PRINCIPLES OF TOXICOLOGY

190 IMMUNOTOXICITY: TOXIC EFFECTS ON THE IMMUNE SYSTEM
polymorphonuclear and mononuclear phagocytic cells. Parts of this nonspecific immune system may
contribute to the pathogenesis of an inflammatory response, and certain aspects of this system may be
important in the etiology of autoimmunity.
Acquired immunity, in contrast, is highly specific and increases in magnitude with successive
exposure to foreign substances. Substances that trigger these specific immune responses are termed
immunogens, and may be either foreign or endogenous. In many cases, immunogens are proteins,
although a variety of macromolecules can be immunogenic under appropriate circumstances, including
polysaccharides, nucleic acids, and ribonucleic acids. There are two types of acquired immune
responses: humoral immunity and cell-mediated immunity. Humoral immunity involves the production
of proteins capable of binding to foreign substances. These belong to a special class of proteins called
immunoglobulins, and the proteins themselves are called antibodies. The substances to which the
antibodies bind are called antigens. Antibody binding can neutralize toxins, cause agglutination of
bacteria and other microorganisms, and lead to precipitation of soluble foreign proteins. Each of these
is important in defense of the host. In cell-mediated immunity, specialized cells rather than antibodies
are responsible for the destruction of foreign cells.
A critical function of the immune system is to effectively distinguish between macromolecules that
belong, or do not belong, in the body. The specific immune response is believed to be highly
individualistic, a process which defines “self” while also defending the organism against “nonself.”
This is evident by the response to certain environmental toxicants, to allergens or antigens, and the
specific rejection of allografts. Recognition of “self” is known to be guided, in part, by genetic
variations in proteins of the class I and II major histocompatibility complex (MHC). Initially, the ability
of the immune system to differentiate “self” from “nonself” is an educational process. During
maturation, the system must ignore an infinite variety of self-molecules and yet be primed and ready
to respond to an array of exogenous antigens. Immunomodulatory control mechanisms lead to immune
tolerance of self and carefully orchestrate the immune response to targets and removal of foreign
macromolecules and cells. These control mechanisms arise from interactions among the several
different cell types with roles in proper immune function.
Lymphocytes are considered to be the major cells involved in a specific immune response in
humans. They are derived from pluripotent stem cells and undergo an orderly differentiation and
maturation process to become T cells or B cells (see Figure 4.1 in the chapter on hematotoxicity), with
critical functional roles in the host defense. T-cell development occurs primarily in the thymus, where
cell surface protein markers are acquired during the selection and differentiation process. These protein
markers are called CD antigens (for cluster of differentiation), and at least 78 different CD antigens
have been identified in humans. The presence of certain CD antigens, detectable by immunofluorescence,
has been used to positively identify immunocytes. In general, mature T cells are characterized
by the presence of CD3 + and CD4 + or CD8 + surface markers and are devoid of surface or cytoplasmic
immunoglobulin. There are various subtypes of T cells, such as T-helper (T H ) cells, T-suppressor (T S )
cells, and cytotoxic cells (T C ). T H lymphocytes carry the CD4 + marker, while T S and T C lymphocytes
have the CD8 + marker. Together, these T-lymphocyte populations play a vital role in initiating and
regulating the immune response.
Human B cells develop from stem cells in the fetal liver and, after birth, B-cell development occurs
principally in the bone marrow. B-cell development and maturation are characterized by class-specific
immunoglobulin (Ig) expression on the cell surface. Monoclonal reagents can identify the Ig expressed
on the surface of B cells. Immunophenotypic characterization of cells via these markers has proved to
be invaluable in certain clinical situations and a useful research tool. B cells play an important role in
recognition of antigens and are responsible for antibody production.
Another important cell in the specific immune response is the antigen-presenting cell (APC). These
cells make first contact with the antigen and may also process the antigen; that is, modify it in such a
way as to enable its recognition by T cells. This category of cells is defined more by function than cell
type. In general, the most important APCs are tissue macrophages and peripheral blood monocytes,
although cells of other types (e.g., Langerhans cells in the skin, dendritic cells in lymphoid tissue) may
also perform this function.