Page 1046 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 75 Immunological Diseases of the Gastrointestinal Tract 1009

small intestinal bacterial overgrowth, etc.). Conversely, constipa- IFN-γ, IL-12, IL-23, and IL-17. The anti–IFN-γ monoclonal
tion in Crohn disease can be a sign of stricturing of the bowel. antibody (mAb) fontolizumab showed no clinical efficacy in
Rectal bleeding results from mucosal friability and ulceration. Crohn disease (but did decrease C-reactive protein [CRP]
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In addition, fever, unexplained weight loss, fatigue, anemia, and levels ). However, anti–IL-12/-23 p40 subunit mAbs targeting
growth retardation (in children) can accompany the GI complaints the Th1 and Th17 pathways resulted in clinical improvement
or even be the primary presentation. Extraintestinal manifestations that led to the current use of ustekinumab for Crohn disease. 35,36
of Crohn disease include arthritis, uveitis, inflammatory skin Unexpectedly, antibodies targeting IL-17A alone (secukinumab)
lesions (pyoderma gangrenosum and erythema nodosum), and or the IL-17AR receptor subunit (transducing IL-17A, -17E,
stomatitis. The arthritis can affect the axial (spine and pelvis) and -17F intracellular signals) either did not show clinical
and articular skeleton, with the latter more often mirroring the improvement (and was associated with increased fungal infec-
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activity of the gut disease. The joint complaints range from usual tions ) or even induced clinical deterioration (the anti–IL-17AR
arthralgias to frank synovitis with swelling and tenderness antibody).
(without erosive joint destruction). The uveitis most commonly To date, it is estimated from multiple genome polymorphism
occurs as episcleritis and iritis. Many of these lesions will subside studies that over 160 IBD susceptibility loci exist, most associated
with effective therapy aimed at the gut, but they can also have with risk of both Crohn disease and UC, 30 loci associated only
independent courses that require site-targeted treatment. with Crohn disease, and 23 loci associated only with UC. However,
The incidence of Crohn disease in North American populations it was further estimated that all the loci together could account
has been estimated to be ≈3.1–14.6 cases/100 000 person-years. for no more than 13.6% of Crohn disease and 7.5% of UC
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Ashkenazi Jewish heritage confers increased risk in Caucasians, disease risk. Although most of these loci are in the noncoding
whereas African Americans seem to have rates similar to those regions of genes thought to modulate gene expression, the actual
of non-Jewish Caucasians, and Hispanics and Asians have much genes implicated have roles in the immune response and epithelial
lower rates. 26,27 There is a genetic risk with up to 10-fold increased integrity, providing biological plausibility for their involvement
rates of IBD in relatives of patients with Crohn disease and a in IBD. Several examples stand out: (i) the NOD2 gene, encodes
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30% concordance rate in monozygotic twin pairs. The typical an intracellular protein that binds muramyl dipeptide (MDP),
patient is diagnosed in his or her second or third decade, and a component of the bacterial cell wall TLR2 ligand peptidoglycan.
there is no significant gender preference. The only environmental Disease-associated mutations in the MDP-sensing leucine-rich
exposure that has been repeatedly linked to risk of Crohn disease repeat domain of NOD2 are associated with defective activation
has been tobacco use. of nuclear factor (NF)-κB. This disrupts the microbe recognition
The majority (up to 70%) of Crohn patients experience a pathway, but because NOD2 is also expressed by small intestinal
remitting and relapsing course, but some have chronically active epithelial Paneth cells, mucosal production of antimicrobial
symptoms refractory to medication. The recognized phenotypes defensins is decreased as well. (ii) The ATG16L1 autophagy gene
of disease include inflammatory (manifesting primarily as is important for the metabolism of autologous cell proteins as
intestinal edema and ulceration), fibrostenotic (luminal narrowing well as intracellular microbes. Expression of the Crohn disease–
by fibrous strictures dominate with symptoms of painful obstruc- associated Thr300Ala polymorphic ATG16L1 sequence in a colon
tion), and fistulizing (inflammatory tracts between the bowel cancer cell line showed in vitro inhibition of packaging of
and other intestines, the bladder, vagina, skin, and other struc- intracellular Salmonella into autophagosomes, supporting the
tures). Although the majority of patients have inflammatory hypothesis that this mutation could lead to impaired clearance
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disease at the time of diagnosis, over time this phenotype changes of microbes and chronic inflammation. This ATG16L1 poly-
so that after 20 years of disease duration, up to 70% and 18% morphism provides a caspase cleavage site that enhances degrada-
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of patients with Crohn disease report penetrating and fibrostenotic tion of this allele and leads to defective autophagy. (iii) A
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complications, respectively. Accompanying this change in polymorphism in the coding region of the IL-23 receptor gene
phenotype is the need for surgical treatment in most patients (Arg381Gln) found in 14% of healthy controls is associated with
after 20 years of disease duration. protection from Crohn disease (less so UC) and is associated
with decreased Th17 cascade effector cells. 41
Immune Pathophysiology The emergence of the role of the commensal microbiota in
The current paradigm of Crohn disease inflammatory origins immune homeostasis has produced renewed interest in its role
is a dysregulated immune response to gut commensal microbial in IBD, where a number of studies show a dysbiosis compared
components (antigens and pathogen-associated molecular with the healthy gut microbiota. This change in the microbiota
patterns). Initial rodent colitis models showed a predominant in IBD has been characterized as a flipping of the Bacteroidetes-
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T-helper cell-1 (Th1) inflammation, where the colitis could be to-Firmicutes phyla ratio with reduction in Firmicutes. In
blocked or reversed by treatment with anti–IL-12 antibodies. addition, Crohn disease has been associated with a reduction
Roles for IL-23 and IL-17 in Crohn disease were later supported in the butyrate-producing Faecalibacterium prausnitzii compared
by the IL-10–deficient mouse model of spontaneous colitis and with healthy controls, but it is not known whether this is a
the cell transfer model of induced colitis, where colitogenic naïve cause or effect of the gut inflammation. The roles of antibiot-
+
CD4 CD45RB high T cells from wild-type mice are infused into T ics, probiotics, prebiotics, or actively changing the microbiota
cell–deficient mice. 30,31 However, despite the important role of through fecal transplant have not been clarified sufficiently to
the IL-23/IL-17 axis in the transfer model of colitis, blockade of employ these strategies as conventional treatments in Crohn
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IFN-γ activity also prevented development of gut inflammation. disease.
Although studies of Crohn disease confirm that production of
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IL-12, IL-23, IFN-γ, and IL-17 are significantly elevated, the Diagnosis
hierarchy of cytokine control of inflammation in Crohn disease The diagnosis of Crohn disease is based on findings from
has been tested by clinical trials using agents that have targeted radiographic, endoscopic, and histological examinations. In