70
SECTION I
Cellular & Molecular Basis for Medical Physiology
responses, such as endothelial and epithelial cells. The activat-
ed cells produce their effects via the release of cytokines, as
well as, in some cases, complement and other systems.
An important link in innate immunity in
Drosophila
is a
receptor protein named
toll,
which binds fungal antigens and
triggers activation of genes coding for antifungal proteins. An
expanding list of toll-like receptors (TLRs) have now been
identified in humans. One of these, TLR4, binds bacterial
lipopolysaccharide and a protein called CD14, and this initiates
a cascade of intracellular events that activate transcription of
genes for a variety of proteins involved in innate immune
responses. This is important because bacterial lipopolysaccha-
ride produced by gram-negative organisms is the cause of septic
shock. TLR2 mediates the response to microbial lipoproteins,
TLR6 cooperates with TLR2 in recognizing certain peptidogly-
cans, and TLR9 recognizes the DNA of certain bacteria.
ACQUIRED IMMUNITY
As noted previously, the key to acquired immunity is the abil-
ity of lymphocytes to produce antibodies (in the case of B
cells) or cell-surface receptors (in the case of T cells) that are
specific for one of the many millions of foreign agents that
may invade the body. The antigens stimulating production of
T cell receptors or antibodies are usually proteins and
polypeptides, but antibodies can also be formed against nucle-
ic acids and lipids if these are presented as nucleoproteins and
lipoproteins, and antibodies to smaller molecules can be pro-
duced experimentally if the molecules are bound to protein.
Acquired immunity has two components: humoral immunity
and cellular immunity. Humoral immunity is mediated by
circulating immunoglobulin antibodies in the γ-globulin frac-
tion of the plasma proteins. Immunoglobulins are produced
by differentiated forms of B lymphocytes known as plasma
cells, and they activate the complement system and attack and
neutralize antigens. Humoral immunity is a major defense
against bacterial infections. Cellular immunity is mediated by
T lymphocytes. It is responsible for delayed allergic reactions
and rejection of transplants of foreign tissue. Cytotoxic T cells
attack and destroy cells that have the antigen which activated
them. They kill by inserting perforins (see above) and by initi-
ating apoptosis. Cellular immunity constitutes a major de-
fense against infections due to viruses, fungi, and a few
bacteria such as the tubercle bacillus. It also helps defend
against tumors.
DEVELOPMENT OF THE IMMUNE SYSTEM
During fetal development, and to a much lesser extent during
adult life, lymphocyte precursors come from the bone mar-
row. Those that populate the thymus (Figure 3–5) become
transformed by the environment in this organ into T lympho-
cytes. In birds, the precursors that populate the bursa of
Fabricius, a lymphoid structure near the cloaca, become trans-
formed into B lymphocytes. There is no bursa in mammals,
and the transformation to B lymphocytes occurs in bursal
equivalents, that is, the fetal liver and, after birth, the bone
marrow. After residence in the thymus or liver, many of the T
and B lymphocytes migrate to the lymph nodes.
T and B lymphocytes are morphologically indistinguishable
but can be identified by markers on their cell membranes. B
cells differentiate into plasma cells and memory B cells.
There are three major types of T cells: cytotoxic T cells,
helper T cells, and memory T cells. There are two subtypes
of helper T cells: T helper 1 (TH1) cells secrete IL-2 and γ-
interferon and are concerned primarily with cellular immu-
nity; T helper 2 (TH2) cells secrete IL-4 and IL-5 and interact
primarily with B cells in relation to humoral immunity. Cyto-
toxic T cells destroy transplanted and other foreign cells, with
their development aided and directed by helper T cells. Mark-
ers on the surface of lymphocytes are assigned CD (clusters of
differentiation) numbers on the basis of their reactions to a
FIGURE 3–5 Development of the system mediating acquired immunity.
Thymus
T lymphocytes
Memory
T cells
Bone marrow
lymphocyte
precursors
Helper T cells
(CD4 T cells)
B lymphocytes
Bursal equivalent
(liver, bone marrow)
Memory
B cells
Plasma
cells
IgG
IgA
IgM
IgD
IgE
Humoral
immunity
Cellular
immunity
Cytotoxic
T cells
(mostly CD8
T cells)