Adaptive Inmunity Flashcards
Describe the basic structure of an antibody molecule
Symmetrical
Two heavy chains
Two light chains
Connected by disulphides bridges
The hinge region allows flexibility of the Fab- from parallel to right angles between arms
Fc region bound by Fc receptors made only from heavy chains
Fab is made from V(L), V(C), V(H), V(H1)
The variable regions comprise the antibody binding sites
How do B cells recognise antigens?
Surface immunoglobulins
CD79 co receptors signal inside the cell once antigens have bound
Ig recognise antigens with their variable regions of heavy and light chains- hyper variable regions (complementarity-determining regions; CVR)
How do T cells recognise antigens?
Surface bound T-cell receptors (alpha-beta or gamma-delta)
Made of Valpha, Calpha, Vbeta, Cbeta
Resembles the Fab region of an immunoglobulin
CD3 complex signals inside the cell when the peptide/MHC binding site binds a cell surface antigen
Has either a CD4 (T cell helper) or CH8 (T cell cytotoxic)
The recognise small peptides in the groove of MHC molecules
Describe MHCs
Class 1 bind to CD8+ T cells- present on most cell types for virus defence
Class 2 bind CD4+ T cells- present on cells that signal to T cells eg. B cells, macrophage, dendritic cells, epithelial cells of the thymus
Describe MHCs
Class 1 bind to CD8+ T cells- present on most cell types for virus defence
Class 2 bind CD4+ T cells- present on cells that signal to T cells eg. B cells, macrophage, dendritic cells, epithelial cells of the thymus
Describe the thymus
Thymectomy or Di George syndrome leads to fewer total lymphocytes, reduced graft rejection and reduced antibody responses
The thymus involuted with age- T cells produced decrease- in health this is five because they are long lived
Two main cellular elements- haemopoietic bone marrow/fetal liver derived precursors
Non- haemopoietic stromal cells thT provide the niche
Blood vessel enters in the medulla with the medullary epithelium then there is the cortical epithelium with dendritic cells at the boundary, the subcapsular epithelium and then the capsule
Describe the stages of T cell development
Double negative- CD4-CD8- In blood stream, migrate through the cortex towards the capsule
Double positive- CD4+CD8+ Migrate through the cortex to the medulla
CD4+ single positive or CD8+ single positive Found in the medulla
Describe the first checkpoint in T cell development
Maturation from double negative to double positive
-commitment to the T cell lineage- notch signals from the thymic epithelial cells into alpha-beta T cells
Cellular expansion- controlled by interleukins 7 and 15 and stem cell growth factor. Act on IL7- and IL15-receptor and c-kit (also have IL2 receptor) on double negative thymocyte
Rearrangement of genes encoding the T cell receptor- VDJ recombination of the beta chain
How are T cells with fully rearranged TCR-beta chain genes selected?
Pre-T cell receptor complex
Expressed only on the double negative thymocytes
Consists of TCR-beta protein, CD3 and pre-Talpha
Assembly of this pre-T cell receptor signals for the cell to stop further beta rearrangement (allelic exclusion), CD4, CD8 expression, TCR-alpha rearrangement and cellular expansion
Describe the need for positive and negative selection of TCRs
Genetic rearrangement is random so need to expand useful TCRs, recognise peptide-MHC of low affinity and avidity and remove any harmful TCRs, recognise peptide/MHC at high affinity and acidity via positive and negative selection
Describe positive and negative selection
Affinity model- low affinity give positive selection
High affinity gives negative section
Avidity model- low avidity gives positive selection
High avidity give negative selection
Negative selection occurs via apoptosis
Positive selection happens in the cortex- there is a random binding of the TCR CD4 or CD8 to the MHC2 or MHC1 complex respectively on the thymic epithelium giving a single positive cell
Negative selection happens in the medulla- high affinity/avidity➡️apoptosis
How are antigens presented on dentritic cells?
Antigen uptake via macropinocytosis
Expression on MHCs via the endogenous pathway for MHC1 expression- cytosolic derived proteins degraded and the peptide added to MHC1 in the RER and then trafficked to the surface
Exogenous expression for MHC2 as the externally derived protein meets MHC2 on its way to the surface (CLIP prevents other proteins binding until then)
Cross presentation of exogenous proteins will end up in the class1 pathway for viral protein presentation for other cells
How dendritic cells mature?
Immature peripheral DCs have a variety of PRRs that are activated by PAMPs➡️ TLR signalling induces CCT7 and enhances antigen processing➡️ migrate into lymphoid tissues and increase expression of MHC and co-stimulatory molecules
Mature dendritic cells enter the lymph node form infects tissue and can transfer antigens to resident dendritic cells that can stimulate T cells
How are T cells activated?
T cells enter the lymph node via the high endothelial venules and migrate into the T cell areas
Dendritic cells migrate there too and the T cells wonder over the DCs and if they are activated proliferate and differentiate before they can exit the lymph node
Describe the molecular interactions between dendritic cells and T cells
MHC2-TCR + CD4- signal 1 Activation
CD28-CD80 CD86- signal 2 survival
Cytokines- signal 3 differentiation
What is the importance of IL2 in driving T cell proliferation?
Resting T cells express a low affinity IL2 receptor (beta, gamma chains only)
Activated T cells express a high affinity IL2 receptor (with the alpha chain) and secrets IL2
Binding of IL2 sing aka did the T cells to enter the cell cycle so induces proliferation
Name the different types of effector T cell subsets
CD8 cytotoxic T cells- kills virus infected cells
CD4 Th2 cells- activate infected macrophages and help B cells for antibody production
CD4 Th2 cells- provide help to B cells for Ab production especially switching to IgE
CD4 Th17 cell- enhance neutrophil response- promote barrier integrity
Tfh cells- isotype switching
CD4 regulatory T cells- suppress T cell responses
Describe the differentiation of CD4+ Th1 cells
Differentiate in presence of IL12 and produce IFN-gamma gat enhances differentiation in a positive feedback loop- TF is T-bet
Control rather than elimination- IFN-gamma stimulates infected macrophages to help control infection with increased MHC and co-stimulatory molecule expression, NO production, phagolysosomes maturation and TNF-alpha production
Describe the differentiation and function of CD4+ Th2 cells
Stimulated by IL4 Secrete IL4,5,13 TF is GATA3 Promotes resistance to large extracellular helminth parasites IL4 promotes class switch to IgE Drives macrophage activation
Describe the differentiation and function of CD4+ Th17 cells
Differentiation stimulated by IL-1beta, IL6, IL21 and maintained by IL23
TF is ROR-gamma-t
Secrets IL17
Protects against fungal infection and some bacteria
Increases neutrophil recruitment
Controls epithelial barrier function
Describe the differentiation and function of CD4+ T follicular helper cells
Differentiate by IL21
TF is Bcl6
Express the CXCR5 chemokine receptor to allow migration towards B cell areas
Act within the second lymphoid compartment to help B cells
Describe the differentiation and function of CD4+ T regulatory cells
nTreg cells derived from self-binding T cells
pTreg cells derived from any peripheral immune response
Differentiate in the presence of TGF-beta and retinoic acid
TF- FoxP3
Restrict other immune responses and T cell proliferation
Block signal 2 for autoimmune T cells causing them to apoptose and can inhibit tumour immunity
Name some B cell markers
CD20
CD19
CD86
CD40
What are the B cell populations?
B2Foll- follicular B cells T dependent response such as proteins Broad repertoire- includes protein Found in spleen and lymph nodes IgM+, IgD+, some CD21, high CD23 B2MZ- marginal zone B cells Naive and memory cells T-independent- narrow repertoire Spleen- few cells soon after birth IgM+, low IgD, high B220, high CD21, low CD23
B1- (confirmed in mice) produce natural antibody and antibody to capsular polysaccharides Self-renewing Limited repertoire- T independent Few in spleen many in peritoneal cavity IgM+, CD70-, CD20+, CD27+
Describe the life a B cell
Generation in bone marrow- B cell precursor rearranges its immunoglobulin genes
Negative selection in bone marrow- immature B cell bound to self cell surface receptor removed from repertoire
B cells migrate to the peripheral lymphoid organs- mature B cell bound to the foreign antigen is activated
Antibody secreted and memory cells in bone marrow and lymphoid tissue- active B cells give rise to plasma cells and memory cells
Describe B cell development
Develop on stromal surface - different stromal cells have different effects during development eg. CXCL12 expressing cells and IL7 expressing cells
Defined by Ig rearrangement
Heavy chain first- germline in stem cell➡️ D-J rearranging in early pro-B cell➡️ V-DJ rearranging in the late pro-B cell➡️ VDJ rearranged, mau chain transiently at the surface as part of pre-B cell receptor in large pre-B cells- mostly intracellular
Then light chain-
V-J rearrangement in and intracellular mau chain in small pre-B cell
VJ rearranged and IgM expressed on cell surface
VJ rearranged and IgD and IgM made from alternatively spliced H Cain transcripts
Rearrangement happen on one chromosome and if it is unsuccessful it is tried on the second- allelic exclusion
What happens to prevent autoimmunity from B cells?
Multivalvent the self molecule➡️ clonal deletion or receptor editing➡️ apoptosis
Soluble self molecule➡️ migrates to periphery and become and Anergic B cell
Low-affinity noncross-linking self molecule➡️ migrate to the periphery and becomes a clonally ignorant nature B cell
No self reaction➡️ migrates to the periphery and becomes a mature B cell
Describe plasma cells
Low surface Ig
No MHC2
High Ig secretion rate
No growth, somatic hypermutation or isotype switching because they are terminally differentiated
What are three pathways to generating antibody?
- B1 cells can make natural antibody without stimulus to a limited repertoire of antigens and in a T-independent manner
- Extra follicular antibody- red pulp in spleen, medullary cords of lymph nodes responses may be T dependent or independent depending on antigen- Ab affinity usually low
- Germinal centres are structure in which plasma cells that secrete high-affinity antibody and memory B cells develop and need T cells
Describe briefly T-independent
Age is encountered in the periphery or in the MZ➡️ Ag-activated B cells transit via T zone➡️ extra follicular plasmablast growth resulting in rapid ab production
High conc of TI-1 antigen (LPS) ➡️polyclonal B-cell activation, non-specific antibody response
Low conc of TI-1 antigen➡️ TI-1 antigen specific antibody response
TI-2 antigens alone can signal to B cells to produce IgM antibody
Briefly describe the generation of primary T-dependent response
Naive T cells are primed by cognate integration with dendritic cells➡️
Virgin or memory B cells, on binding ag, move to T zone ⬆️CCR7 ➡️
Germinal centres gradually produce persistent high affinity ab and memory B cells➡️
➡️cognate interaction of primed T- and activated B cells in the T zone➡️ extra follicular plasmablast growth resulting in rapid ab production in the medulla
What is the role of the Tfh cell in the T-dependent response?
To be primed they recognise peptide/MHC2 by DC
To positively select B cells they recognise peptide/MHC2 by B cell- signal through cognate interaction
Essential additional molecules- CD40 for B cells, CD40L for T cells, ICOSL for B cells and ICOS for T cells
Cytokines (IL4,6,21 and IFN-gamma) help reinforce cognate interaction
Describe T cell help for B cell activation in the TD response
Tfh cell and B cell interact through TCR (+CD4)-peptide/MHC2, CD28-B7, CD40L-CD40
After antigen uptake, processing and presentation it up regulates B7 which binds to CD28➡️ CD28 transmits signals to the Th cell that include the stabilisation of mRNA for cytokines and ligands
Th cell induced to express CD40L (and releases cytokines) which binds to CD40 to give a strong activation signal
What is the importance for the germinal centres?
Long-lived plasma cell and memory B cells are derived there
Class switch to IgG or IgA- requires further Ig gen recombination that needs to be controlled
Names cells found in the germinal centre
Centroblasts- proliferating GC B cells that undergo somatic hypermutation- dark zone
Centrocytes- GC B cells that have undergone affinity maturation and are out of the cell cycle- light zone
Follicular dendritic cells- they have native antigen bound to their surface and the centrocytes compete to bind the antigen- light zone
Tfh cells- GC T cells any give out survive signals to centrocytes aches gene come out of the dark zone- light zone
Name some important molecules involved in the Germinal centre responses
Activation induced cytidine deaminase (AID) essential for class switch recombination and IgV hypermutation
BCL-6 master transcription factor for GC B cell commitment and generation of Tfh cells
CD40 on B cells and CD40L on T cells
IL21 for Thf cell development
Blimp1 is a transcription factor required for the plasma cell programme
After initial priming what are the two actions B cells can take?
- Extra follicular responses where B cells differentiate to become IgM an IgG plasma cells moderate affinity antibody
- Enter germinal centre response that gives rise to plasma cells producing high affinity, class switched antibody and memory cells
Describe the germinal centre reaction
B cells entering the GC response form rapidly dividing centric lasts in the dark zone- each centroblast undergoes random point mutations within its IgV region genes
These then exit the cell cycle and becomes centrocytes then competes for he antigen held in the form of immune complexes in follicular dendritic cells in the GC light zone
Those centrocytes that have mutated to high affinity antigen receptors, compete most successfully and can the seek out antigen specific Th cells for cognate interaction in order to receive rescue signals- the rest die
Positively selected centrocytes than exit the GC either as plasma cells or as memory cells
Name the different antibody classes
IgG IgM- low affinity pentamer IgD- membrane bound IgA- mucous membrane dimer IgE- mast cells
What are the functions of antibodies?
Neutralisation- virus entry, bacterial adhesion, toxins
Complement activation- classical pathway
Opsonisation- bind Fc receptors on phagocytes
Type1 hypersensitivity- Multivalvent antigen cross links bound IgE antibody causing granule release from mast cells
Antibody-dependent cellular cytotoxicity- bind target cell bind NK cells with Fc receptors (CD16) target cell dies
Immune complex formation- small ag-ab completes form in circulation ➡️ complement activation- C3b ➡️ CR1 receptors on RBCs bind the C3b ➡️ phagocytes in spleen and liver remove the complexes from the RBC surface
Describe the action of IgA
Transported through the gut epithelium by the polymeric Ig receptor
Binds to the layer of mucous and neutralises pathogens and their toxins
Is also in breast milk and is transferred into the child
Describe IgG in child bearing
Can be transported across the placenta by TcRn
IgM are John t transferred
Last about 6-8 weeks
How are anti-rhesus antibodies significant in a child bearing?
If mother is rhesus negative and child is rhesus positive blood can be mixed during delivery and TD mother will produces antibodies against the the rhesus possible blood so if the second child is also positive the anti-Rh antibodies will cross the placenta and attack the fetal RBCs
