Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders causing immune dysfunction that manifest with increased susceptibility to infection. Some PID patients may also have autoimmune and autoinflammatory manifestations. In many cases, PIDs are monogenic disorders that follow Mendelian inheritance and mutations in more than 250 genes have been shown to cause PIDs. However, in the majority of PID patients the causative mutations remain unknown. Here I report a study of a patient from a consanguineous family who presented in infancy with colitis, autoimmune hepatitis, autoimmune anemia and thrombocytopenia. The patient also suffered recurrent respiratory infections leading to bronchiectasis and had several episodes of severe varicella zoster virus (VZV) infections, including pneumonia and meningitis. Immunologically, the patient had increased IgM and IgG levels, absent IgA, low specific antibodies and multiple auto-antibodies, including anti-Interferon- antibodies. Whole blood stimulation assays identified an increased production of the pro-inflammatory cytokine IL-6. Throughout his life the patient received immunosuppressive therapy. Whole exome sequencing of the patient discovered a homozygous frameshift mutation in the ZC3H12A gene that encodes the Regnase-1 protein also known as MCPIP1. Regnase-1 is a regulatory RNase that directly degrades mRNAs of several pro-inflammatory genes, e.g. mRNA of cytokine IL-6, thus curbing the immune activation. The presentation of the patient resembled the phenotype of the Regnase-1-knockout mice that developed spontaneous systemic inflammation, disorganisation of lymphoid organs, severe anaemia and hyperimmunoglobulinemia, with the increased production of IL-6. I studied expression of the mutant Regnase-1 protein using commercial antibodies; also a new custom-made antibody that detects the truncated mutant Regnase-1 protein was developed. Analysis of the patient-derived cells demonstrated absence of the full-length Regnase-1 protein. Cloning and forced expression of the truncated mutant protein showed that it is mislocalized inside the cells and is functionally impaired. Studies of the iPSC-derived macrophages, EBV-transformed B cells and primary fibroblasts of the patient demonstrated increased levels of the IL-6 mRNA in the resting cells. They also showed impaired regulation of the truncated mutant Regnase-1 protein and IL-6 mRNA levels after cell stimulation. Mutations in Regnase-1 have never been associated with human diseases previously. Therefore, this study describes a novel PID caused by the Regnase-1 deficiency.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24491号 / 医博第4933号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 齋藤 潤, 教授 髙折 晃史, 教授 上野 英樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM