Deze Engelse samenvatting bevat een ruim overzicht van onderwerpen besproken in hoofdstuk 9 van Parham et al. 2012 'The immune System'. Onder andere: effector B-cel functie, antilichaam functies, B-cel activatie en maturatie door dendritische cellen en T-cellen.
Het bevat alle belangrijken concept...
THE IMMUNE SYSTEM – PARHAM 4TH EDITION
CHAPTER 9
In the development of a vaccine, pharma companies aim at the induction of a neutralizing antibody. One that makes
the pathogen not able to infect human host cells.
First, antibodies are needed to quickly bind pathogens: low-affinity IgM enters.
Secondly, antibodies are needed to bind strongly.
This is done through somatic hypermutation,
and isotype switch induced by cytokines of the TFH cells.
Activation: Cross-linking of BCR and co-receptor stimulation
B-cell activation requires the cross-linking of surface IgM (it resembles T-cell activation).
1) Clustering of receptors.
2) Kinases such as Blk, Fyn, Lyn phosphorylate the ITAMs associated with the BCR.
3) Doubly phosphorylated Igβ is the binding site for tyrosine kinase Syk.
4) Syk initiates an intracellular signaling pathway leading to altered gene expression.
It also requires signals from the B-cell co-receptor:
- CR2 = CD21 = complement receptor 2 recognizes iC3b and C3d
- CD19 = signaling chain
- CD81 = binds to CD19 and brings it to the B-cell surface.
When the BCR binds an antigen, the B-cell co-receptor binds C3d.
The receptors are phosphorylated together.
CD4 T cells activate B-cell immunity
Almost all naive B-cells need a CD4 T FH cell to activate them via their MHC:peptide presentation.
DiGeorge syndrome patients do not have a thymus and low-none T cells. Their B-cells cannot make antibodies, so
patients suffer from opportunistic infections. The only treatment option is a thymus transplant. Patients do have B-1
cells that make low-affinity IgM. The antigens these B-1 cells recognize are called thymus-independent antigens.
Follicular dendritic cells
FDCs are derived from stromal cells and differentiate under regulation of TNF-
α and lymphotoxins.
These cells display intact antigens to B-cells.
They are well-suited for this because:
- They have large dendrites and a great surface.
- They do not have any phagocytic capacity.
Receptors for antigens are CR1 (for complement C3b) and CR2 (for C3d).
Subcapsular sinus macrophages resemble FDCs in that they do not phagocytose
and use CR1 and CR2 for antigen catching and presentation.
Medullary sinus macrophages are HIGHLY phagocytic: they filter out remaining
pathogens and antigens at the end of the lymph node.
, B-cell movement: to T-cell area
Routes of arrival:
Via the HEV, attracted by CCL19 and CCL21 and into the B-cell follicle by CXCL13.
Via the afferent lymph vessel. The B-cell follows the subcapsular sinus and if a subcapsular sinus macrophage
presents a specific antigen, the B-cell enters to interact with T FH cells to complete activation.
The B-cell follows different steps on different locations in the lymph node:
1) B-cells encounter an antigen presented by FDC in the primary follicle.
2) It induces expression of CD69 which prevents S1P expression (see chapter 8).
3) Endocytosis of the antigen and MHC II presentation.
4) Expression of CCR7 starts which follows the CCL21 and CCDL19.
5) The B-cell moves to the T- and B-cell border; TFH cells are present.
6) B-cell and TFH cell form a conjugate pair.
7) Expression of CD40 on the B-cell and CD40 ligand on the T-cell.
8) In the B-cell: upregulation of NFκB (transcription factor) and ICAM-1. B (transcription factor) and ICAM-1.
9) Reorganization of the T-cell’s cytoskeleton and Golgi apparatus facilitates
cytokine delivery via the immunological synapse.
Clonal expansion
The B-cell can take different routes to become different cells:
o B-cells can stay in the medullary cords to divide = the primary focus
Dividing T- and B-cell conjugates give rise to B lymphoblasts secreting IgM.
Some stay in the medullary cords due to IL-5 and IL-6 by T FH cells.
B-lymphocyte-induced maturation protein-1 (BLIMP-1) causes them to terminally differentiate into
plasma cells producing only immunoglobulin.
o B-cells can move to the primary follicles = the secondary focus
1) B-cells become centroblasts, activated by cytokines (IL-6, IL-15)
and BAFF secreted by FDCs.
2) The T-helper cells also divide.
3) B-cell produces activation-induced cytidine deaminase (AID) for somatic
hypermutation and isotype switching.
4) Primary " secondary follicle because of the massive proliferation.
This is a germinal center reaction.
5) The germinal centers (GCs) are concentrated places of dividing T- and B-cells.
Swelling of the lymph nodes is a direct result from GC formation!
6) Naive B-cells try to look for antigen at the GC; they form the ‘mantle zone’.
7) Dark zone of the GC forms = now that centroblasts are denser.
8) Centroblasts give rise to centrocytes:
- Divide more slowly
- Are mutated and switch in isotype
- Now re-express cell-surface immunoglobulin
9) Centrocytes into the light zone with less B-cells and more FDCs and TFH cells.
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