Page 233 - Clinical Immunology_ Principles and Practice ( PDFDrive )

212 Part One Principles of Immune Response

Several factors produced or induced by gut microbes have The increasing incidence of autoimmune disease in industrial-
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been shown to be essential for microbiota-dependent Treg ized countries has been linked to use of antibiotics, improved
accumulation, particularly in the colonic lamina propria. The sanitation, and consumption of processed foods rich in fat and
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capsular polysaccharide A (PSA) moiety of Bacteroides fragilis, carbohydrates but negligibly low in fiber. These practices limit
which mediates the interaction between the bacterium and the microbiota diversity and deplete the bacteria that “educate” the
colonic mucosa, can also act via the TLR–MyD88 pathway to developing immune system, leaving it prone to overreaction to
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promote expansion of IL-10–producing colonic Tregs. Clostridial subsequent challenges.
strains stimulate production of TGF-β by intestinal immune There are several observational, clinical, and epidemiological
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cells. This, in turn, enhances Foxp3 Treg induction. Clostridia reports, supported by a growing body of experimental findings
are also very adept at anaerobic fermentation of indigestible in support of this concept. For example, vancomycin treatment
fiber. Thus their production of butyrate might be another in young mice increases their susceptibility to asthma as well as
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mechanism whereby they can enhance accumulation of Foxp3 food allergy, in large part as a result of depletion of clostridial
Tregs in the colonic lamina propria. 19 strains known to promote colonic Treg induction and expansion.
Early life treatment with low-dose antibiotics results in increased
CD4 T-Helper Cells risk susceptibility to obesity and corresponding alterations in
In the intestines of both mice and humans, both IFN-γ–producing immune gene expression in the ileum. Individuals who had
Th1 and T-helper “IL-17–producing” (Th17) cells are present limited sanitary amenities during childhood or were raised around
(Chapter 16). Although detectable even at steady state, these livestock are at reduced risk of developing IBD (Chapter 75)
populations, reactive to microbial antigens, are largely held in during adulthood. This latter phenomenon is commonly attrib-
check by the intestinal immunoregulatory system. In some cases, uted to the acquisition of a diverse microbiota in these microbially
expression of the Th cell signature (transcription factors and enriched environments. However, such living conditions also
cytokines) of distinct lineages can overlap with each other or pose an increased risk of parasitic helminth infection. This concept
with the Treg transcription factor Foxp3, denoting either a common is supported by experimental data showing that treatment with
progenitor or the dynamic lineage transitions that can ensue in Trichuris muris prevents development of experimental colitis in
response to competing immune signals. In the absence of regulatory mice deficient for the IBD-related gene Nod2.
pathways, for example, in IL-10 deficiency, the numbers and
frequencies increase gradually, coincident with the onset of chronic IMMUNE SYSTEM—MICROBIOTA CROSS-TALK IN
inflammation. The same is true during GI infection (see below), INTESTINAL INFLAMMATION
where the ability of invasive bacteria or viruses to enter a cell,
or the physical interaction of the bacteria with the intestinal The immune system and the microbiota are in constant dialogue
epithelium, culminates in induction and expansion of Th1 and at steady state. Throughout an individual’s life, the microbiota
Th17 cells, respectively, in the intestinal lamina propria. undergoes transient shifts in response to external influences.
These include infections; medications, such as antibiotics; and
Mucosal B Cells dietary changes. The timing, magnitude, and targets of these
With increasing colonization comes an increased likelihood of perturbations can result in immune responses aimed at resetting
epithelial breach, particularly by bacteria capable of penetrating this balance or limiting host collateral damage. Furthermore,
the inner mucus layer and gain access to the intestinal epithelium. feces of patients with certain extraintestinal chronic inflammatory
By intercalating dendrites between epithelial cells and into the diseases also display reduced microbial abundance and diversity
lumen, DCs in the intestinal lamina propria are able to sample relative to their healthy counterparts. This may reflect the role
the luminal bacteria. These antigen-loaded DCs migrate to the of the intestinal microbiota in the etiology of diseases, the impact
mesenteric lymph nodes, where they interact with B and T cells of tissue-specific inflammation on the microbiota, or both.
to induce B-cell production of anticommensal IgA. These IgA-
producing plasma cells migrate to the intestinal lamina propria, Gastrointestinal Infection
where they secrete IgA dimers that migrate across the epithelium The microbiota helps provide resistance to pathogenic invasion
and into the lumen. There they bind commensals and thus at mucosal sites. This can occur either indirectly by enhancing
limit their translocation. In germ-free mice, the absence of the barrier defenses through various immune and nonimmune
microbiota and resultant absence of IgA production is seemingly mechanisms or directly by competing with harmful microbes.
replaced by IgE class switching (Chapter 4) in mucosal lymphoid Nevertheless, several organisms still manage to breach these
tissues and a corresponding increase in susceptibility to oral defenses. Such pathogen invasion induces production of proinflam-
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antigen-induced systemic anaphylaxis. Therefore the microbiota matory cytokines by innate cells that can appropriately expand
itself helps limit hyperreactivity to allergens and parasite challenge the magnitude of the immune response by signaling the differentia-
throughout an individual’s life. tion of Th cells. The soluble products of these cells recruit other
immune cells and collectively aid in pathogen eradication and
IMMUNE CONSEQUENCES OF EARLY sometimes in repairing any physical damage to the intestinal
MICROBIAL MANIPULATION barrier. Unimpeded inflammatory responses can be destructive
to host tissue, and thus immunosuppressive mechanisms are
Because the microbiota is so essential to the early postnatal induced that help to restore immune homeostasis.
maturation of the immune system, the consequences of manipula- In a healthy host, GI infections are largely self-limiting.
tion or insufficiency of the microbiota can impact host immunity However the temporary disruption of microbial homeostasis
throughout life. Microbial disruption, particularly during the (dysbiosis) can have lasting effects on host health. In the cases
neonatal–infancy period, is being associated with increased risk of Salmonella enterica serovar typhimurium (S. typhimurium)
of autoimmunity and chronic inflammation later in life. and E. coli infection in mice, the associated inflammation can