region (small portion) of an
antigen that the antibody recognises
- Antigens
- Antigenicity is the ability to
combine with antibodies
- Immunogenicity is the ability to induce
humoral (or cell mediated) immune
response
- Foreigness
- Molecular size (large molecules are generally
more immunogenic than small ones)
- Chemical composition
- Heterogeneity
- Generation of antibody diveristy
- Can produce billions of different antibodies
- Production of variable regions of light and heavy
antibody genes by DNA rearrangement
- In all cells apart form B-cells
immunoglobulin genes are in a form
that cannot be expressed
- J = Joining, D = Diversity,
V = variable
- Random recombination of gene segments
produces diveristy
- Recombine signal sequences (RSSs) flank the 3' of V segment,
both sides of D segment and 5' of J segement
- Recombination can only occur between RSSs of different types
- Ensures correct order of joining
- RAG = Recombination activating gene - mediates recombination
- Additional diversity is added by recombination enzymes
- P-nucleotides generate palindromic sequences
at the cut ends of DNA strands
- N-nucleotides are added at random to the cut end
by terminal deoxynucleotidyl transferase (TfT)
- Overview
- 1. RAG complex binds to and cleaves recobination
signal sequences to yield a DNA hairpin
- 2. RAG-mediated cleavage of hairpin
generates palindromic P-nucleotides
- 3. N-nucleotide additions by TdT
- 4. Pairing of strands
- 5. Unpaired nucleotides are removed by an
exonuclease
- 6. These gaps are filled by DNA synthesis
and ligation to form coding joint
- Naive B-cells use alternative splicing to yield IgM or IgD
- Membrane bound immunoglobulins are
complexed with other proteins to
functional B-cell receptors
- Each B-cell has a single antigen specificity
- Immunoglobulin gene rearrangement
tightly regulated so that only on H and on
L chain are expressed
- B-cells that don't produce functional
immunoglobulin are eliminated from
population
- Development on B-cells
- 1. Generation of B cells in
bone marrow
- 2. Elimination of self reactive
B cells in bone marrow
- 3. Activation of B cells by foreign
antigen in secondary limphoid tissues
- 4. Differentiation to antibody-secreting plasma cells
and memory cells in the secondary lymphoid tissues
- Stages of B-cell development are marked by steps in
rearrangement and expression of immunoglobulin genes
- Only B-cells that produce functional
immunoglobulin can survive
- Get a number of chances
- 55 billion B-cells per day are lost in the bone marrow
because they fail to make functional Ig or are self reactive
- Mature naive B-cells compete for
access to lymphoid follicles
- when mature B-cells leave the bone marrow they
circulate between the blood and secondary lymphoid
tissues (lymph nodes, spleen)
- within these tissues B-cells congregate in primary
lymphoid follicles
- Naive B-cells must pause in these follicles in order to
receive survival signal s form follicular dendritic cells (a
specialised stromal cell)
- B-cell
- Before encountering an antigen, a mature
B-cell expresses antibody in a membrane
bound form
- When a foreign antigen binds to this
immunoglobulin, the B-cell is stimulated to
proliferate and gives rise to plasma and
memory cells
- B-cells that encounter antigen
- Mature naive B-cells encounter specific antigen in secondary lymphoid tissue
- Activated by CD4 helper T-cells
- These T-cells provide signals that activate
the B-cells to proliferate and differentiate
further
- Some differentiate into plasma cells
- Some migrate to primary follicle, change morphology and become
secondary lymphoid follicle containing a germinal centre
- Here activated B-cells become large proliferating lymphoblasts called centroblasts
- Centroblasts mature into isotype switched somatically
hypermutated non-dividing centrocytes
- Those cells that have the highest affinity for antigen are
selected for by affinity maturation
- Cells that survive affinity maturation proliferate and differentiate
into plasma cells and memory B cells that persists for a long period
of time
- Cell mediated
- T-cell receptor
- Always membrane bound
- Diversity is generated by gene rearrangmenet
- Similar to rearrangement of iG genes
- Uses RAG1 and RAG2
- Addition of P and N nucleotides
- Associates with other proteins
- CD proteins (CD3)
- Antigen processing and presentaiton
- T cell receptors can only recognise
antigens that are bound to MHC
molecules
- MHC = Major Histocompatibility Complex
- Membrane glycoproteins
- Function is to bind antigen
and present it to T-cells
- MHCI and MHCII have
similar 3D structure but
formed in different ways
- MHC class I
- Bind to CD8
- Peptides are generated in the
cytosol by proteasome
- Transported into the ER by transporter
associated with antigen processing (TAP)
- Associate with MHCI
- Transported to cell surface
- MHC I molecules cannot leave the ER
unless they have bound peptide
- Almost all cells express MHC I molecules
- Erythrocytes lack MHCI, a property that probably allows malarial
parasites to persistently infect these cells
- MHC class II
- Bind to CD4
- Antigens are taken up by phagocytosis or
endocytosis
- Degraded by proteases in lysosome
- Do not bind peptides in the ER
- Bacterial super-antigens
- Bind simutaneously to MHCII and
T-cell receptors
- Can stimulate up to 20% of total CD-4 T-cell population
- Results in systemic toxicity and
suppression of adaptive immune response
- 2 main classes of T-cell
- CD4 co-receptor needed for T-cell
recognition of MHCII peptides
- TH1 cells
- Activate tissue macrophages to
take up antigen
- Stimulate B-cells to produce antibody
- TH2 cells
- TH2 stimulation of naive B-cells
- During infection contain activated pathogen specific
TH2 effector cells
- Mature naive B-cells passing through lymphoid
tissue pick up antigen, process it and present it on
MHCII
- When B-cell presents antigen recognised by T-cell (TH2), it become trapped
- IFN-gamma can induce expression of MHCII molecules on cells that
do not normally produce them
- Presentation of antigen to CD4 T-cells can thus be increased in inflamed tissues
- MHCII presents peptides derived from
extracellular pathogens (antigens from
outside the cell)
- CD8 co-receptor needed for T cell recognition of
MHCI peptides
- Cytotoxic
- MHCI responsible for presenting peptides derived
from intracellular antigens (antigens produced without
own own cytoplasm
- Professional APCs
(Antigen presenting cells)
- MHC class II alert CD4 positive T-cell of
infection (extracellular)
- Expressed on professional APCs
- Macrophages
- B-cells
- Dendritic cells
- Supply co-stimulatory signal to T-cells
- Generated by B7 on APC stimulating CD28
on naive T-cells
- Macrophages
- Phagocytic
- Have receptors for bacterial carbohydrate
- Inducible B7 expression
- Dendritic Cells
- Initiate T-cell responses against viruses
- Possibly have specialised antigen processing
- Immature dendritic cells do not have co-stimulatory acitivity
- When they ingest antigens, they migrate to
lymph node and become activated
- T-cell Development
- T-cells originate from stem cells in bone marrow
- Mature in thymus
- Thymus is a primary lymphoid organ as its concern is the production
of useful lymphocytes and not with their applications to specific
infections
- Most active in young
- Increases in size up to puberty
- Immature CD3-4-8- (double negative)
- Become immature CD3+4+8+ (double positive
- Mature CD4+8- and CD4-8+
- T-cell mediated immunity
- Activation
- Dendritic cells take up bacterial antigens in
the skin and then move to a lymphatic
vessel
- Dendritic cells bearing antigen enter the lymph
node, where they settle in the T-cell areas
- T cells that do not encounter specific antigen
leave a lymph node through lympatics
- T-cells that encounter specific antigen
proliferate and differentiate to effector cells
- Naive T cells express the
low affinity IL-2 receptor
- Activated T-cells express
the high affinity IL-2
receptor and secrete IL-2
- Binding of IL-2 to the
high affinity receptor
sends a signal to the
T-cell
- The signal sent from the IL-2 receptor
induces T-cell proliferation
- Activated CD4 T-cells can differentiate in
different ways that favour humoral or cell
mediated immune response
- Naive CD8 T-cells can be
activated in different ways
- Generally needs stronger co-stimulatory activity
- Dendritic cells
- APCs with help of CD4 positive T-cell
- Effector T-cells
- Can be stimulated by antigen in absence
of co-stimulatory signal
- Functions are performed by cytokines and cytotoxins
- Selective killing
- Collision and non-specific adhesion
- Specific recognition redistributes cytoskeleton and cytoplasmic
components of T-cell
- Release of granules at site of cell contact
- Apoptosis
- Cytotoxic T-cell (CTL) recognises virus-infected cell
- CTL programs target cell to die
- Co-operation between B and T-cells occurs that are
specific for the same antigen (usually different epitopes)
- Responds to challenge with a high
degree of specificity
- Memory