Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings
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ORIGINAL ARTICLE
Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings Corinne L. Foley 1,2 & Sareea S. Al Remeithi 3 & Christopher T. Towe 4 & Andrew Dauber 5 & Philippe F. Backeljauw 2 & Leah Tyzinski 2 & Ashish R. Kumar 6 & Vivian Hwa 2 Received: 14 August 2020 / Accepted: 2 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Patients with rare homozygous mutations in signal transducer and activator of transcription 5B (STAT5B) develop immunodeficiency resulting in chronic eczema, chronic infections, autoimmunity, and chronic lung disease. STAT5B-deficient patients are typically diagnosed in the teenage years, limiting our understanding of the development of associated phenotypic immune abnormalities. We report the first detailed chronological account of post-natal immune dysfunction associated with STAT5B deficiency in humans. Annual immunophenotyping of three siblings carrying a novel homozygous nonsense mutation in STAT5B was carried out over 4 years between the ages of 7 months to 8 years. All three siblings demonstrated consistent B cell hyperactivity including elevated IgE levels and autoantibody production, associated with diagnoses of atopy and autoimmunity. Total T cell levels in each sibling remained normal, with regulatory T cells decreasing in the oldest sibling. Interestingly, a skewing toward memory T cells was identified, with the greatest changes in CD8+ effector memory T cells. These results suggest an importance of STAT5B in B cell function and naïve versus memory T cell survival. Progressive dysregulation of FOXP3+ regulatory T cells and CD8+ memory T cell subsets reveal a crucial role of STAT5B in T cell homeostasis. The early diagnosis and focused immune evaluations of these three young STAT5B-deficient siblings support an important role of STAT5B in adaptive immune development and function. Keywords STAT5B . adaptive immunity . memory T cells . regulatory T cells . development
Introduction Homozygous recessive mutations in signal transducer and activator of transcription 5B (STAT5B) in humans result in
growth hormone insensitivity (GHI) and primary immunodeficiency. STAT5B deficiency (MIM 245590) presents as severe short stature, chronic eczema, autoimmunity, recurrent infections, and chronic pulmonary complications. STAT5B-
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-020-00884-6) contains supplementary material, which is available to authorized users. * Ashish R. Kumar [email protected] * Vivian Hwa [email protected] 1
2
Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
3
Division of Endocrinology, Department of PediatricsSheikh Khalifa Medic
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