B Cell Development in Bone Marrow and Peripheral Lymphoid Tissue Part II March 23, 2009 10:00-11:00

THE FOUR PHASES OF B CELL DEVELOPMENT

CHANGES IN IMMUNOGLOBULIN EXPRESSION DURING B CELL DEVELOPMENT IN THE BONE MARROW ANTIGEN DEPENDENT Random generation of repertoire results in self-reactive B cells

ELIMINATION OF SELF REACTIVE B CELLS Anergy is the inability to respond

STRONG INTERACTION WITH SELF CAN TRIGGER RECEPTOR EDITING AND RESCUE THE B CELL

The keys to survival: Entry into a follicle Stimulation with antigen TICKLE ME OR I DIE B cells move between blood, lymphoid tissue,and lymphatics The largest collection of lymphoid tissue is in the gut The keys to survival: Entry into a follicle Stimulation with antigen

B CELLS GET SURVIVAL SIGNALS IN PRIMARY FOLLICLES Recirculating B cells try to gain access to primary follicles Primary follicles are organized structures with FDCs

ANTIGEN STIMULATED B CELLS FORM GERMINAL CENTERS B cells that find antigen form a primary focus in the T cell zone Cells from the primary focus enter follicle and form a germinal center

ISOTYPE SWITCHING OCCURS IN GERMINAL CENTERS S regions are repetitive sequence 5’ to every C except Cd Recombination occurs between S regions Intervening DNA is deleted and VDJ becomes associated with a new CH

AFFFINITY MATURATION OCCURS IN GERMINAL CENTERS The process that increases diversity is called SOMATIC HYPERMUTATION The result is AFFINITY MATURATION

B CELLS DIFFERENTIATE INTO MEMORY OR PLASMA CELLS IN SECONDARY LYMPHOID TISSUE B cells must enter germinal center to become memory cells B cells can become plasma cells without entering the germinal center

A SECOND POPULATION OF B CELLS THAT COMES FIRST B cells are first produced in the bone marrow after birth B-1 B cells arise during embryonic development B-1 cells were first identified by expression of CD5 B-1 cells are less abundant, but predominate in pleural and peritoneal cavities CLL is frequently a CD5 expressing tumor

CD5 VS CONVENTIONAL B CELLS

USE OF MICROARRAY ANALYSIS TO DEFINE B CELL STAGES

EXPRESSION PROFILING OF LYMPHOMAS Nature (2000) 403:503

FOLLICULAR LYMPHOMAS RETAIN CHARACTERISTICS OF GERMINAL CENTER B CELLS

TUMOR COUNTERPARTS OF NORMAL CELLS

B CELL LIFE CYCLE

SUMMARY: B CELL DEVELOPMENT IN BONE MARROW Phase 1 Phase 2 ANTIGEN DEPENDENT

SUMMARY: B CELL DEVELOPMENT IN SECONDARY LYMPHOID TISSUE Phase 3 Phase 4 IgD