Intestinal Research

Case Report

Miscellaneous

A case of autoimmune enteropathy with CTLA4 haploinsufficiency: Haruka Miyazaki, Namiko Hoshi, Michitaka Kohashi, Eri Tokunaga, Yuna Ku, Haruka Takenaka, Makoto Ooi, Nobuyuki Yamamoto, Suguru Uemura, Noriyuki Nishimura, Kazumoto Iijima, Keisuke Jimbo, Tsubasa Okano, Akihiro Hoshino, Kohsuke Imai, Hirokazu Kanegane, Ichiro Kobayashi, Yuzo Kodama; Intest Res 2022;20(1):144-149. Published online January 22, 2021; DOI: https://doi.org/10.5217/ir.2020.00041

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.

Citations

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World Journal of Gastroenterology.2026;[Epub] CrossRef
Clinical and genetic features of CTLA-4 haploinsufficiency: a prospective study in China
Guishan Liu, Jingyuan Zhang, Di Wu, Jin Xu, Jiayuan Dai, Min Shen
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Review

Inflammatory bowel diseases

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease: Katsuyoshi Matsuoka; Intest Res 2020;18(3):275-281. Published online June 3, 2020; DOI: https://doi.org/10.5217/ir.2020.00002

Abstract PDF PubReader ePub

Thiopurine has been used to maintain remission and to reduce antidrug antibody formation in monoclonal antibody therapy in patients with inflammatory bowel disease (IBD). The use of thiopurine is limited by side effects such as leukopenia. Thiopurine S-methyltransferase (TPMT) variants are associated with thiopurine-induced leukopenia in Westerners, but the frequency of the risk alleles is low in Asians. Recently, a variant in the nudix hydrolase 15 (NUDT15) gene (R139C, c.415C > T) was reported to be associated with early severe leukopenia in Asians. NUDT15 is an enzyme that converts 6-thio-(deoxy)guanosine triphosphate (6-T(d)GTP) to 6-thio-(deoxy)guanosine monophosphate (6-T(d)GMTP). The R139C variant impairs the stability of the protein and increases incorporation of 6-TGTP and 6-TdGTP into RNA and DNA, respectively, resulting in leukopenia. The frequency of C/C, C/T, and T/T are approximately 80%, 20%, and 1%, respectively in East Asians. Early leukopenia occurred in less than 3% of patients with C/C and in around 20% of those with C/T, whereas it occurred in almost all patients with T/T. Patients homozygous for this variant also develop severe hair loss. The measurement of NUDT15 R139C can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of IBD.

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