Feed

CD70 deficiency, mostly recognized by immune dysregulation, hemophagocytic lymphohistiocytosis, lymphoproliferation, and malignancy, was recently associated with severe and accelerated diabetes in mice. Such a causal relationship is not previously reported in humans. The aim of this study is to describe the first case of CD70 deficiency manifesting with severe onset type 1 diabetes mellitus (T1DM). Changes to glycemic control following hematopoietic stem cell transplantation and accompanying autoimmunity are defined. Immunophenotype analysis, next-generation-primary immunodeficiency panel analysis, and Sanger sequencing were conducted. Then, segregation analysis and functional studies were carried out for validation of the homozygous missense variant in CD70. Following confirmation of CD70 deficiency, hematopoietic stem cell transplantation (HSCT) was carried out. A comprehensive review of clinical history, alongside biochemical and immunologic investigations, was carried out to identify the natural history as well as immune and endocrine phenotypes. Presentation of severe-onset T1DM with severe diabetic ketoacidosis, multiorgan dysfunction, and unexplained findings during follow-up (recurrent diabetic ketoacidosis episodes, unexplained recurring skin lesions, and celiac disease) prompted an evaluation for underlying etiology, and CD70 deficiency was diagnosed. Timely HSCT was curative for CD70 deficiency. Following HSCT, glycemic control was improved (median HbA1c: 8.1% [7.6-8.6] vs 6.5% [5.8-7.0]), total daily insulin dose was reduced from 0.85 to 0.62 U/kg/d, and recurrent episodes of diabetic ketoacidosis ceased. It was concluded that, a homozygous missense variant in CD70, causing CD70 deficiency, may be associated with severe onset T1DM, confirming the significance of intact CD27/CD70 co-stimulation in the prevention of pancreatic β-cell autoimmunity. The CD27/CD70 pathway represents a potential target for immunotherapy trials in T1DM.