IMMUNOLOGY

Bios 328a textbook-based study of immunologySpring 2003

http://www.lehigh.edu/~sk08/Courses/Bios328/mainpage.htm

B-CELLS…• Origin…• Development…• SelectionS• ActivationS

•Progenitor B cells (pro-B-cells) bearing a CD45R marker develop – in the bone marrow – into immature and then mature B cells.

•Then, they migrate to peripheral lymph nodes. •Those developmental events are physically and physiologically distinct; the former are antigen independent; the latter are antigen dependent.

NEGATIVE selection:

• crosslinkage of mIgM on immature B cells can cause cells to die within the bone marrow

• aka: CLONAL DELETION

Nota bene:

• Prior to clonal deletion, development is antigen independent.

• Negative selection and positive selection are antigen dependent.

• Recognition of the ANTIGEN in the periphery leads to positive selection…

• aka CLONAL EXPANSION

SELECTION does not equal ACTIVATION…

Recall that a B-CELL needs a signal from a T-HELPER CELL

SELECTION does not equal ACTIVATION…

Recall that a B-CELL needs a signal from a T-HELPER CELL

Signaling is synergistic…

Consider howcytokines function.

Remember theirpotencyand locality.

SELECTION does not equal ACTIVATION…

Recall that a B-CELL needs a signal from a T-HELPER CELL

Activation….• Activation occurs when a B-cell associates with a T-helper cell

through a ternary complex; this association establishes specificity (the B-cell will have processed the antigen and presented it through MHC-II, thus selecting a specific T-helper cell lineage).

• Pairing between B7 on the B-cell and CD28 on the T-helper cell constitutes a co-stimulatory signal which will activate the T-helper cell. (The identities of the co-stimulatory proteins are “specific”; but these same proteins are involved regardless of the identity of the antigen).

• The T-helper cell , once activated, synthesizes CD40L. Now, pairing occurs between CD40 on the B-cell and CD40L on the T-helper cell . This association constitutes a co-stimulatory signal which activates the B-cell.

• Thus, there is “mutuality” between the B-cell activating the T-helper cell and the activated T-helper cell, in turn, activating the B-cell.

• (This “mutuality” should not obscure that the process is “antigen-driven.”)

• Cytokines of various types are secreted by T-helper cell and are received by differentiating B-cells.

• The various cytokines affect what immunoglobulin isotypes will be produced by plasma cells.

Where is activation happening?And what is happening?

The primary response is initiated in the paracortex.

T-cells respond to processed antigen that is typically delivered from a site of origin by dendritic cells.

B-cells see the same antigen in an unprocessed form in the lymph.

The T-cells and B-cells, now both

activated, form associations which allow proper signaling.

The B-cells migrate to the periphery of the paracortex and form foci where they mature into plasma cells which secrete, first, IgM and then IgG.

Some B-cells – along with some T-helper cell’s – migrate to primary follicles in the cortex.

Primary follicles develop into secondary follicles

The secondary follicles have an area of proliferation (a germinal center) where B-cells proliferate and differentiate.

Follicular dendritic cells… not an APC!The follicular dendritic cells do not originate in the

bone marrow and do not have MHC-II.

Rather, the follicular dendritic cell contains Fc receptors, receptors which can capture immunoglobulins through their constant region.

Thus, the follicular dendritic cells become decorated with Ab complexed to whole (unprocessed) antigen. Stated another way, these follicles have a rich supply of the filtered antigen

The dendrites are fragile and can break in to (non-nucleated) beads (about 0.3-0.4 µm in diameter); these beads are called “iccosomes” (immune-complex coated bodies); they can persist for several months.

How do the primary and secondary responses differ?

How do the primary and secondary responses differ? The secondary response is

more intense because:

(i) there are more memory cells specific for an antigen than there are naive cells,

(ii) the immunoglobulins of memory cells have experienced affinity maturation and bind to antigen more strongly,

(iii) memory cells have a

much more extensive exposure to antigen (presented by follicular dendritic cells), and

(iv) activation of memory cells requires a less strong stimulation.