Ganong's Review of Medical Physiology, 23rd Edition

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)