Immunotherapy for Infectious Diseases

64 Kunert and Katinger
IMMUNOGLOBULINS
Immunoglobulins (Igs) are part of the adaptive immune system and basically fulfill
two major biologic functions related to the variable and constant regions of the antibody
molecule common to all immunoglobulins (Fig.1). The first function, carried out
by the variable region, is the recognition and specific binding to antigens, either soluble
antigens such as toxins, or solid antigens such as viruses or microorganisms. The
constant region of the molecule mediates various effector functions and subclasses of
immunoglobulins.
Antibodies (Ab) or immunoglobulins are glycoproteins generated in all mammals.
A cascade of immunoglobulins is produced upon stimulation with a foreign immunogenic
antigen. During the maturation of the immunologic cascade, five distinct
immunoglobulin classes can evolve, IgG, IgA, IgM, IgD, and IgE, which differ in size
as well as amino acid and carbohydrate composition of the heavy chains. Figure 2
shows the monomeric and oligomeric structures of IgG, IgA, and IgM. The different
regions of the basic Ig monomere are described in Figure 1. IgG is a monomeric protein
representing approx. 70% of the antibody pool in the human serum. IgM molecules
are the first antibodies to be expressed in the course of an immunogenic response
to an antigen. The pentameric structure of IgM is stabilized by a peptide structure
called the joining (J) chain. The dimeric structure of IgA is an immunologic barrier in
seromucosal secretions. IgD acts in conjunction with antigen-triggered lymphocyte differentiation.
IgE is displayed on the surface membrane of basophilic and mast cells and
is often associated with allergic symptoms.
Humoral Immune Response and the Cellular Basis of Immune Response
Primary contact of invading antigens with the cells of the immune system either triggers
tolerance or induces an immune reaction. The form of antigen presentation determines
whether a cell-mediated or an antibody response is elicited. The antigen moves
to the local lymph nodes, where it is endocytosed by antigen-presenting cells (APCs)
and presented together with class II major histocompatibility complex (MHC) molecules
on the surface of the cells. The degradation and transport through the endoplasmatic
reticulum is mediated by class I MHC molecules. Many additional ligands and
receptors like CD40/CD40 ligand or interleukin (IL)-2/IL-2 receptor support the interaction
of T- and T/B-cell collaboration. T-helper cells cooperate with B-cells to induce
antibody production.
B-Cell Development
B-cell development starts in the fetal liver, before the bone marrow becomes the
dominant hematopoietic organ. Pre-B-cells begin differentiating and proliferating in
response to signals of local stromal cells. As shown in Figure 3 in more detail, pre-Bcells
rearrange their heavy-chain variable-region gene segments and express signal
transduction receptors for further development. After also rearranging the gene segments
of the light chain, the premature IgM B-cells migrate from the bone marrow to
the secondary lymphoid tissue, where antigen contact and cytokine interaction with Thelper
cells take place. Further differentiation to plasma cells prepares them for subclass
switch and expression of high quantities of soluble immunoglobulins.