Page 312 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 20 Host Defenses at Mucosal Surfaces 293

B-Cell Isotype Switching and IgA Plasma Nasal mucosa CpG ODN
Cell Differentiation pFL
Isotype switching is preceded by transcriptional activation of Antigens
the isotype in question (Chapter 4). IL-4 and TGF-β induce
+
surface IgM-positive (sIgM ) B cells to switch to IgE and IgA.
+
+
TGF-β 1 can induce sIgM to sIgA B-cell switches, and addition
of TGF-β 1 to LPS-triggered mouse B-cell cultures increased IgA B
synthesis. In humans, anti-CD40 stimulation of tonsillar B cells, B B B
together with TGF-β 1 in the presence of IL-10, stimulates IgA T T Ag-specific sIgA Ab
1
synthesis. Cα 1 transcripts can also be induced by B-cell mitogen T
plus TGF-β, and Cα 2 transcripts can be induced by TGF-β together T
with IL-10. FL
+
DCs can also induce surface IgA B cells via direct stimulation of
B cells with B-cell activation factor of the TNF family (BAFF) and
25
a proliferation-inducing ligand (APRIL). APRIL–transmembrane
activator and CAML interactor (TACI) signaling plays a key role
25
in CD40-independent IgA class switching in mice. In humans,
functional mutations in TACI can result in IgA deficiency (IgAD; FIG 20.7 Dendritic Cell (DC) Targeting With a Nasal Adjuvant.
+
Chapter 34). Differentiation of sIgA B cells into IgA-producing Nasal administration of CpG oligodeoxynucleotide (ODN) and
plasma cells is dependent on IL-5 and IL-6. 26 plasmid expressing FLT3 ligand cDNA (pFL) specifically target
DCs in nasal-associated lymphoid tissues (NALTs). These nasal
DC-targeting vaccines successfully elicit protective antigen-specific
VACCINE DEVELOPMENT AND MUCOSAL secretory immunoglobulin A (SIgA) antibody responses in older
IMMUNE RESPONSES adults.
Mucosal sIgA antibodies, as well as Th cell and cytotoxic T
lymphocyte (CTL) responses, can be induced by pathogens trig- mucosal adjuvants. In fact, CT promotes CD4 Th2 and Th17
gering the organized mucosal inductive sites. Effective protection responses, whereas LT-I also induces a CD4 Th1 (i.e., IFN-γ)
27
against virulent mucosal pathogens requires prophylactic immune response. As discussed below, studies with mutants of these
responses that can be achieved through mucosal vaccines. In enterotoxins and other toxins (e.g., Bacillus anthracis edema
28
contrast to conventional injected vaccines, those administered via toxin ) have shown that their enzymatic activity are dispensable
mucosal routes can trigger both mucosal immune responses as a for vaccination.
first line of defense at the portal of pathogen entry and systemic
immune responses that neutralize pathogens that have penetrated Central Nervous System Targeting Is a Safety Concern
that barrier. Thus safe adjuvants boosting SIgA antibodies and With Nasal Vaccines
mucosal immunity are being developed for mucosal vaccines. Cholera induces diarrhea as a result of its ability to elevate
These efforts are in large part as a result of knowledge gained cAMP in epithelial cells, thereby promoting secretion of water
from studies of bacterial enterotoxins and nontoxic derivatives and chloride ions into the intestinal lumen. Diarrhea is thus
(Fig. 20.7). the primary limiting factor for the use of oral enterotoxin as
an adjuvant in humans. The olfactory neuroepithelium in
Lessons From Studies of Bacterial Enterotoxins the nasopharynx constitutes approximately 50% of the nasal
Earlier studies of cholera toxin (CT) and heat-labile toxin I (LT-I) surface and has direct neuronal connection to the olfactory bulbs
from Escherichia coli helped establish that mucosal (i.e., oral or (OBs) in the central nervous system (CNS). Nasally delivered
nasal) administration of vaccines was an effective approach for enterotoxins can enter and/or target olfactory neurons and
the induction of both mucosal and systemic immunity to therefore gain access to OBs and deeper structures in the brain
coadministered vaccine antigens (Chapter 90). These closely parenchyma. These adverse effects are, in large part, mediated
related molecules are AB-type toxins consisting of two structurally by the ADP–ribosyl transferase activity and the nature of the
and functionally separate enzymatic A subunits and binding B cellular receptors targeted. Both CT and LT-I bind to GM1 on
subunits (see Fig. 20.7). The B subunit of cholera toxin (CT-B) epithelial cells and require endocytosis followed by transport
binds to GM1 gangliosides, whereas the B subunit of heat-labile across the epithelial cell to reach the basolateral membrane. GM1
toxin I (LT-B) binds to GM1 as well as GM2 asialo-GM1 gan- gangliosides are also abundantly expressed by the neuronal and
29
gliosides. The A subunits of these toxins are adenosine diphosphate microglial cells of the CNS. CT or CT-B, when administered
(ADP)–ribosyl transferases. Binding of the B subunits to gan- nasally to mice, enters the olfactory nerves and epithelium (ON/E)
30
glioside receptors on target cells allows the A subunits to reach and OBs by mechanisms that are selectively dependent on GM1.
the cytosol where they elevate cyclic adenosine monophosphate The targeting of CNS tissues by nasally administered bacterial
(cAMP) levels. enterotoxins is clearly related to a higher incidence of Bell palsy
(facial paresis) among volunteers of a nasal vaccination trial given
Cellular Targets of Vaccine Adjuvants Can Shape the LT-I as mucosal adjuvant. Bell palsy among study subjects that in
Immune Response 2000 received nonliving nasal influenza vaccine (Nasalflu) led to
Studies with CT and LT-I revealed the importance of the cellular its withdrawal from the market (www.niaid.nih.gov/dmid/enteric/
targets for shaping the profile of immune responses induced by intranasal.htm).