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1

Innate immunity

Rapid response
Recognise patterns e.g. via PRRs e.g. MBL, scavenger receptors
increases cytokines, costimulatory molecules to allow for adaptive response
direct response for host defence - phagocytosis, antimicrobial activity

2

Adaptive response

Slow response, recognition intially low affinity receptors
Response - T and B cells with receptors encoded by fully rearranged genes
Memory

3

Comparison of B-cell add T-cell development

both develop in specialised microenvironments - bone marrow for B cells, thymus for T cells

B cells made in BM for life, T cells in thymus, decrease at puberty, also generated in other sites, long-lived peripheral T-cell pool

both have diverse Ag receptor repertoire via gene rearrangement

4

What guides B and T cell development?

Stromal cells

compartmentalised distinct stromal cells for T cells

stromal cells in bone marrow for B cells

both involve cell death via apoptosis

5

Changes in lymphoid cell antigens as they mature

As lymphocytes mature from a common lymphoid progenitor, they bifurcate at B cell/T cell stage and then express different antigens on their surface. These cluster as the cell matures.

6

B cell development

Common lymphoid progenitor, Pro-B, large Pre-B, small Pre-B, immature

Want to develop memory B cells and plasma cells

7

Plasma cells

Produce antibodies

Connector between innate and immune response

8

Phases of development

1st phase: Generation of antigen receptor by V(D)J rearrangement

2nd phase: refinement of Ag receptor repertoire. Antigen receptor is tested for antigen recognition. Positive selection: for Ag receptor that recognises self Ag weakly
Negative selection: for Ag receptor binds strongly to self Ags - these are eliminiated via apoptosis

3rd phase: stimulation by foreign Ag
- clonal selection of lymphocytes
-generation of effector and memory lymphocytes

9

Where do the diffferent phases of lymphocyte development take place?

1st phase (generation of antigen receptor) and 2nd phase (refining antigen receptor repertoire) in primary lymphoid organs

3rd phase - stimulation by foreign antigen - secondary lymphoid organs

10

What are the two types of B-cell antigens?

thymus dependent and thymus independent antigens

11

Thymus dependent antigens

Dependent upon helper T cells to induce antibody production. Proteins.

12

Thymus independent antigens

does not need helper T cells to induce antibody production.
Polysaccharides, lipids.

13

What kind of signalling is needed to engage an antigen receptor?

2 signal model: engagement of antigen receptor (BCR, “signal 1”) is not sufficient to activate B cell. Also need co-stimulatory signal (“signal 2”).

In T-cell independent and dependent B-cells

14

Features of a T-cell independent response

-Simple, repetitive antigens (often carbohydrates)
-Mostly IgM
-Modest affinity
-No memory
-B cells activated by direct BCR crosslinking
-B cells can also be activated via Toll-like receptors (TLRs)

15

How do T-independent antigens activate B-cells?

T-independent antigens activate B-cells by direct BCR aggregation

16

Stages of antigen dependent B-cell development

Organisation of lymphoid organs
T-independent B cell activation
T-cell / B-cell collaboration
Class switch recombination

17

T-cell/B-cell collaboration

- Required for antibody response to complex antigens-- proteins, lipids
- Requires direct, physical B-T interaction
- Involves multiple cell surface receptors on T and B cells
- Both B and T cell must recognise antigen (but not necessarily the same epitope)
- Both B and T cells need signal 1 (through antigen receptor) and signal 2 (co-stimulation)

18

T-cell dependent B-cell response

Sequence of events:
Antigen binding to BCR provides “Signal 1” to B-cell.
Antigen is internalised, processed and antigenic peptides are displayed on MHC for T-cell recognition.
TH (helper T-cell) recognizes antigen-MHC complex via the T-cell antigen receptor (TCR): provides “Signal 1” to T-cell.
CD80/CD86 on B-cell binding to CD28 on T-cell provides “Signal 2” to T-cell.
T-cell activation leads to up-regulation of CD40L which bind to CD40 providing “Signal 2” to B-cell.
Cytokine production by activated T-cell also help to activate B-cell.
B-cell proliferates and differentiates into antibody secreting B cell (plasma cell).

19

Antigen recognition by B-cells vs T-cells

Both form their antigen receptors by V(D)J recombination

B-cell receptor (BCR) consists of 2 HC and 2 LC (membrane and secreted Ig).
T-cell receptor (TCR) consists of ab heterodimer (membrane form only).

Both signal by associating with signaling complex in membrane:
Ig-alpha and Ig-beta for B-cells, CD3 complex for T-cells.

B-cells can bind intact protein antigen in solution.
T-cells bind peptides displayed on the surface of another cell : an “antigen presenting cell” (dendritic cell, macrophage, or B-cell).

20

Primary antibody response

After first infection, B cells are activated and antibody secreting cells in peripheral lymphoid tissues, then low-level antibody production

5-10 day lag, smaller peak response, more IgM than IgG, lower average affinity and more variable

21

Secondary antibody response

Happens upon repeat infection

usually 1-3 days, larger peak response, relative increase in IgG and under certain situations IgA or IgE (heavy class switching)
higher average affinity (affinity maturation)