Biology of the B Lymphocyte

Review: 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

Specificity Memory Discrimination b/w “self” and “nonself”

Sites of Early B-Cell Differentiation

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) 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

Differentiation pathway of B lymphocytes (Figure 7.1 Handout)

Pro-B Cell Earliest distinguishable cell in the B cell lineage DH-DH rearrangement No Ig product

Pre-B Cell VHDHJH rearrangement Synthesizes chain Surrogate light chains – from two non-rearranging

genes5 and VpreB

B Cell Receptor (BCR)

Pre –BCR Ig (CD79a) and Ig (CD 79b)

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 + chain

B-Cell Receptor H chain of the BCR may be , or

B Cell Ontogeny Cells that do not express pre-BCR die by apoptosis Cells expressing pre-BCR undergo “positive

selection” 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 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 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”

Deletion (apoptosis) Anergy (inactivation)

Self reactive B cells may also undergo “receptor editing” to generate a new (foreign) specificity

“rescued” from inactivation

Mature B Cells Development of IgM+IgD+ mature B cells

Predominantly in bone marrow Can also occur in secondary lymphoid organs

Activation 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

Plasma cells class switching Memory B cells class switch but non-proliferating, long-

lived

Memory B Cells

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

Most B cells are B-2 type B-1 cells

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 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 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

Ig (CD79a) and Ig (CD79b) Immunoreceptor tyrosine-based activation motif

“other” molecules – increase the activatory signal CD19, CD21, CD81

B Cell Membrane Proteins

Molecules involved in Ag presentation 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) 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 Costimulatory molecules Interact with T cell

membrane molecules to enhance activation B7

Resting mature B cells Low levels B7 Poor APC

Activated B cells High levels of B7 Very efficient APC

CD40 Critical role in isotype switching Interacts with CD154 (CD40L or CD40 Ligand) on T cells Human X-linked hyper-IgM syndrome

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

Fc receptor FcRII (CD32) 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 FcRI (CD64) – restricted distribution

The Major Histocompatibility Complex in the Immune Response

T cells evolved to deal with Ags inside the cell 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) 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 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.

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 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 Most other species follow the human

nomenclature BoLA bovine SLA swine

MHC Complex 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 2-microglobulin (2m)

MHC Complex MHC Class II

Produces three cell surface molecules HLA-DP, HLA-DQ and HLA-DR

Each comprise an and chain DP chain always pairs with DP (DQ and DR behave

similarly) The and chain of each molecule are coded by an A

and a B gene, respectively The genes coding for DP and are known as DPA1 and

DPB1, DQ and DQ 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 molecule

Murine MHC Complex Murine MHC, H-2 located on chromosome 17 Murine MHC class I

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 with2m

Murine MHC class II I-A and I-E 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