Institut für Experimentelle Immunologie, Universitätsspital Zürich, Zürich, Switzerland
Address for correspondence: Andrew J. Macpherson, Institut für Experimentelle Immunologie, Universitätsspital Zürich, Schmelzbergstrasse, 12, CH8091 Zürich, Switzerland. Voice: +41-1-255-3788; fax: +41-1-255-4420. amacpher{at}pathol.unizh.ch
Mammals coexist with a luxuriant load of bacteria in the lower
intestine (up to 10
12 organisms/g of intestinal contents). Although
these bacteria do not cause disease if they remain within the
intestinal lumen, they contain abundant immunostimulatory molecules
that trigger immunopathology if the bacteria penetrate the body
in large numbers. The physical barrier consists only of a single
epithelial cell layer with overlying mucus, but comparisons
between animals kept in germ-free conditions and those colonized
with bacteria show that bacteria induce both mucosal B cells
and some T cell subsets; these adaptations are assumed to function
as an immune barrier against bacterial penetration, but the
mechanisms are poorly understood. In mice with normal intestinal
flora, but no pathogens, there is a secretory IgA response against
bacterial membrane proteins and other cell wall components.
Whereas induction of IgA against cholera toxin is highly T help
dependent, secretory IgA against commensal bacteria is induced
by both T independent and T dependent pathways. When animals
are kept in clean conditions and free of pathogens, there is
still a profound intestinal secretory IgA response against the
commensal intestinal flora. However, T dependent serum IgG responses
against commensal bacteria do not occur in immunocompetent animals
unless they are deliberately injected intravenously with 10
4 to 10
6 organisms. In other words, unmanipulated pathogen-free
mice are systemically ignorant but not tolerant of their commensal
flora despite the mucosal immune response to these organisms.
In mice that are challenged with intestinal doses of commensal
bacteria, small numbers of commensals penetrate the epithelial
cell layer and survive within dendritic cells (DC). These commensal-loaded
DC induce IgA, but because they are confined within the mucosal
immune system by the mesenteric lymph nodes, they do not induce
systemic immune responses. In this way the mucosal immune responses
to commensals are geographically and functionally separated
from systemic immunity.
