Page 235 - Clinical Immunology_ Principles and Practice ( PDFDrive )

214 Part One Principles of Immune Response

bacteria. Murine norovirus induces inflammation in mice with secretion of cytokines, including IL-6 and TNF-α. Obesity-related
disruption in the IBD susceptibility gene Atg16L1. Antibiotic inflammation also contributes to defective insulin signaling or
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administration reverses this viral-induced disease. Conversely, insulin resistance, a major player in the transition from metabolic
antiviral pretreatment of otherwise healthy mice can exacerbate syndrome to diseases, including type 2 diabetes, hepatic steatosis,
acute experimental colitis by disrupting the production of and cardiovascular disease. 37
antiinflammatory IFN-β. 34 Although the microbiota (usually fecal) is distinct in certain
non-GI diseases, including ankylosing spondylitis (Chapter 57),
EXTRAINTESTINAL MANIFESTATIONS OF GUT multiple sclerosis (Chapter 66), and asthma (Chapter 41), whether
MICROBIOTA–IMMUNE SYSTEM INTERACTION these changes precede or follow disease development is not clear.
One measure might be the effect of microbiota-induced immune
Obesity develops when energy intake exceeds expenditure and mediators on disease pathology in extraintestinal tissues. For
culminates in deposition of excess adipose tissue. The associated example, although gut microbes that can adhere to the epithelial
chronic complications, collectively and clinically referred to as cells induce robust expression of IL-17, their functions in the
metabolic syndrome, include hyperglycemia, hypertriglyceridemia, gut are largely protective. In contrast, microbiota-induced IL-17
dyslipidemia, and hypertension. Studies in mice and humans can be proinflammatory in extraintestinal tissues. In germ-free
have revealed that there are alterations in the gut microbiota in mice colonized with SFB and subjected to experimental models
certain conditions, such as obesity and associated metabolic of arthritis or multiple sclerosis, severe IL-17–dependent disease
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diseases brought on by increased gut permeability, immune develops. Elevated induction of RORγt and IL-17 in the central
responsiveness, and aberrant bacterial translocation. nervous system is also a hallmark of virus-induced maternal
Perhaps the most striking evidence for the direct role of the immune activation (MIA), which can lead to autism spectrum
microbiota in at least sustaining the obese phenotype was seen disorder (ASD)–like symptoms in a murine model.
in mice transplanted with human fecal microbiota from obese
or lean cotwins. Mice transplanted with the obese microbiota CANCER AND THE MICROBIOTA
displayed increased weight gain and adipose tissue relative to
those transplanted with the microbiota of the lean cotwins. 35 The tissue-specific immune inflammatory response that is neces-
Obesity has been associated an increased abundance of sary for pathogen eradication or to restore host–microbiota
Firmicutes relative to Bacteroidetes, and differential responses homeostasis can be deleterious to the host if allowed to reach
of the lean and obese microbiota to the caloric content of the chronicity. In addition to causing permanent tissue damage
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diet. The altered composition can also lead to a reduction in (scarring), such a chronic inflammatory response predisposes
microbial gene richness, which, in turn, affects the “inflammatory to tumor development and the production of neo-self antigens
tone” of the microbiota and likely contributes the chronic low- that are now recognized as foreign to the host. The antitumor
grade inflammation characteristic of obesity. Lipopolysaccharides immunity that ensues possesses characteristics similar to those
(LPSs), also known as endotoxins, derived from the outer cell of the antipathogen response and ultimately has the same
membrane of gram-negative bacteria, are found at low concentra- goal—eradication of a foreign body. Likewise, antiinflammatory
tions in the circulation of healthy individuals but are dramatically or regulatory mechanisms are deployed to limit the magnitude
increased in obese individuals and even more so in those who and duration of the inflammatory response in an effort to restore
develop type 2 diabetes. LPS infiltrates tissues, including the immune homeostasis (Fig. 14.5). However, continued tumor
liver and adipose tissues, and the activation of macrophages via growth means that the “foreign” antigens have not been eradicated,
TLR4 initiates an innate immune response characterized by and/or new ones are continually being generated. In response

Immune
regulation

Antitumor
immunity
Immune Inflammation Cancer
homeostasis (antimicrobe immunity)
Infection,
environmental stimuli,
dysbiosis

Intestinal
microbiota
FIG 14.5 Microbiota–Immunity–Cancer Triad. The reciprocal interaction of intestinal microbiota
and the immune system induces default regulatory pathways that help maintain intestinal immune
homeostasis. Factors that promote microbial dysbiosis, such as infection and other environmental
insults, can disrupt immune homeostasis. This can result in proinflammatory responses targeting
the causative agent, accompanied by immune regulatory responses that aim to reset immune
balance. The perpetuation of the inflammatory response enhances the likelihood of progression
to cancer. In response to the novel antigens generated in the tumor, an immune response is
initiated with the goal of eradicating the tumor. As this response bears similar characteristics to
an antipathogen response, it is subject to the same immune suppressive mechanisms.