Transcript Biology of the B Lymphocyte

Biology of the B Lymphocyte
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Review:
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B cells can develop a vast repertoire of antigenic specificities
Diversity – the ability to respond to many different antigenic
determinants (epitopes) even if they have not been
previously encountered
Development of lymphocytes and how they are
responsible for
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Specificity
Memory
Discrimination b/w “self” and “nonself”
Sites of Early B-Cell Differentiation
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Synthesis of Ab was shown to require the presence of
an organ called the bursa of Fabricius (chickens)
Cells that developed into mature Ab forming cells
were called bursa-derived or B cells
B cell differentiation (humans)
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Liver in early fetus
During fetal development and throughout the rest of life
switches to bone marrow
Bone marrow is the primary lymphoid organ for B-cell
differentiation
Ontogeny of the B Lymphocyte
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Differentiation pathway of B lymphocytes
(Figure 7.1
Handout)
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Pro-B Cell
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Earliest distinguishable cell in the B cell lineage
DH-DH rearrangement
No Ig product
Pre-B Cell
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VHDHJH rearrangement
Synthesizes m chain
Surrogate light chains – from two non-rearranging genes l5
and VpreB
B Cell Receptor (BCR)
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Pre –BCR
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Iga (CD79a) and Igb (CD 79b)
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Associated with Ig molecules on all cells of the B cell lineage
Do not bind Ag
Signal transduction – transmit signal into cell after binding of
Ag to the V regions of Ig H and L chains
Surrogate light chains + m chain
B-Cell Receptor
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H chain of the BCR may be m, d, g, a, or e
B Cell Ontogeny
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Cells that do not express pre-BCR die by apoptosis
Cells expressing pre-BCR undergo “positive selection”
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Signals via the pre-BCR induce cells to proliferate
Surrogate light chain synthesis is shut down
Light chain rearrangement starts
Further H chain rearrangement is stopped
Immature B Cells
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Light chains pair with m chains (membrane-bound
monomeric form)
Immature B cells can recognize and respond to foreign Ag,
but this interaction results in long-lasting inactivation rather
than expansion and differentiation
Immature B Cells
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Interaction of self molecules and immature B cells is
important in development of “self-tolerance” in the
bone marrow
B cells with potential reactivity to self are prevented
from responding  “negative selection”
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Deletion (apoptosis)
Anergy (inactivation)
Self reactive B cells may also undergo “receptor
editing” to generate a new (foreign) specificity
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“rescued” from inactivation
Mature B Cells
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Development of IgM+IgD+ mature B cells
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Predominantly in bone marrow
Can also occur in secondary lymphoid organs
Activation
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Response to foreign Ag
Occurs primarily in secondary lymphoid organs (lymph node
and spleen) in the germinal centers
Enlarge to become B cell “blasts”
Proliferate and differentiate
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Plasma cells  class switching
Memory B cells  class switch but non-proliferating, long-lived
Memory B Cells
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Generation is associated with class switch and
somatic hypermutation in the germinal centers of
spleen and lymph node
Germinal centers provide an environment where B
cells with mutations for high affinity for Ag are
clonally selected and expanded
Serve as memory cells for subsequent responses
Affinity maturation increases the production of high
affinity Ab in the secondary response
B-1 or CD5+ B Cells
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Most B cells are B-2 type
B-1 cells
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Minor population in spleen and lymph nodes
Predominate in the peritoneal and pleural cavities
Express CD5
Synthesize predominantly low affinity IgM in response to
bacterial polysaccharide Ags
B Cell Membrane Proteins
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Ab production is a multi-step process that generally requires the
mutual interaction b/w B cells and T cells
Important molecules on the B cell can be categorized as
 Ag-binding molecules: membrane Ig
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Distinguished B cells from other lymphocytes and mononuclear
cells
Signal transduction molecules associated with mIg –
transduce signals into the B cell following Ag binding to Ig
 Iga (CD79a) and Igb (CD79b)
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Immunoreceptor tyrosine-based activation motif
“other” molecules – increase the activatory signal
 CD19, CD21, CD81
B Cell Membrane Proteins
Molecules involved in Ag presentation
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To activate T cells Ag must be presented by APC
B cells (like other APC) act as APC for T cells
B cells share important characteristics with other APC
B cells express class II MHC molecules constitutively
(always expressed)
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Increase MHC class II expression by IL-4
Present Ag to CD4+ T cells (helper T cells)
MHC class II is expressed on all cells in the B cell lineage apart
from the pro-B cell
B Cell Membrane Proteins
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Costimulatory molecules  Interact with T cell membrane
molecules to enhance activation
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B7
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Resting mature B cells
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Activated B cells
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Low levels B7
Poor APC
High levels of B7
Very efficient APC
CD40
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Critical role in isotype switching
Interacts with CD154 (CD40L or CD40 Ligand) on T cells
Human X-linked hyper-IgM syndrome
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Boys with a mutation in CD40 ligand gene (either not expressed or
nonfunctional) make only IgM Ab –cannot switch to any other isotype
B Cell Membrane Proteins
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Fc receptor FcgRII (CD32)
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Virtually all B cell express a low affinity receptor for the Fc
portion of IgG
Involved in “Ab feedback” to inactivate B cells to inhibit Ab
production
FcgRI (CD64) – restricted distribution
The Major Histocompatibility
Complex in the Immune Response
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T cells evolved to deal with Ags inside the cell
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Viruses, bacteria and parasites that invade cells
T cells use an Ag recognition system (TCR) that
interacts with a fragment of an Ag presented on the
surface of a cell bound to MHC gene product
Major histocompatibility complex (MHC)
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Role is to bind to peptide fragments derived from protein
Ags and then present them to T cells
Binding of MHC molecules to peptide is selective – binds to
only certain peptides
MHC Molecules
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MHC molecules may be viewed as a third set of
recognition molecules for Ag in the immune response,
in addition to the Ag-specific T-cell and B-cell
receptors.
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Important in rejection of tissues (mice studies)
Every vertebrate species has MHC genes and products
Transplantation rejection responses are dominated by T cells
MHC plays a central role in T cell interactions  both T cell
development in the thymus and response of T cells to Ag
MHC restriction of T-cell responses
Variability of MHC Genes & Products
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Two major sets of MHC genes and products
MHC class I
 MHC class II
Human MHC region (chromosome 6) known as HLA (human
leukocyte Ag)
Murine MHC region (chromosome 17) referred to as H-2
MHC molecules are members of the Ig superfamily and contain
Ig-like globular domains
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Most other species follow the human nomenclature
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BoLA  bovine
SLA  swine
MHC Complex
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MHC is referred to as a “complex” because the genes are closely
linked and inherited as a unit
The set of genes inherited by an individual from one parent is
known as a haplotype
MHC Class I (humans)
 Three independent human class I genes  HLA-A, HLA-B,
and HLA-C
 Always expressed at the surface in association with a
molecule known as b2-microglobulin (b2m)
MHC Complex
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MHC Class II
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Produces three cell surface molecules  HLA-DP, HLA-DQ
and HLA-DR
Each comprise an a and b chain
DPa chain always pairs with DPb (DQ and DR behave
similarly)
The a and b chain of each molecule are coded by an A and a
B gene, respectively
The genes coding for DP a and b are known as DPA1 and
DPB1, DQ a and DQ b as DQA1 and DQB1, respectively
DR region has seven DRB genes and one A gene – the
product of the A gene (DRA1) combines with the product of
one of the DRB genes to generate a DR ab molecule
Murine MHC Complex
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Murine MHC, H-2 located on chromosome 17
Murine MHC class I
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High degree of homology b/w human and mouse indicating a
common ancestral origin
Three mouse genes and products  H-2K, H-2D and H-2L
Expressed on cell surface with b2m
Murine MHC class II
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I-Aab and I-Eab
Genes are referred to as H-2I-Aa and Ab and H-2I-Ea and Eb
Mouse I-A genes and products are homologous to human MHC
class II DP
Mouse I-E genes and products are homologous to human MHC
class II DR