Page 234 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 14 The Microbiota in Immunity and Inflammation 213

drive production of substances that favor pathogen growth or abundance of Faecalibacterium prausnitzii, a member of Clos-
enable the pathogen to outcompete resident microbes. The tridium cluster IV that induces an antiinflammatory phenotype
inflammatory response to the enteric pathogen Citrobacter in immune cells, has also been associated with IBD and risk of
rodentium promotes a restructuring of the microbiota that can relapse in distinct patient cohorts. Whether dysbiosis is a cause
predispose to chronic inflammation. Similarly, Yersinia pseudo- or consequence of disease is debatable. Dysbiosis can occur in
28
tuberculosis infection results in chronic inflammation and disease-free relatives of patients with IBD, which is consistent
long-term defective lymphatic communication between the gut with a genetic influence on microbiota composition. However,
and mesenteric lymph nodes. These changes are supported by several inflammatory mediators very effectively promote dysbiosis
the dysbiotic microbiota. 23 in experimental systems, supporting the notion that inflammation
Infection of mice with the protozoan parasite Toxoplasma gondii precedes microbial disruption.
(T. gondii) induces production of IL-12, which, in turn, promotes Genome-wide association studies (GWAS; Chapter 33) of
the differentiation of IFN-γ–secreting Th1 cells. IFN-γ is essential diverse populations of patients with IBD of different races,
for pathogen control and promotes dysbiosis via targeted destruc- ethnicities, and geographical locations have all identified over
tion of Paneth cells. The production of IL-10 by a subset of the 160 genetic loci that harbor polymorphisms that segregate with
Th1 cells helps overcome the inflammation, whereas IL-10–deficient clinical disease. Several of the genes identified encode immune-
mice succumb to the infection. Even when the infection is con- related proteins involved in detecting and/or responding directly
trolled, however, the brief disruption in Treg homeostasis enables to microbial products, inducing or amplifying the immune
systemic dissemination of commensal bacteria and a temporary response to microbial challenge, or restoring and/or maintaining
disruption in tolerance to the microbiota. 24 immune homeostasis with intestinal microbes. 29
Certain microbes also induce specific immune responses simply The first gene to be causally linked to IBD is NOD2, which
by their physical interaction with host cells. The ability of certain encodes the nucleotide-binding oligomerization domain–
bacteria to bind directly to the intestinal epithelium is central to containing protein 2, a microbial sensor that enables the immune
their ability to provoke a Th17 cell response that culminates in system to recognize and respond to intracellular fragments of
30
the accumulation of these cells in the underlying lamina propria. bacterial peptidoglycan. Loss-of-function (LOF) mutations in
In mice, this is vividly displayed following infection with bacterial NOD2 (i.e., defective microbial recognition) predisposes to
species, including the Clostridium spp., Candidatus arthromitus intestinal inflammation, but only in response to infection or
(segmented filamentous bacteria [SFB]), Citrobacter rodentium, injury. This is consistent with the “multiple hit” model of IBD
and enterohemorrhagic E. coli (EHEC) O157:H7, which can breach pathogenesis. NOD2 deficiency is associated with reduced numbers
the mucous barrier and adhere directly to intestinal epithelial cells. of intestinal goblet cells and therefore reduced mucous production,
In the case of C. rodentium and EHEC, this results in a temporary hyperactive IELs in the small intestine, and increased expansion
31
effacing of the epithelial cell layer, local inflammation, diarrhea, of the commensal Bacteroides vulgatus. Interestingly, all of these
and weight loss and in robust induction of Th17 cells. The same abnormalities can be prevented in mice infected with the helminth
phenomenon can be reproduced if germ-free mice are colonized Trichuris muris. Nevertheless, to date, helminth infection as a
with E. coli –adherent bacteria derived from patients with ulcerative therapy for human IBD has been largely unsuccessful.
25
colitis. Production of IL-17 as a result of the presence of SFB in Another immune-related IBD risk allele identified by GWAS
the terminal ileum provides colonization resistance to C. rodentium. is IL10, which encodes the immunosuppressive cytokine, IL-10.
Induction of this immune pathway is stimulated by a microbial In addition, rare LOF mutations in IL10RA, or IL10RB, which
breach and helps restore epithelial integrity and limit further encode the IL-10 receptor α and β chains, respectively, are found
invasion. This provides an explanation for the therapeutic blockade in a subset of patients with very-early-onset IBD. Mice with
of IL-17 being ineffective in the treatment of IBD, and even global or even CD4- or Foxp3-specific deletion of IL10 develop
exacerbating the disease, even though it was successful in reversing spontaneous colitis, which is dependent on the presence of the
symptoms of psoriasis (Chapter 64). 26 microbiota. The importance of the microbiota is highlighted by
the varying kinetics and severity (ranging from complete protec-
Inflammatory Bowel Disease tion to severe inflammation) of disease in different animal colonies
IBD is a collective term that refers to a group of chronic relapsing– or even in the same colony at different points in time. Disease
remitting inflammatory disorders that can occur anywhere along is more consistent and severe and can even progress to colorectal
the GI tract. The two main forms of IBD, Crohn disease and cancer in mice colonized with Helicobacter spp. Thus IL-10, which
ulcerative colitis, have similar clinical presentations but can differ can be produced by multiple hematopoietic and nonhematopoietic
in terms of histopathological features, affected sites, and risk of cells, is critical for maintaining tolerance to the microbiota,
malignancy. Although disease onset can be impacted by a vast array particularly in the presence of species that can progressively
of genetic, environmental, and immune factors, IBD is characterized disrupt the homeostasis of the microbiota.
by dysregulated immune responses to microbial antigens. Experimental studies have also suggested a role for the
Although no single causative microbe or microbial cluster nonprokaryotic inhabitants of the intestines in maintaining the
has been identified, there is strong correlative evidence in support status quo, thus limiting susceptibility to IBD. Fungi interact
of a dominant role for the microbiota in disease development with the immune system via the receptor dectin-1. A single
and function. First, antibiotic therapy continues to be very effective polymorphism in CLEC7A, which encodes dectin-1, has been
27
in patients with inflammation in the lower bowel. Second, in linked to a severe form of ulcerative colitis. Accordingly, dectin-1
treatment-naïve patients with IBD, there is increased abundance deficiency in mice precipitates increased susceptibility to chemical-
of mucosa-associated pathobionts, including Enterobacteriaceae, induced colitis, and long-term antifungal treatment results in
Pasteurellaceae, Veillonellaceae, and Fusobacteriaceae. Conversely, increased severity of acute and chronic experimental colitis. 32
a decrease in “beneficial” microbes, including Erysipelotrichales, Members of the virome can either promote or prevent develop-
Bacteroidales, and Clostridiales, has been observed. Reduced ment of IBD-like symptoms via their interactions with intestinal