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.