8. B-cells and humoral immune response Flashcards
Negative selection
Aim: elimination of self-specific B-cells
- In bone marrow
- Guided by autoantigens of bone marrow
- Receptor editing: autoreactive B cells can reactivate their RAG genes to create not self-reactive BCR
Development before antigen
Bone marrow: gene rearrangement
Immature B cell (IgM) -> mature B cell (w/BCR - IgM and IgD)
Development after antigen (what happens after encounter antigen)
Periphery
- Antigen presentation to Th cells
- B cell ctivation, proliferation
- Affinity maturation
- Differentiation to plasma and memory cells
- Isotype switch
- Effector action
Gene rearrangement
Variable region
- V(D)J recombination
- Either in H-chain or L-chain
Constant region
- Antibody isotype (alpha, delta, gamma, mu, epsilon)
*BCR: either IgD or IgM, while secreted form can be anyone
Mechanisms responsible for full diversity of BCRs
V(D)J rearrangement
1) Germline diversity
2) Combinatory diversity
3) Junctional diversity
Post- V(D)J rearrangement
4) Receptor editing
5) Somatic hypermutation
6) Receptor revision
Types of B cells
1) Follicular B cells
- In spleen or other lymphoid organs
- TD-response (Thymus dep.) - protein antigen+Th cell
- Isotype-switched, high affinity antibodies (IgG, IgA, IgE). Long-living plasma cells
2) Marginal zone B cells
- In spleen or other lymphoid organs
- TI-response (Thymus indep.) - polysacch, lipids etc
- Mainly IgM. Short-living plasma cells
3) B-1 B cells
- Mucosal tissues, peritoneal cavity
- TI-response (Thymus indep.) - polysacch, lipids etc
- Mainly IgM. Short-living plasma cells
Life-span of B cells
Only a few days
- Many die without meeting their antigen
B-cell activation
- In secondary lymphoid organs
- Meeting appropriate antigen
Primary lymphoid follicle (in lymph node)
Mostly B cells
Paracortical area (in lymph node)
Mostly T cells
Antigen presentation to Th cells
By dendritic cells - MHC II-peptide complex => TCR+CD4 - CD80/CD86 => CD28 - CD40 => CD40L Th0 becomes Th2 (IL-4, -5 and -13)
T-cell/B-cell reciprocal activation
- B cells are APCs: endocytose, process and present appropriate antigen to Th2
- Antigen-specific B cells interact with antigen-activated Th2 cells to form a primary focus
Intracellular signaling pathways in B cells when encountering antigen
Initiated by cross-linking of BRCs by multivalent antigen (Between IgM and IgD på bildet) - required for activation
Activation signals
1) BCR => antigen
2) Costimulation by Th cell (TCR+CD4 => MHC II+peptide on B cell)
“Co-recognition”: same antigen recognized by B- and T-cells (but diff. epitopes)
B cell activation by help of Th cell (steps)
1) B-cell antigen recognition (1st signal) + Th2 cell antigen recognition
2) Th cell activation => CD40 ligand expression => CD40-CD40L interaction (2nd signal)
3) Th2 cytokine production - IL-4, -5, -6 (3rd signal)
4) B- cell activation (kan også bli direkte aktivert av 2 tror jeg)
* 4th signal: CR2 on B cell bind to complement fragment on antigen
What immunoglobulin is produced first
IgM
Antibody class switching
- Germinal center reaction
Follicular DC - IL-6 => Follicular Th cell - IL-21 => B cell (isotype switch) => Plasma cells (long-lived) and memory B cells
Functional results of interaction between CD40 and CD40L
- Generation of germinal centers, proliferation, secretion of antibodies
- Affinity maturation
- Isotype-switch
- Generation of memory cells
Affinity maturation
Happens with the clonal expansion
- BCRs with high affinity for the antigen also have a higher chance of survival
- Somatic hypermutation generate variability of Ig genes variable domain (BCRs have diff. affinity to antigen)
“Repertoire diversification”
Key enzymes in somatic hypermutation
1) AID (activation-induced cytidine deaminase)
- Expressed in activated germinal center B cells
- Cytosine => uridine
- “Transition mutations”
2) UNG (uracil-N-glycosylase)
- Uridine => abasic
- Removes uracil to form apyrimidinic residue
- “Transversion mutations”
Selection of surface BCR
- By antigens on surface of follicular DCs
- Folicular DC have FcR and CR3
=> binds to antibody and C3b on antigen - B cells bound to other side of antigen
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Germinal center
- Formed by antigen-specific dividing B cells
- All B cells in each germinal center is derived from only one founder cell
- Where DC keeps Ag’s for B cells
Polyclonal antibodies
Many different B cell clones (antibodies) created due to 1 pathogen containing many different epitopes
Class (isotype) switch
- Occur in peripheral lymphoid tissues
- Constant region of H-chain change, variable region remains the same
- IgM (and IgD) is produced first
- IFNγ => IgG
- IL-5 => IgA
- IL-4 and IL-13 => IgE
- Switch regions: S
- AID contributes
