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Isolated Autoimmune Enteropathy Associated With Autoantibodies to a Novel 28-kDa Duodenal Antigen

Jimbo, Keisuke*; Arai, Katsuhiro; Kobayashi, Ichiro; Matsuoka, Kentaro§; Shimizu, Hirotaka; Yanagi, Tadahiro; Kubota, Mitsuru||; Ohtsuka, Yoshikazu*; Shimizu, Toshiaki*; Nakazawa, Atsuko§

Journal of Pediatric Gastroenterology and Nutrition: March 2015 - Volume 60 - Issue 3 - p e17–e19
doi: 10.1097/MPG.0b013e3182a936dc
Case Reports

*Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine

Division of Gastroenterology, National Center for Child Health and Development, Tokyo

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo

§Department of Pathology, National Center for Child Health and Development, Tokyo

||Division of General Pediatrics, Saitama Children's Medical Center, Saitama, Japan.

Address correspondence and reprint requests to Keisuke Jimbo, MD, Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan (e-mail:

Received 14 August, 2013

Accepted 14 August, 2013

The authors report no conflicts of interest.

Autoimmune enteropathy (AIE) is a rare gastrointestinal disorder characterized by protracted diarrhea with severe enteropathy and villous atrophy; no response to exclusion diets; presence of circulating anti-enterocyte antibodies, anti-goblet cell antibodies, or evidence of other autoimmune disease; and no severe immunodeficiency (1,2). Most patients with early-onset AIE carry mutation of foxp3 gene, a causative gene of immunedysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (3,4). Although autoantibodies to enterocytes are hallmark of AIE, only 2 autoantigens, autoimmune enteropathy-related 75 kDa antigen (AIE-75) and villin, have been identified (5,6). Herein, we report a 2-month-old boy with protracted diarrhea associated with severely disrupted intestinal mucosa and presence of autoantibodies to a novel 28-kDa antigen in the duodenum.

The patient was born to non-consanguineous parents at 40 weeks’ gestation with birth weight of 2870 g. At 1 month of age, he was presented with severe diarrhea with sepsis, and was admitted to the referring hospital. He recovered from sepsis but still required total parenteral nutrition because of diarrhea unresponsive to antibiotics or fasting. At 2 month of age, he was transferred to National Center for Child Health and Development, for his second episode of sepsis. His body height and weight were 52 cm (−3.1 standard deviation), and 4670 g (body mass index 17.2 percentile), respectively. Laboratory examination demonstrated hypoproteinemia (2.8 g/dL) and hypoalbuminemia (1.8 g/dL). Elevated fecal sodium (132 mEq/L) and chloride (123 mEq/L) levels, as well as decreased fecal osmotic gap (0.96 mOsm/L), were observed. Workups for enteric infection, immunodeficiency, mitochondrial dysfunction, and endocrinological disorder failed to identify any cause of the protracted diarrhea. Foxp3 gene mutations were not detected.

Because of secretary nature of his diarrhea, he required up to 16 mEq · kg−1 · day−1 of sodium supplementation. Esophagogastroduodenoscopy demonstrated edematous duodenal mucosa. Colonoscopy demonstrated edematous colonic mucosa with scattered hemorrhagic spots and erosions (Fig. 1).



The histological examination of his duodenal and colonic mucosa showed severe glandular destruction, marked infiltration mainly composed of lymphocytes, plasma cells, and eosinophils in the lamina propria with relatively preserved epithelium with paucity of intraepithelial lymphocytes (7). There was subtotal villous atrophy of the duodenal mucosa and apoptosis of crypt cells in the colonic mucosa (Fig. 1). Infiltrating lymphocytes were mainly CD3- and CD8-positive cells by immunohistochemistry. Cryptitis, crypt abscess, and granuloma were not found.

Immunohistochemical studies and Western blot analyses were performed as previously described (5,6,8). The serum of the patient reacted with apical side of the villi in the normal blood group O donor tissue sections (Fig. 2). Western blot analyses using human duodenal tissue crude extract as an antigen demonstrated that the patient's serum reacted with 28-kDa antigen but not with AIE-75 or villin (Fig. 3). The reactivity to the 28-kDa duodenal antigen was not detected in the sera of 20 patients with connective tissue disease, 6 patients with genetically confirmed IPEX syndrome, or 20 healthy controls (data not shown).





We diagnosed him as having AIE, and started a 3-day course of methylprednisolone pulse therapy followed by prednisolone (2 mg · kg−1 · day−1). Concomitant immunosuppressive therapy with tacrolimus and azathioprine were also initiated (2). As his diarrhea subsides, the dose of prednisolone was gradually decreased. Two month after initiation of the treatment, esophagogastroduodenoscopy and colonoscopy revealed relatively atrophic but noninflamed-looking intestinal mucosa. Histology showed the regeneration of crypt cells, improvement of villous atrophy, and marked reduction of infiltrating cells. Patient is presently 3-year old, still requiring small dose of corticosteroids, tacrolimus, and azathioprine to maintain remission. His growth remains appropriate for his age.

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The present case showed severe diarrhea associated with glandular destruction, marked stromal infiltration of activated T lymphocytes, subtotal villous atrophy, and apoptosis of crypt cells. Although the histological findings of the small intestine and colon were more destructive in our patient than those of typical AIE (2,3,8), the presence of anti-enterocyte autoantibodies supports the diagnosis of AIE.

IPEX syndrome is a major cause of early-onset AIE associated with other autoimmune diseases (4). Our patient had no other autoimmune complications of IPEX syndrome except for AIE (2,3). Furthermore, genetic analyses demonstrated no mutation of foxp3 gene. Accordingly, the present case must be isolated AIE or IPEX-like syndrome. Although CD25 deficiency is a cause of IPEX-like syndrome, our patient has normal expression of CD25 on the peripheral T cells (data not shown). Anti-AIE-75 and villin antibodies had been identified as a marker of AIE, but are presently thought to be specific to IPEX syndrome (2,3,5,6). Lack of the antibodies in our patient further confirms the specificity of anti-AIE-75 and anti-villin antibodies in IPEX syndrome. In addition, autoantibodies to the 55-kDa antigen have been reported in a case of AIE but were not detected in our patient (9). Instead, the serum of our patient reacted with a 28-kDa antigen in the duodenal extract. Thus, autoantibodies to the novel antigen may be associated with isolated AIE with severe mucosal destruction. Identification of the 28-kDa antigen is necessary for further studies on the relation between clinical severity of isolated AIE and the antibodies.

Previous reports have indicated that combination therapy with corticosteroid and tacrolimus is effective in IPEX syndrome (2). Our patient achieved clinical and histological remission with combination of corticosteroid, azathioprine, and tacrolimus despite the severe histological findings before treatment. Hematopoietic stem cell transplantation is the only curative treatment of IPEX syndrome (2,3). Nevertheless, hematopoietic stem cell transplantation seems to be quite challenging in our patient because isolated AIE is rare and has no evidence of genetic background. Indeed, there was no family history of the similar disease in our patient; however, some early-onset autoimmune diseases such as autoimmune neutropenia are known to be self-limiting (10). Close and careful follow-up on the immunosuppressive therapy is necessary.

In conclusion, early-onset isolated AIE is distinct from IPEX syndrome in both genetic and serological features. Autoantibody to a novel 28-kDa duodenal antigen may be involved in the pathogenesis of severe mucosal destruction. Combination therapy with corticosteroid, tacrolimus, and azathiopurine could be a choice in such cases.

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The authors are grateful to Yuko Kojima, PhD, of the Division of Laboratory of Biomedical Imaging Research, Biomedical Research Center, and Juntendo University Graduate School of Medicine for their extended histological technical support. We thank Dr Kanegane, of the Department of Pediatrics, Toyama University School of Medicine for genetic analysis of the foxp3 gene.

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