Abnormal Immune Response

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Celiac Disease

CD is complex autoimmune enteropathy caused by a permanent sensitivity to gluten in genetically predisposed individuals. European and US studies indicate the prevalence of CD in children between 2.5 and 15 years is approximately 3-13 per 1,000 children [13]. Previously considered rare in children in developing countries, more recent evidence challenges this view [14]. In some ways, CD also represents an important form of food-allergic enteropathy. Small bowel damage occurs following mucosal exposure to ingested wheat gluten and similar grains, most notably rye and barely. Unlike other food-allergic enteropathies, CD susceptibility is determined in part by a common HLA association, namely the major histocompatibility complex class II antigens HLA-DQ2 (86-100% patients) and HLA-DQ8 (5% patients) haplotypes. Gliadin, the main wheat protein, presented by HLA-DQ2 and/or HLA-DQ8 molecules to T cells stimulates production of proinflammatory cytokines that damage intestinal mucosa and activate plasma cells to produce antibodies to gliadin, tissue transglutaminase (TTG), and endomysium.

While symptoms can be protean and nongastrointestinal, the classical clinical expression of CD in children is a persistent malabsorptive enteropathy and diarrhea, malnutrition, abdominal pain, vomiting and abdominal disten-tion. Nongastrointestinal symptoms may predominate and occur in the apparent absence or subtle gastrointestinal symptoms and include proximal muscle wasting, dermatitis herpetiformis, dental enamel hypoplasia of permanent teeth, osteoporosis, short stature, delayed puberty, iron deficiency anemia resistant to oral iron, among others. The risk of CD is much higher among first-degree than second-degree relatives and in children with certain chronic disease such as type-1 diabetes mellitus (2-5%) and autoimmune disorders, IgA deficiency (10%), Down's syndrome (10%), Turner's syndrome, and Williams syndrome.

Diagnosis of CD is defined by characteristic changes seen on small intestinal histology: villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes. With the advent of accurate serologic markers and in cases where there is full clinical remission with gluten withdrawal from diet, it is no longer considered necessary to confirm the diagnosis by gluten challenge and repeat biopsy. Of available serological tests, neither IgG nor IgA antigliadin antibody test is routinely recommended due to variable sensitivity and specificity. Measurement of IgA antibody to human recombinant TTG is recommended and is highly sensitive and specific; IgA antibody to endomysium is as accurate as TTG but observer dependent and hence subject to error. In patients with features suggestive of CD concomitant assessment for IgA deficiency is helpful since IgA deficiency is associated with CD and a low TTG IgA in this context is not reassuring. In such a case, TTG IgG levels should be determined. Once the diagnosis is confirmed, the only treatment is lifelong use of a gluten-free diet. Compliance in children and especially the adolescent is always a problem. TTG level may be used to monitor dietary adherence.

Food-Induced Allergic Enteropathy

There are three clinically distinct food protein-induced gastrointestinal disorders that can involve the small bowel and cause persistent diarrhea: enterocolitis syndrome, enteropathy, and eosinophilic gastroenteritis. Food protein enterocolitis syndrome is a cell-mediated hypersensitivity disorder that typically occurs in infants within the first 3 months of life, most commonly in reaction to ingested dairy or soy protein [15]. The disease process is often restricted to the distal colon and is the most common cause of bloody stool in infants in developed countries following enteric Salmonella infection. Involvement of the small bowel as well as colon typically manifests as watery or bloody diarrhea, vomiting, and failure to thrive if diagnosis is delayed. Food protein-induced enteropathy (excluding CD) is an uncommon condition that occurs within the first several months of life and is manifested by persistent diarrhea and malabsorption; clinical presentation is the same as classical CD but usually with vomiting. Histological changes can be very similar to that found in CD, but less severe [16]. There is patchy distribution of mucosal damage, some degree of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. As with dietary protein enterocolitis, dairy and soy protein are the typical offending antigens. The underlying immune dysregulation shares many of the features of CD; its relationship, if any, to the dietary protein enterocolitis syndrome is unknown. Eosinophilic gastroenteritis is a rare, incompletely understood disorder that at times but not always is associated with an identifiable dietary antigen. It is IgE and/or cell-mediated and can occur at any age. Clinical presentation depends on the anatomic site of gastrointestinal involvement and depth of eosinophilic infiltration; when manifested as an enteropathy, diarrhea, iron deficiency anemia, and protein-losing enteropathy are characteristic. In contrast to food protein-induced enteropathy, eosinophilic inflammation is the distinguishing histolog-ical finding. The double-blind, placebo-controlled oral food challenge remains the gold standard for diagnosis of food-induced allergic disorders especially for cell-mediated sensitivities, but there are often practical limitations to its use. Diagnosis therefore often depends heavily on the medical history, attempting to determine if a food reaction is a possible cause, the specific food implicated, and whether the condition likely represents a cell-mediated or IgE reaction. Skin prick tests are useful in screening for IgE-mediated food sensitivity, with a larger size wheal increasing the specificity. The greatest value of skin testing is a negative test, which confirms the absence of an IgE-mediated dietary allergy. However a positive skin test combined with an unequivocal history implicating a specific food is considered diagnostic by many. RAST testing provides similar qualitative diagnostic information but is increasingly being replaced by quantitative food-specific serum IgE which has greater positive predictive value. Intestinal biopsy has a particular complementary role in diagnosis of food allergic enteropathy.

Autoimmune Enteropathy

Autoimmune enteropathy is a rare disorder that usually results in death in early infancy or childhood. Its hallmarks are severe, protracted diarrhea and antienterocyte antibodies along the apex and basolateral enterocyte border

Fig. 2. Conceptual framework of Crohn's disease etiology. IBD = Inflammatory bowel disease.

[17]. It is frequently associated with extraintestinal disease including diabetes mellitus, glomerulopathy, and hemolytic disease as well as immunodeficiency such as IPEX (immunodysregulation, polyendocrinopathy and enteropathy, X-linked) syndrome.

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