Page 1044 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 75 Immunological Diseases of the Gastrointestinal Tract 1007

gut (primarily the small intestine). In the absence of dietary specificity), it remains important for several reasons: (i) Currently,
gluten or the specific MHC molecules HLA-DQ2 or -DQ8, celiac the serologic markers should only be used as a screening test,
disease, theoretically, cannot occur. Dietary gluten, largely from identifying which patients are at highest risk for the disease and
wheat, barley, and rye, exists in polymeric (glutenin) and appropriate for biopsy confirmation; (ii) even in the presence
monomeric (gliadin) form and is incompletely digested to small of celiac-susceptible HLA genes, only a minority of persons will
peptides by gut luminal enzymes because of their high glutamine develop celiac disease (latent disease), so evaluating nonspecific
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and proline content. These large gluten peptides cross the symptoms will require histological examination; and (iii) because
epithelial barrier and bind to the specific HLA-DQ2 or -DQ8 the treatment can be life altering, the most comprehensive
molecules. The enzyme tissue transglutaminase can deamidate information is needed to make a definitive diagnosis.
gluten peptides, and the resulting negatively charged gluten Beyond celiac disease, a true gluten-induced enteropathy, other
peptides actually have increased affinity for the HLA binding gluten-centric entities have been identified, namely, non–celiac
site. Gut microbes also can affect the immunogenicity of gluten disease gluten sensitivity and IgE-mediated gluten allergy.
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peptides via their own proteolytic enzymes. The gluten peptide- Non–celiac disease gluten sensitivity includes a set of poorly
activated T cells produce proinflammatory cytokines interferon-γ characterized gut and extraintestinal symptoms that lack the
(IFN-γ), interleukin-18 (IL-18), tumor necrosis factor (TNFGr-), defining features of celiac disease yet respond to a gluten-free
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and IL-21. The activated T cells also induce B-cell maturation diet (GFD). Increased levels of serum markers for bacterial
to plasma cells producing antibodies to gluten peptides as well translocation (lipopolysaccharide [LPS]-binding protein, soluble
as the tissue transglutaminase. The reason for tissue transglu- CD14) and epithelial damage (circulating fatty acid binding
taminase being targeted for autoantibody production and its protein 2) that is reversed following a wheat-free diet in a subset
role in disease is unknown. of subjects suggests altered gut permeability related to wheat and
According to animal models, the activated T cells are not cereal exposure may be a factor contributing to symptoms. 23
sufficient to induce the epithelial damage and villus blunting.
The characteristic villus atrophy is induced by gut APC- and Treatment
epithelial cell–produced IL-15, which enhances infiltration of The treatment of celiac disease is avoidance of gluten, specifically
CD8 T cells into the epithelium and upregulates NKG2D receptors foods containing wheat, barley, and rye. The expected response
on intraepithelial T lymphocytes (IELs) conferring cytotoxicity to gluten restriction is the resolution of symptoms and malabsorp-
against the epithelium. More recently, it was found that the IEL tion. Follow-up endoscopy to assess response to therapy should
signaling induced by NKG2D ligands MICA/B upregulated on be done only after 6–12 months of a strict GFD, although full
epithelial cells stimulates a leukotriene pathway (together with recovery of the villus mucosa may take several years. There are
IL-15 exposure) that itself produces cysteinyl leukotrienes (CystLT) no accurate biomarkers to monitor adherence to a GFD, although
that appear to drive the IEL-based killing. The impact of this one indication may be a fall in the pretreatment level IgA anti-TTG
observation is the possible use of montelukast, a CystLT inhibitor serum antibodies; therefore, follow-up endoscopy with biopsy
and drug widely used in allergic asthma, to treat celiac disease. 18 is needed to document restoration of the villus architecture.
Beyond the HLA associations with disease, genome-wide Symptom improvement, correction of malabsorption, and
association studies (GWAS) have linked over 30 disease susceptibil- regrowth of villi (seen by endoscopy or video capsule) may not
ity loci with non-HLA regions. One such locus is a polymorphism reflect complete full histological healing, yet the long-term risk
in lnc13, a long noncoding RNA, which affects its binding with of partial histological recovery is unknown.
a heterogeneous nuclear ribonucleoprotein to undo its repression About 5% of patients with celiac disease do not respond to
of other genes, including inflammatory mediators. 19 a GFD. Ensuring a strict adherence to a GFD is important to
identify the reasons for nonresponse, whether through inadvertent
Diagnosis gluten exposure or whether the inflammation is truly refractory
The diagnostic workup of celiac disease is initiated by both to a strict GFD. One group of patients with the so-called refractory
suggestive symptoms and signs (weight loss, chronic diarrhea) celiac disease with polyclonal IEL populations may respond to
as well as by atypical presentations, such as specific micronutrient corticosteroids and immunosuppressant treatment; another group
deficiencies or unexplained hyperamylasemia or hypertransami- with monoclonal IELs do not respond to such treatment and
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nasemia. Initial tests include measuring serum immunoglobulin are at increased risk of lymphoma. 24
A (IgA) antibodies against tissue transglutaminase and endomysial The majority of patients with celiac disease respond positively
proteins, which have an estimated specificity/sensitivity of to a GFD with return of normal gut absorption. However, ongoing
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95%/95% and 100%/>90%, respectively. It is necessary to inflammation is associated with risk of small bowel lymphoma,
measure a total serum IgA level at the same time to be certain so ensuring adherence to a GFD and documenting mucosal
that these IgA-based screening tests do not yield false–negative healing can affect the natural history of this disease. Finally,
results. However, in the setting of IgA deficiency (where celiac since first-degree relatives are at increased risk of celiac disease,
disease has an increased incidence), elevated IgG anti–tissue patients should be advised of serum antibody screening of these
transglutaminase (TTG) or deamidated gliadin levels and family members.
identification of celiac disease susceptibility HLA genes can help
determine the risk and presence of disease. CROHN DISEASE
In any case, an important part of celiac diagnosis is biopsy
of the upper small intestine mucosa (Fig. 75.1B,C); typically Crohn disease is a chronic idiopathic inflammation of the gut
three to four endoscopic biopsy specimens are obtained from characterized by transmural involvement of the bowel wall
both the duodenal bulb and the distal duodenum. Although the (mucosa, muscle layer, and serosa) (Fig. 75.1D). Although often
absolute requirement for histological diagnosis of celiac disease referred to as “terminal ileitis,” the majority of patients with
may be debated (and cannot be used alone because of lack of Crohn disease have colonic inflammation in addition or solely.