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CHaPTEr 20 Host Defenses at Mucosal Surfaces 295

ON THE HOrIZON Expression in the lower lungs is restricted to the pulmonary
Development of Transgenic Plants as Vehicle for alveolar cells.
In female reproductive tissues, the expression of pIgR is
Vaccine Administration influenced by the sex hormones. It is low in the vagina, absent
• The MucoRice system is a novel strategy for vaccine development. in the ovary and myometrium, and very high in the fallopian
• The MucoRice system may also be used as a passive neutralizing tubes and uterus. Normal kidneys do not express pIgR, whereas
antibody delivery system. epithelial cells in the lower urinary tract may normally express
pIgR and transport pIgA into urine. The expression of pIgR can
be upregulated by cytokines, such as IFN-γ, TNF-α, IL-1α, IL-1β,
SYNTHESIS AND FUNCTIONS OF and TGF-β.
SECRETORY ANTIBODIES IgA-Mediated Inhibition of Microbial Adherence

Mucosal sIgA differs from serum IgA in both molecular composi- The inhibition of microbial adherence plays a critical initial role
tion and specific antibody activity. Humans possess two Cα gene in the protection of the host. This inhibition is mediated by both
segments, Cα1 and Cα2 (Chapter 4), the use of which defines specific and nonspecific mechanisms. The surface of microorgan-
8
the two IgA subclasses, IgA1 and IgA2. These IgA subtypes isms interacting with sIgA becomes less hydrophobic and thus
differ primarily in their hinge regions (Chapter 15). IgA1 antibod- more likely to be entrapped in mucus. SIgA and pIgA are more
ies contain an additional 13 amino acids in the hinge region, effective at agglutinating microorganisms than is membrane-
and this renders them more flexible and susceptible to IgA1- bound IgA, and the agglutinating ability of sIgA specific for
specific proteases produced by certain bacteria. IgA1-secreting capsular polysaccharides of Haemophilus influenzae appears to
cells are prevalent in most human mucosal tissues, especially be crucial to preventing colonization by H. influenzae. 47
the small intestine and the respiratory tract, whereas the human
colon and genital tract are enriched by IgA2-secreting cells. SIgA Neutralization by sIgA of Viruses, Enzymes, and Toxins
are mostly viewed as a barrier at mucosal surfaces to prevent SIgA antibodies have been shown to be effective at neutralizing
adhesion and colonization of pathogens, as well as an effective viruses in several experimental systems (e.g., influenza virus,
means to neutralize viruses and toxins, although these antibodies Epstein-Barr virus [EBV], HIV, etc.) and at different steps in the
confer the additional advantage of providing antiinflammatory infectious process. SIgA specific for influenza hemagglutinin can
properties. 8 interfere with the initial binding of influenza virus to target cells
In external secretions, adult levels of sIgA are reached consider- or with the internalization and the intracellular replication of
ably earlier (1 month to 2 years) than in the serum (adolescence). the virus. In vitro experiments employing polarized murine
Approximately 98% of SIgA antibodies are produced locally in epithelial cells have demonstrated that antibodies specific to
mucosal tissues, with only a minor fraction deriving from the rotavirus and hepatitis virus can neutralize the viruses inside
circulation. epithelial cells. Finally, sIgA can neutralize the catalytic activity
of many enzymes of microbial origin.
KEY CONCEPTS Antiinflammatory Actions Mediated by SIgA Antibodies
Secretory Immunoglobulin A (SIgA) IgA antibodies are unable to activate complement by either the
classical or the alternative pathway (Chapter 21). Nevertheless,
• Unlike serum IgA, mucosal secretion of IgA reaches adult levels early
in life (1 month to 2 years after birth). they can interfere with IgM- and IgG-mediated complement
8
• The polymeric Ig receptor (pIgR) is expressed on the basolateral surface activation. SIgA can inhibit phagocytosis, bactericidal activity,
of epithelial cells and facilitates the active transport of secretory IgA, and chemotaxis by polymorphonuclear neutrophils (PMNs),
as well as pentameric IgM, into mucosal secretions. monocytes, and MØs. IgA can downregulate the synthesis of
• SIgA protects the host by inhibiting microbial adherence; neutralizing TNF-α and IL-6, as well as enhancing the production of IL-1R
viruses, enzymes, and toxins; and engaging in antiinflammatory activities antagonists by LPS-activated human monocytes. Thus the
by means of inhibiting IgM and IgG complement activation.
• Clinically, selective IgA deficiency, which is the most common primary antiinflammatory properties of IgA are of significant importance
immune deficiency, is characterized by recurrent mucosal infections, for the integrity of the mucosa in that IgA can limit bystander
including sinusitis, otitis media, bronchitis, and pneumonias of viral tissue damage that may result from the continuous interactions
or bacterial origin, as well as acute diarrhea caused by viruses, bacteria, of the mucosa with myriad dietary and environmental antigens.
or parasites, such as Giardia lamblia. Systemically, circulating IgA also appears to help limit inflam-
matory reactions that result from complement fixation and
phagocyte activation, and it contributes to the inhibition of
Polymeric Immunoglobulin Receptor and plgA Transport IgE-dependent anaphylactic responses.
The polymeric Ig receptor (pIgR) is synthesized as a transmem-
brane protein by epithelial cells and is found on the basolateral IgA Deficiency
surface of epithelial cells. It acts as a receptor for the endocytosis Selective IgAD is the most common primary immune deficiency
of pIgA and pentameric IgM, both of which contain a J-chain. (PID) in individuals of European descent (Chapter 34). The
The pIgR is produced by bronchial epithelial cells, renal tubules, clinical diagnosis of IgAD depends on the relative absence of IgA
1
glands, and the epithelia of the small and large intestines. The in the serum. However, the most important manifestations of the
pIgR is not expressed by the FAE (including M cells) of PPs, but disorder primarily reflect the absence of both sIgA1 and sIgA2
only by the adjacent columnar epithelial cells. Further, pIgR is in the external secretions. Thus IgAD affects both the mucosal
expressed in the upper respiratory tract, which includes the nasal and systemic immune compartments, with only rare individuals
cavity, tonsils, trachea, bronchi, and tracheobronchial glands. exhibiting a superselective loss of either IgA1 or IgA2 alone. 48