BIO 343 Lecture Notes - Lecture 6: Lymphopoiesis, Immunoglobulin Light Chain, Natural Killer T Cell
Immunology Chapter 6: Development of B Lymphocytes
Hayden Casassa
• B cells develop in the bone marrow and later migrate to secondary lymphoid tissue such as the spleen,
lymph nodes, and Peyer’s patches
o B cells were discovered in Chickens
• Earliest identifiable B cell is the Pro-B cell
o Pro-B cells differentiated from a common lymphoid progenitor in the bone marrow
o Differentiation is the process by which a less specialized cell becomes a more specialized cell
o Hematopoietic stem cell →lymphoid precursor→Pro-B cell (& NK/T cell precursor)
• Pro-B cell
o Rearranged its H chain genes (VDJ) but not light chains. Many B cells fail to properly rearrange
their H chain genes and are signaled to die via apoptosis
o Development of Pro-B cell to Pre-B cell to an Immature IgM+ (IgD-) B cell occurs in bone marrow
• Pre-B cells
o Express a functional H chain that combines with Surrogate Light chains to form a pre-BCR.
▪ Surrogate light chain resembles light chain but are simply there to test functionality of
Heavy chain
▪ Surrogate light chain isn’t diverse and is the same throughout
o The formation of the pre-BCR is for the chain to demonstrate its ability to properly rearrange
and to function in combining with L chains
o It must pass this 1st checkpoint in B cell development
→
If not then apoptosis
▪ If it makes functional heavy chain, then it is officially Pre-B cell
▪ IgB and IgA are there for signaling
• Formation of Immature B cell
o These cells have rearranged their “real” light chains and express functional light chains that
form IgM on the cell surfaces
o This is the 2nd checkpoint
→
can it rearrange/produce functional L chains
o Over half of your developing B cells undergo apoptosis and die in the BM because they can’t
rearrange and produce functional H and/or L chain genes
o If it passes… then we have immature B cell and only expresses IgM (NO IgD)
o Body messes up constantly and somatic recombination happens a lot
• X-Linked (Ogden Bruton’s) Agammaglobulinemia
o No mature B cells or antibodies because B cell development is blocked at pre-B cells stage
o Genetic Defect mutation of Bruton’s Tyrosine Kinase (Btk)
▪ This kinase is needed for Pre-BCR signaling
o Treatment is Ab from healthy human plasma
• Child’s B cell Development was blocked at Pre-B cell stage (Checkpoint 2)
o If you are missing VTK the signal is never received so the cell sits there
o Therefore, cell isn’t “told” to undergo further differentiation
• Gene Rearrangement has now produced immature B cells with a wide range of specificities
o Many are autoreactive cells with affinity for “Self-antigens” that are human components
o There are three possible fates
▪ Change their BCR via receptor editing by further rearrangement of light chain
▪ Clonal Deletion in Marrow(Apoptosis)→ Recognize multivalent
▪ Anergy (Inactivated)→ Recognize Univalent
• Clonal Deletion
o Elimination of self-reactive immature B cells
o If B cell sees self-reactive immature B cells it induces to undergo apoptosis
o If it doesn’t see, it will move to blood and be allowed to leave and express IgD
• Anergy
o Immature B cell recognizes monovalent self-Antigens and become inactive
▪ Rendered unresponsive to antigens (become anergic)
▪ Cells lose IgM expression and then later lose IgD
▪ Allowed to exit bone marrow and enter circulation (survive 1-5 days)
o Key is soluble antigen doesn’t kill the cell… losing BCR is what causes it to die
Anergy→
Clonal
Deletion
• 55 billion B cells die in bone marrow every day from being unable to make functional IgM
o Also, due to clonal deletion and Anergy at immature B cell stage (2nd checkpoint)
• Central vs Peripheral Tolerance
o Central tolerance→ Tolerance to self-antigens that is generated in B and T cell populations
during their development in primary lymphoid organs (Bone marrow and Thymus)
▪ Established in B cells by clonal deletion and rendering self-reacting B cells anergic
▪ In other words, most important tenant of immune system is self-tolerance to not react
with own proteins which occur in bone marrow or thymus to remove cells that could
react with itself
o Peripheral Tolerance→
▪ Despite clonal deletion, some cells that leave bone marrow react with itself
▪ Mechanisms that allow tolerance outside of primary lymphoid organs
• Pathway of Immature B cells (that pass the checkpoint)
o To mature and survive, immature B cells that leave marrow must access lymphoid follicles
▪ There, they compete with each other and not all of them survive
