Immunological Inflammatory Diarrheal Disorders

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Clinical Considerations

The neonatal course is completely normal. Onset of intestinal symptoms is within the first months of life and it is rarely isolated, in contrast to congenital early onset enterocyte disorders. Diarrhea is often bloody and most often systemic inflammatory symptoms exist, i.e. fever, elevated inflammatory markers in blood and stools. Changes in the mode of alimentation, such as withdrawal of breastfeeding, the introduction of cow's milk proteins, but sometimes even a simple viral infection or a vaccination, may precede the onset of GI symptoms. A main characteristic of inflammatory or autoimmune enteropathy (AIE) is a protein-losing enteropathy, seen in low serum albumin levels and a markedly enhanced ^-antitrypsin clearance [15]. Complete bowel rest may improve diarrhea; however, in severe courses diarrhea often persists. This situation represents a diagnostic challenge, since the clinical pictures of children suffering from an early-onset enterocyte intrinsic defect and children with an immunological disorder overlap considerably. We recently evaluated the diagnostic value of measuring inflammatory markers in the stools to distinguish immunoinflammatory diarrheal GI disorders from constitutive enterocyte disorders in infants presenting with severe diarrhea within the first year of life [16]. The simple fecal test allowed with a specificity close to 100% to eliminate an inflammatory affection if fecal calprotectin levels were within the normal range. Contrary to autoimmune inflammatory enteropathies, allergic reactions always respond to and theoretically are healed on complete bowel rest. However, on re-alimentation, the symptoms reappear immediately if the causative antigen is re-introduced.

If a child presents with an AIE, the onset is often within the first 3 or 4 months in the form of severe diarrhea which can be bloody [15]. The majority of boys with AIE present in addition with severe atopic skin disease, hema-tological abnormalities along with endocrinopathy, such as insulin-dependent diabetes mellitus or thyroiditis. This association was described as IPEX (immune dysregulation, polyendocrinopathy, autoimmune enteropathy, X-linked) syndrome [15, 17, 18]. It is interesting to note that boys with IPEX also show severe immunoallergic symptoms with a strong Th2 response and hyper-IgE syndrome having some similarities with extremely severe food allergy. Isolated or oligosymptomatic forms of severe AIE exist in both, boys and girls. Prior to the onset of AIE/IPEX, these children develop completely normal, and no antenatal or neonatal particularities exist [19]. It is important to stress that the family history is most often positive for various autoimmune diseases. This indicates a particular genetic background, pointing to disease susceptibility genes. Another particularity is the exclusive occurrence of a subtype of AIE in boys, which indicates an X-linked mode of transmission. Inflammatory bowel disease (Crohn's disease or ulcerative colitis) is extremely rare in this age group; however, it has to be considered as a differential diagnosis.

The onset of food allergy-induced enteropathy/colitis is less severe compared to AIE/IPEX. However, severe forms exist as - in extreme cases - food protein-induced enterocolitis syndrome. Besides the presentation as upper GI disease, the onset is in the form of diarrhea and rectal bleeding combined with failure to thrive [20]. Often atopic skin and pulmonary symptoms are associated with the GI symptoms. The family history for atopy is often positive, and several affected children within one family are not exceptional. Once more this points to a particular genetic background and potential susceptibility genes. Systemic inflammatory symptoms are rare; however, inflammatory signs at the intestinal mucosal level are typical for this disease entity, as is the occurrence of protein-losing enteropathy. Biological exams help to make the diagnosis if IgE levels are enhanced with specific RASTs. However, food allergies are frequently related to delayed type 4 hypersensitivity reactions and show no biological or immunological abnormalities. Skin patch tests most often are not helpful in the diagnosis. Food allergy can share the clinical picture of celiac disease, which has to be ruled out combining serological and if necessary histological evaluations.

Molecular Considerations

Genetic mapping studies of several families with boys suffering from AIE made it possible to identify a disease causing mutation in a gene located on the X chromosome Xp11.23-q13.3 [21, 22]. This gene was namedFOXP3 and encodes a 48-kD protein of the forkhead (FKH)/winged helix transcription factor family, named scurfin. Scurfin is predominantly expressed in CD4+/CD25+ T cells with regulatory functions. Experimental data suggest that scurfin is implicated in the regulation and suppression of T cell activation [23]. In a recent review of boys with IPEX [17], a loss of function mutations was reported within the coding region of FOXP3, whereas in one family, a mutation in the 3'-untranslated region of FOXP3 was observed. Two additional patients with typical clinical symptoms of IPEX did not show any mutations within the coding regions of FOXP3, suggesting that regulatory or conditional mutations may occur outside FOXP3, such as described by Bennett et al. [24] in the polyadenylation signal following the final coding exon of FOXP3. This may result in a decreased FOXP3 messenger ribonucleic acid (RNA) expression, probably owing to nonspecific degradation of aberrant RNA. Similar to loss of function mutations in FOXP3, this results in a decreased or completely suppressed scurfin expression causing an altered biological function. In addition, it is possible that other forms of IPEX or AIE exist that are not related to mutations in the FOXP3 gene and that are transmitted either with an X-chromosomal or an autosomic trait. Owen et al. [25] reported on two families with several members presenting with clinical IPEX. In one family a novel FOXP3 mutation was identified with a single base deletion at codon 76 of exon 2, resulting in a frameshift mutation, whereas in the second family the FOXP3 locus was excluded by recombination and muta-tional analysis was negative. Since one girl was affected in this family, one can speculate about an autosomal locus.

The structure of the FOXP3 protein, scurfin, suggests that it has deoxyri-bonucleic acid (DNA) binding activity and may serve as nuclear transcription factor. Schubert et al. [23] demonstrated that scurfin acts as a repressor of transcription and regulator of T cell activation. Intact scurfin represses transcription of a reporter containing a multimeric FKH-binding site. Such FKH-binding sites are located adjacent to nuclear factor of activated T cells (NFAT), regulatory sites in various cytokine promoters such as IL-2, or granulocyte-macrophage colony-stimulating factor enhancer. Therefore, intact

Regulator Cell Activation
Fig. 5. AIE: complete villous atrophy and a major inflammatory infiltrate of mononuclear and some polynuclear cells within the lamina propria of the duodenum.

scurfy seems to be capable of directly repressing NFAT-mediated transcription of the IL-2 gene in CD4+ T cells upon activation [23]. In addition, scurfin seems to play an important role in thymic maturation of regulatory T cells. Nonfunctional (due to maturation or structural defects) or absent regulatory T cells cause highly overactivated T cell reactions, since the natural inhibitor fails. A tremendous T cell-mediated inflammatory reaction within the GI tract causes severe epithelial cell and mucosal destruction without villous atrophy and erosions or ulcerations (fig. 5).

In general, allergic reactions can occur as acute type 1 IgE-mediated or as delayed type 4 IgE-independent and Th2-cell-mediated reactions. Food allergy is often IgE independent and we are only beginning to understand some of the molecular events of food allergy-induced enteropathy. Allergic reactions of the GI tract are particularly intriguing, since, normally, upon oral ingestion of a potential allergen an anti-inflammatory TGF-^-mediated response develops, a mechanism described as oral tolerance. In contrast, par-enteral administration of the same antigen provokes a marked T cell-driven inflammatory response. Therefore, it was suggested that a defect in or a loss of anti-inflammatory control mechanisms might be a key step in the development of food allergy [20]. The number of TGF-^-producing T cells, presumably regulatory T cells, was reported to be reduced in the duodenal mucosa of children with food allergy [26]. That regulatory T cells play an important role in food allergy is largely supported by the observation of allergic symptoms including food allergy in patients with the IPEX syndrome. The commensal intestinal flora was proposed as an environmental factor involved in the stimulation of the mucosal immune system. It was suggested that changes in the composition of the intestinal microflora early in life may result in an insufficient stimulation of innate immune response contributing to impaired development of regulatory T cells [27].

Additional factors, potentially affecting the function of the intestinal barrier, also seem to play a key role in the onset of food allergy-induced enteropathy. Increased intestinal permeability and increased uptake of allergens were described in children with cow's milk protein allergy [20]. The molecular basis of the pathological transport of allergens via intact entero-cytes was recently revealed [28] with an IL-4-induced upregulation of CD23, a low-affinity IgE type II transmembrane glycoprotein, on IEC. This causes an exaggerated IgE-CD23-mediated endosomal uptake of allergens, which are subsequently released at the basolateral side of enterocytes. Eosinophils, basophils, monocytes, mast and T cells recruited to the lamina propria release upon interaction with this allergen large amounts of prostaglandins, leukotrienes, histamine, tryptase and various cytokines. In the resulting acute phase, inflammatory reactions provoke GI (vomiting, diarrhea, bleeding) and systemic symptoms (fever, anaphylaxis, etc.). Th2 cytokines, such as IL-4, IL-5 and IL-13, are responsible for an Ig switch to IgE, chemoattraction and accumulation of inflammatory cells such as eosinophils and basophils and T cells within the intestinal mucosa. On histological examination, villous atrophy along with an intense polymorph inflammatory infiltrate of the lamina propria and an enhanced number of intraepithelial T cells is seen in food-allergic enteropathy. Theoretically, food allergy is cured by an avoidance diet; however, this is not always so easy and a high degree of morbidity can be caused by this disorder.

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Food Allergies

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