294
Carbohydrate Antigens
but not sufFcient to induce class switching
and antibody production. Secondary sig-
naling is required for induction of class
switching and for the terminal differen-
tiation of B-cells into antibody-secreting
cells (ASCs). This is signiFcantly different
from the B-cell activation by a T-dependent
protein antigen.
B-cell activation via TD antigens is initi-
ated by antigen-speciFc, MHC-restricted,
T-cell–B-cell interactions. As a conse-
quence of the Frst initiation, additional
molecular interactions, such as CD40 and
CD40 ligand, and CD28/CTLA4-Ig with
B7-1/B7-2, can proceed. These molecular
events further activate the interaction of
T-cells and B-cells. The CD40–CD40 lig-
and interaction is particularly important
in the TD antibody response. Blocking this
molecular interaction also blocks the TD
antibody response.
B-cells stimulated by TI and TD anti-
gens may undergo different pathways
of cellular activation and differentiation,
that is, germinal center reactions and
antibody-secreting cell responses. TD anti-
gens induce both germinal centers (GC)s
and ASCs. Many critical molecular and
cellular events take place in GCs: clonal
selection and differentiation of B-memory
cells, IgH-class switching, somatic hyper-
mutation and afFnity maturation, and the
production of precursors of ASCs. By con-
trast, most TI antigens induce an ASC
response without GC induction. Thus, the
typical TI-antigen response fails to induce
memory cells, somatic mutation, and class
switching (IgM to IgG). As a consequence,
antibodies to polysaccharides and other
T-independent antigens are generally in
germ-line gene conFgurations without so-
matic mutations in their V regions. These
antibodies were thought to be natural an-
tibodies of relatively low afFnity and are
frequently isotype and idiotype restricted.
5.2
Complexity of Anticarbohydrate Responses
Given the structural diversity of carbo-
hydrate antigens and the presence of
families of cellular receptors with car-
bohydrate binding activities (lectins), the
complexity of anticarbohydrate immune
responses
in vivo
must be emphasized.
This point was highlighted by a series of
immunological studies on two microbial
polysaccharides,
α
(1
6) dextran (N279)
and
α
(1
3)
α
(1
6) dextran (B1355S).
Dextran B1355S and N279 are pro-
duced by different strains of
Leuconostoc
mesenteroides
. Structurally, they differ only
in their composition of glycosidic link-
ages. N279 is the simplest dextran with
α
(1
6)linked internal linear chains pre-
dominating; B1355S is the prototype of
dextrans having signiFcant proportions
of non-
α
(1
6)linkages. Therefore, the
tertiary structure of B1355S differs strik-
ingly from that of N279. The predom-
inant antigenic determinant of B1355S
is
the
linear
backbone
of
alternating
α
(1
3)
α
(1
6)linkages.
α
(1
6) dextran
has type D conformation, as a flexible
coil in solution. However, by insertion
of
α
(1
3)linkages into a
α
(1
6)linked
linear chain, this structure may be com-
pletely altered. The backbone of alternating
α
(1
3)
α
(1
6)linkages is much more
rigid than the
α
(1
6) glycosidic internal
linear chain.
When the two glucose-composed poly-
saccharides
were
used
to
immunize
mice, distinct patterns of B-cell responses
were induced. These include the reper-
toires of their speciFc antibodies and
the pathways of splenic B-cell activation.
α
(1
3)
α
(1
6) dextran elicits a highly re-
stricted VHJ558/
λ
1 dominant response,
while the
α
(1
6) dextran responses are
highly diverse. Moreover, unlike
α
(1
3)
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