Intest Res.  2022 Jan;20(1):144-149. 10.5217/ir.2020.00041.

A case of autoimmune enteropathy with CTLA4 haploinsufficiency

• Miyazaki H
• Hoshi N
• Kohashi M
• Tokunaga E
• Ku Y
• Takenaka H
• Ooi M
• Yamamoto N
• Uemura S
• Nishimura N
• Iijima K
• Jimbo K
• Okano T
• Hoshino A
• Imai K
• Kanegane H
• Kobayashi I
• Kodama Y

• KMID: 2525081
• DOI: http://doi.org/10.5217/ir.2020.00041

Abstract

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.

Keyword

Autoimmune enteropathy; CTLA4; Regulatory T cell; 6-Mercaptopurine

Figure

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  Fig. 1. Endoscopic and histopathological findings. Initial endoscopy showed villous atrophy of duodenum (A: duodenal second portion). Colon was intact endoscopically (B). Pathology of the duodenum demonstrated severe villous atrophy, infiltration of lymphocytes and plasma cells (C: H&E, ×4), and crypt apoptosis (arrows) (D: H&E, ×40). Pathology of the colon also showed infiltration of lymphocytes and plasma cells and crypt apoptosis (E: H&E, ×20).

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  Fig. 2. Results of immunostaining and Western blotting. Immunostaining was performed using the serum of healthy donor (A) and our patient (B). Immunostaining of the normal small intestine tissue with the patient’s serum showed positive staining, which was seen as a thick band along the intestinal epithelium (×200). (C) Western blotting using our patient’s serum showed positive band. Serum from an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patient with autoimmune enteropathy (AIE) was used as positive control.

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  Fig. 3. The correlation of the platelet count, IgG levels, sIL2R levels, symptoms, dose of PSL and 6-MP. sIL-2 was not recorded before the onset of AIE. 6-MP, 6-mercaptopurine; AIE, autoimmune enteropathy; AIHA, autoimmune hemolytic anemia; IgG, immunoglobulin G; ITP, immune thrombocytopenic purpura; Plt, platelet count, PSL, prednisolone; sIL-2R, soluble interleukin-2 receptor.

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  Fig. 4. Flow cytometry analysis. Expression of CD25+ FOXP3+ T cells gated on CD4+ T cells. CD4+ CD25+ FOXP3+ T cells in the patient were reduced than those in the control.

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  Fig. 5. Endoscopic and histopathological findings. Three years after the diagnosis, atrophy of the duodenum was improved (A: duodenal second portion). Villous atrophy also improved pathologically (B: H&E, ×4), and crypt apoptosis disappeared (C: H&E, ×40).

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