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Chapter 19 Overview and Compartmentalization of the Immune System 205

concurrent processes: class switch recombination (CSR) and somatic endothelial cell activation, leukocyte adhesion to endothelial cells at
hypermutation (SHM) of immunoglobulin genes. CSR allows the B the inflammatory site, and diapedesis of leukocytes into the tissues
cell to express a secreted Ig with unique properties, by replacing the (see Chapter 13). The resulting exudate fluid at the site of vasodilata-
constant region of the BCR/Ig with a different constant region via tion is also rich in plasma proteins that participate in innate immunity,
DNA recombination. SHM can sometimes lead to advantageous such as complement and PRRs. Hence the soluble and cellular
mutations that can allow a BCR to have higher affinity for a patho- components of the innate immune system provide the first line of
genic antigen. These B cells, bearing a higher-affinity BCR than the defense at the tissues where pathogens invade.
B-cell clone that they derived from, are positively selected to The epithelial barriers also contain resident lymphocytes and
proliferate. plasma cells. The lymphoid cells respond to cytokines secreted by
When B-cell proliferation begins, the primary follicle becomes a resident macrophages, such as IL-2, which stimulates T-cell prolif-
secondary follicle. The secondary follicle has two general regions: (1) eration. The ability of macrophages to secrete mediators that cause
a GC filled with proliferating B cells, some T cells, macrophages, and vasodilatation and recruitment of granulocytes, as well as initiate
DC; and (2) the surrounding mantle zone of nonproliferating B cells T-cell activation, illustrates the interplay between innate and adap-
that have not encountered an antigen they recognize. The GC can tive immunity and underscores the point that the innate and adap-
be further divided into dark and light zones, depending on the stage tive immune systems work in concert in host defense. Resident T
of proliferation, as discussed later in “Systemwide Surveillance.” cells and plasma cells in the tissue can respond to antigen, with
local activation of antigen-specific effector T cells and increased
ENCOUNTERS WITH ANTIGEN: THE INFLAMMATORY antibody secretion, respectively, so that the adaptive immune
response is stimulated locally after pathogens are sensed by the
RESPONSE innate immune system.

A primary function of the immune system is to protect against
microbial pathogens. The most common sites for microbes to breach SYSTEMWIDE SURVEILLANCE: THE ROLE OF
the protective barriers of epithelium are the skin and the respiratory, LYMPHATIC CIRCULATION
gastrointestinal, and genitourinary tracts. These tissues directly
encounter the outside world and possess complex, multifaceted Lymphatics are an essential component of the vascular system (Fig.
mechanisms for dealing with antigens. It should be noted, however, 19.3). Even in the absence of inflammation, a fraction of the fluid
that there is a vast array of nonpathogenic microbes that live in close component of blood continually leaves the capillary bed during cir-
proximity to these epithelial barriers, and an emerging body of sci- culation caused by the pressure drop between the arterial and venous
entific work points to the importance of these commensal organisms sides. This fluid bathes the tissues of the body picking up antigens
for maintaining immune homeostasis. 22,23 and cells and then drains into lymphatic channels that interdigitate
To defend against pathogenic organisms, these barriers contain in every capillary bed.
many components of the innate immune system, including macro- At sites of inflammation, the amount of fluid and cells draining
phages and DCs. Some tissues have specialized or unique populations into the local lymphatics increases because of changes in the vascular
of macrophages and DCs, although these cells have many common tone and permeability mediated by macrophage- and neutrophil-
features in different tissues. Macrophages provide a critical first line derived chemokines, lipid mediators, and oxygen radicals. This
of defense against pathogens by directly phagocytizing microorgan- exuded fluid, along with antigen-loaded DCs, T cells, and cytokines,
isms. Macrophages also send the first signals that recruit granulocytes drains from the tissues back through the lymphatic channels.
from the circulation into the tissues (Fig. 19.2). These signals include Lymphatic fluid eventually returns to blood circulation via the
cytokines, nitrous oxide, and leukotrienes that cause vasodilatation, thoracic duct, which drains into the vena cava. However, before

Microbes
Skin

Neutrophil
Macrophage

Lymphocyte

Blood C ytokines
vessel

Fig. 19.2 ENCOUNTERS WITH ANTIGEN. The immune system evolved primarily to protect against
invading microorganisms that penetrate the epithelial coverings of the body. In this schematic, microbes
entering through a break in the skin epithelium are phagocytosed by resident macrophages as the first line of
defense in innate immunity. The macrophages can secrete products that are directly microbicidal, as well as
cytokines and other mediators that cause vasodilatation and endothelial cell separation, to allow influx of
soluble mediators and inflammatory cells such as neutrophils and lymphocytes into the skin. Neutrophils, as
a component of innate immunity, can also directly kill microorganisms, typically by releasing granular contents.
Lymphocytes responding to microbial antigens proliferate and contribute to the adaptive immune response
against microbes.