B cells
Harry W Schroeder Jr MD PhD
Division of Developmental and Clinical Immunology
Departments of Medicine, Microbiology, and Genetics
University of Alabama at Birmingham
Genesis
• B cells derive from hematopoietic stem cells
• Development initiates in bone marrow and fetal
liver
• Developing B cells use gene rearrangement to
construct their antigen receptor
• Immunoglobulin rearrangement is hierarchical
– H chains first
– L chains second, k before l
• Developmental checkpoints are used to test
immunoglobulin function
Early Stages of B cell Development
• Immunoglobulin rearrangement
• Initial testing of the receptor
– Positive selection
• Associates with surrogate & conventional light chain
• The BCR signals - low level self-reactivity
– Negative Selection – unacceptable self-reactivity
• Anergy
• Elimination
– Apoptosis, or
– Rescue by Receptor Editing
B cell Development (Human)
Alternative Splicing Yields
Secretory or Membrane Ig (BCR)
IgM and IgD via Differential Splicing
B cells in the Bone Marrow
Early Checkpoints
Signal transduction in B cells
• Two "domains"
– sIg
– Iga/Igb
• B-cell Receptor – binds antigen
• Iga and Igb transduce the signal
– Cytoplasmic tails contain immunoreceptor
tyrosine-based activation motif (ITAM)
– Activate tyrosine kinases (Src family)
Survival in the Periphery
• Until the B cell makes a contact with an antigen
it can recognize, it must survive in the primary
follicle
• Follicles contain dendritic cells that release
"survival" signals, such as BLyS
• There is presumed to be competition between
new B cells and naïve B cells for space in the
follicle
• The mature B cell has a limited time to find its
antigen before it dies
BLyS Family Ligands and Receptors
Modified from Crowley et al, Semin Immunol 17, 193 (2005)
Modulation of B cell signals
• Activation
– CD19, CD21, & TAPA-1 Complex
• CD19, a member of Ig superfamily
• CD21 (CR2), a receptor for C3d
• CD81 (TAPA-1), a transmembrane protein
– ITAM Motifs
• Inhibition
– CD22
– FcgRII
– ITIM Motifs
Initial Activation
Upregulation of B cell signals
Downregulation of B cell signals
Three Types of Mature B cells
• B-1 cells
– Self-renewing and preferentially produced in the fetus
– Spontaneously produce polyreactive Igs
– Express CD5, Mac-1
• Marginal Zone B cells
– Found in the marginal zone of the spleen
– “Pre-activated”
– Respond quickly to antigens, e.g. polysaccharides
• B-2 cells („Conventional‟ B cells)
– Preferentially produced after birth
– Replaced in bone marrow
– Typically respond to protein Ag, requiring T cell help
Three Types of Mature B cells
Late Stages of B cell Development
• Exposure to antigen in the periphery
– Activation
– Class switching and somatic hypermutation
– Selection for receptor specificity and affinity
– Differentiation into plasma or memory B cells
T-Independent Responses
• Type 1 – Mitogens (LPS)
• Type 2 – Polymeric (polysaccharides,
bacterial flagellin)
Rapid Activation of Marginal Zone B
cells in Response to Strep. pneumoniae
Lopes-Carvalho and Kearney, Immunol Rev 197:192 (2004)
T-Dependent Responses
Somatic Hypermutation and
Affinity Maturation
• Occurs in response to antigen
• Primarily occurs in the germinal center
• Typically requires T cell help
• Mutated antibodies subjected to
competition
• Increased affinity = Success
– Affinity Maturation
Deamination
CU
Somatic Hypermutation
Encounter with an Antigen
Meet a Compatible Helper T cell
Live Life in a Burst of Glory or Grow
Antigen-Driven Differentiation
Antigen-Driven Differentiation
Ontogeny of Immunity