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or IgD) and an epitope on the protein antigen is required to initiate activation of a
naïve B cell. B-cell epitopes are usually composed of the side chains of nonadjacent
amino acids that have been assembled into a three-dimensional conformation on the
protein's surface by the folding of the native polypeptide chain. The size and com-
plexity of a protein and its phylogenetic distance from the host contribute to the
potential of the protein to be recognized by antibody. Antibodies may also interact
with sequential epitopes, segments of consecutive amino acids in the polypeptide
chain of a native protein [N- or C- terminals; intrachain loops], or with an unfolded,
denatured protein.
In addition to the antigen receptor Ig molecule, the B cell possesses a coreceptor
complex that includes CD21. CD21 binds activated components of the innate-
immunity complement system. Optimal naïve B-cell activation occurs against target
protein antigens that activate the alternative complement pathway, creating a cova-
lent complex between the protein and a cleavage product of complement component
C3, called C3d (Carroll 2004). The interaction between the antigen receptor Ig
(which is associated with a signal-generating transmembrane heterodimer Igα/β) and
the CD21 coreceptor, mediated by the protein: C3d complex, generates “Signal 1” to
the B-cell nucleus. Signal 1 must be followed by Signal 2 (T-cell response, see be-
low) for B-cell expansion to occur.
The next step of the process takes place inside the B cell. The target protein:
C3d complex is internalized and then it is degraded to peptides within the endo-
cytic compartment and some of the peptides that are generated bind to Class II
major histocompatability complex (MHC) molecules that migrate to the B-cell
surface. B cells also express the CD40 molecule on their surface and upregulate
expression of other adhesion molecules in anticipation of interacting with an acti-
vated CD4
+
helper T-cell.
Naïve T cells reactive to the same protein antigen that engaged the naïve B cells
are likewise stimulated by antigen-processing cells presenting the cognate T-cell
epitopes in the context of MHC class II on their surface. Thus, “Signal 2” for activa-
tion of a B cell is dependent on (1) proper presentation of the protein antigen by an
antigen-presenting cell and (2) prior activation of a T-cell. This process is described
in the next paragraph, and then the description of B-cell activation is resumed.
In order for APCs to effectively engage T cells, the APC must become activated,
or “mature.” APCs that have ingested a protein mature in response to receiving a
signal at the cell surface, such as engagement of a Toll receptor or the delivery of
cytokines like interleukin 2 (IL-2) to the APC. Contamination of a therapeutic prod-
uct with proinflammatory or nonspecific mitogenic compounds such as lipopolysac-
charide (LPS) could, by binding to a Toll receptor, provide this critical second signal
required for the development of T-cell help.
The activation of a T-cell is also a two-step process. The first step involves
antigen-presenting cells (APC). These cells internalize, process, and present peptide
epitopes derived from the protein antigen, in the context of HLA molecules, to
T cells. These T-cell epitopes are derived from therapeutic proteins in the APC or in
the B cell as follows: the proteins are taken up into endocytic vesicles, and then
digested in a special proteolytic compartment called MIIC. Peptides generated in this
process then compete for binding in the binding cleft of HLA Class II molecules,
