The Immune System 495The genes required for innate immunity are inherited. Since
this limits the number of genes that can be devoted to this task,
innate immune mechanisms combat whole categories of patho-
gens. A category of bacteria called gram-negative, for example,
can be recognized by the presence of particular molecules (called
lipopolysaccharide) on their surfaces. In adaptive immunity,
by contrast, specific features of pathogens are recognized. The
enormous number of different genes required for this task is too
large to be inherited. Instead, the variation is produced by genetic
changes in lymphocytes during the life of each person after birth.
Innate (Nonspecific) Immunity
Innate immunity includes both external and internal defenses.
These defenses are always present in the body and represent
the first line of defense against invasion by potential pathogens.
Invading pathogens, such as bacteria, that have crossed epi-
thelial barriers next enter connective tissues. These invaders—
or chemicals, called toxins, secreted from them—may enter
blood or lymphatic capillaries and be carried to other areas of
the body. Innate immunological defenses are the first employed
to counter the invasion and spread of infection. If these defenses
are not sufficient to destroy the pathogens, lymphocytes may be
recruited and their specific actions used to reinforce the nonspe-
cific immune defenses.
Activation of Innate Immunity
The innate immune system distinguishes between the body’s
own tissue cells (“self ”) and invading pathogens by recog-
nizing molecules termed pathogen-associated molecular
patterns (PAMPs) that are unique to the invaders. The best
known of these PAMPs are lipopolysaccharides (LPS), found
in the envelope of gram-negative bacteria, and peptidoglycan
from the cell walls of gram-positive bacteria.
Some cells of the innate immune system have receptor
proteins—called pathogen recognition receptors —that rec-
ognize PAMPs. The genes that code for these receptor proteins
are inherited through the germ cells (sperm and egg), which is
a distinguishing characteristic of the innate immune system. By
contrast, the adaptive immune system has a greater diversity of
receptor protein genes because of postnatal mutation and recom-
bination of the DNA coding for these receptors (section 15.2).
An important group of pathogen recognition receptors
of the innate immune system are the toll-like receptors, so
named because they are similar to a receptor discovered ear-
lier in fruit flies that was named the toll receptor. ( Toll is Ger-
man for “weird”—flies that have this receptor have a weird
development.) Ten different toll-like receptors have currently
been identified in humans, each specific for a different type of
molecule that is characteristic of invading pathogens but not
of human cells. These 10 toll-like receptors enable our innate
immune system to correctly identify any potential pathogen as
foreign and a fit object for attack. The importance of toll-like
receptors in immunity was recognized in a share of the 2011
Nobel Prize in Physiology or Medicine.
For example, exposure to LPS from bacteria stimulates one
of the toll-like receptors on certain cells of the innate immune
system termed dendritic cells and macrophages. These cells are
stimulated to secrete chemokines (cell attractant molecules),
which recruit other cells of the immune system, and cytokines
(cell growth and regulatory molecules), which promote differ-
ent aspects of immune responses. These include responses of
both the innate immune system—including phagocytosis and
a fever—and the adaptive immune system (B and T lympho-
cytes, discussed later).
Another group of pathogen recognition receptors are called
NOD-like receptors. These are critical for the recognition of
intracellular molecules derived from certain bacteria. These recep-
tors activate the transcription of genes that promote defenses such
as autophagy (chapter 3, section 3.2). Mutated NOD genes are
thought to contribute to Crohn’s disease, where the normal bacte-
rial population of the gut may cause intestinal inflammation.
The complement system helps integrate innate and adap-
tive immune responses. The complement system consists of
proteins in plasma and other body fluids that become activated
when antibodies (part of the adaptive immune system) bond
to their molecular targets, termed antigens (see fig. 15.10 ).
When this occurs, complement proteins—part of the innate
immune system—promote phagocytosis, lysis (destruction) of
the targeted cells, and other aspects of a local inflammation
(discussed in a later section).
A local inflammation can also be produced in the absence of
infection when tissue damage causes necrosis. In this case, the
immmune system is exposed to DAMPs—danger-associated
molecular patterns. DAMPs, like the PAMPs in invading micro-
organisms, stimulate innate immune responses and inflammation.
However, when cells die by apoptosis as part of programmed
cell death (chapter 3, section 3.5), they generally do not express
DAMPs and thus do not provoke inflammation.Phagocytosis
There are three major groups of phagocytic cells: (1) neutrophils;
(2) the cells of the mononuclear phagocyte system, including
monocytes in the blood and macrophages (derived from mono-
cytes) and dendritic cells in the connective tissues; and (3) organ-
specific phagocytes in the liver, spleen, lymph nodes, lungs, and
brain ( table 15.2 ). Organ-specific phagocytes, such as the microg-
lia of the brain, are embryologically and functionally related to
macrophages and may be considered part of the mononuclear
phagocyte system.
The Kupffer cells in the liver, as well as phagocytic cells in the
spleen and lymph nodes, are fixed phagocytes. This term refers
to the fact that these cells are immobile (“fixed”) in the walls of
the sinusoids within these organs. As blood flows through the
sinusoids of the liver and spleen, foreign chemicals and debris
are removed by phagocytosis and chemically inactivated within
the phagocytic cells. Invading pathogens are very effectively
removed in this manner so that blood is usually sterile after a few
passes through the liver and spleen. Fixed phagocytes in lymph
nodes similarly help remove foreign particles from the lymph.