Humoral responses

Structure and function of antibodies
Soluble antibodies are Y-shaped glycoproteins of the
immunoglobulin (Ig) family synthesized and secreted
by plasma cells in response to antigenic stimulation
of naive B cells. Occurring freely in the blood and
lymph, antibodies act as fl exible adapters, allowing
various mediators of the immune system to recognize
specifi c pathogens and their products and to exert
their action. The body can make several million different
antibodies, each one able to recognize a specifi c
infectious agent.
All antibody molecules consist of four polypeptide
chains – two identical heavy chains and two identical
light chains. Each of the arms of the Y-shaped molecule
represents a Fab region, which binds to antigen;
the stem represents the Fc region, which interacts
with immune system mediators. The terminal half
of each of the Y arms is highly variable in its amino
acid sequence from one antibody to the next, the
remainder of the molecule being relatively constant.
These differences give rise to the terms ‘variable’ and
‘constant’ regions. Immunoglobulins are classifi ed on
the basis of structural differences in the heavy chains.
The most important classes are IgG, IgA, IgM, IgD
and IgE. The constant regions of the heavy chains,
and consequently the class of the antibody, can change
during the course of an immune response, although
the antigen specifi city of the antibody is unchanged.
This process is known as antibody class switching and
as a result the effector functions performed by the
antibody will also change.
Phagocytes and natural killer cells, among other
cells, have Fc receptors on their surfaces, allowing
these cells to bind and destroy antibody-coated bacteria
and tumour cells. Antibodies can also bind to
the fi rst component (C1q) of the complement system,
thereby activating the complement cascade.
The primary function of an antibody is to bind
antigens. In a few cases this has a direct effect; for
example, neutralization of toxins by blocking active
sites and inhibition of viral attachment to the target
cell or penetration of the cell. In other cases, including
precipitation of soluble antigen, agglutination of
particulate antigen and activation of the complement
system, secondary effector functions come into play.
These secondary functions result from the formation
of immune complexes between multivalent antigens
and divalent antibody.
The variable region of a particular antibody may
represent a unique structure that has appeared for the
fi rst time within a certain individual. Consequently,
an immune response may be directed against epitopes
on the variable domains. Each of these epitopes is
known as an idiotope and the sum of all the idiotopes
determines the antibody’s idiotype. An immune
response that is elicited by the host’s own antibody
molecules is called an auto-anti-idiotype response
and the ‘anti-antibodies’ that are produced are termed
auto-anti-idiotype antibodies. It has been postulated
(Jerne, 1984) that idiotype and anti-idiotype antibodies
can interact to form a network that can infl uence
the outcome of an immune response.
Antibody responses to different types of antigen
In general, B cell responses to complex protein antigens
require helper T cells; these responses and the
antigens that elicit them are described as T-dependent
(TD). TD responses fall into two categories, primary
and secondary antibody responses. B cells can also
respond to other types of antigen in the absence of T
helper cells, in which case the responses and antigens
are described as T-independent (TI). TI responses
are usually unable to elicit a secondary response. TI
and TD antigens can be distinguished according to
whether or not, respectively, they can stimulate antibody
production in the athymic mouse (mutants
without a functional thymus).
T-dependent (TD) responses
An animal’s fi rst exposure to a TD antigen elicits a primary
response, during which selected B cells undergo
differentiation and clonal expansion to become antibody-
secreting plasma cells. At the same time, other
B cells (and T cells) differentiate and proliferate to
106 Vitamins: their role in the human body
become memory cells. The primary response is characterized
by a lag phase and the production of mainly
the IgM class of antibody. IgM is particularly effective
in activating the complement cascade (15 times more
so than IgG). If the antigenic determinant is present
on a pathogenic microorganism, complement may
either kill the organism directly or stimulate phagocytosis
via complement receptors on phagocytes.
After a plateau of antibody production, the response
declines.
Once primed during the primary response, an animal
can produce a more vigorous secondary response
when subsequently challenged by the same antigen.
This is partly due to the fact that the memory cells
produced during the primary response are more
readily activated by antigen than are resting cells. The
lag phase is much shorter, and antibody production
is higher and more persistent compared with the
primary response. B cells expressing receptors with
a higher affi nity for antigen are selected for clonal
expansion as the secondary response progresses, a
phenomenon known as affi nity maturation. The
switching of antibody class from IgM to other classes
brings other effector functions into play.
T-independent (TI) responses
TI antigens can be divided into type 1 and type 2 antigens
according to whether or not, respectively, they
elicit antibody production in neonatal and xid mice.
The latter mice have a particular X-linked immunodefi
ciency gene called xid which makes them unable
to respond to certain types of antigen.
Type 1 antigens are immunogenic early in life. An
example is the lipopolysaccharide component of
bacterial cell walls. Type 2 antigens are immunogenic
in later life because they have more stringent requirements
for mature B cells and cytokines. Examples are
polysaccharide capsules of bacteria such as Streptococcus
pneumoniae and synthetic polysaccharides like
dextran and Ficoll. In vivo, type 2 antigens localize selectively
on marginal zone macrophages in the spleen.