B cells

1
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

2
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

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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

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B cell Development (Human)
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Alternative Splicing Yields Secretory or Membrane
Ig (BCR)
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IgM and IgD via Differential Splicing
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B cells in the Bone Marrow
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Early Checkpoints
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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)

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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

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BLyS Family Ligands and Receptors
Modified from Crowley et al, Semin Immunol 17,
193 (2005)
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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

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Initial Activation
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Upregulation of B cell signals
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Downregulation of B cell signals
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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

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Three Types of Mature B cells
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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

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T-Independent Responses

• Type 1 Mitogens (LPS)
• Type 2 Polymeric (polysaccharides, bacterial
  flagellin)

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Rapid Activation of Marginal Zone B cells in
Response to Strep. pneumoniae
Lopes-Carvalho and Kearney, Immunol Rev 197192
(2004)
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T-Dependent Responses
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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

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Deamination
C ? U
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Somatic Hypermutation
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Encounter with an Antigen
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Meet a Compatible Helper T cell
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Live Life in a Burst of Glory or Grow
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Antigen-Driven Differentiation
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Antigen-Driven Differentiation
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Ontogeny of Immunity