Immunodeficiency Associated with a STAT-5b Mutation and Growth Hormone Insensitivity.

We recently identified a homozygous mutation in the STAT-5b (signaling transducer and activator of transcription 5b) gene in a female patient with growth hormone insensitivity. The patient had significant growth retardation (height -7.5 SD), despite normal levels of growth hormone (GH) and GH binding protein. Analysis of the GH receptor signaling pathways indicated that the mutation (Ala630 to Pro630) resulted in a protein that could not be activated by GH, and subsequent dysregulation of STAT-5b-dependent genes, such as IGF-I and IGFBP-3. This abstract details an immunodeficiency due to a lack of functional STAT5b. Clinically, the patient had chronic diarrhea as an infant, and suffered several severe infections, including persistent lymphocytic interstitial pneumonia (LIP), a condition associated with children who are HIV-positive or immunodeficient. Laboratory studies showed hypergammaglobulinemia, T-cell lymphopenia with a normal CD4:CD8 T-cell ratio, and total B and NK cells within the normal range. Immunologic analysis showed decreased interleukin (IL)-2 receptor α expression in response to IL-2 on both CD4 and CD8 T cells, despite normal proliferation to mitogens, and normal anti-CD3 proliferation by CFSE analysis. IL-2 mediated γc (common gamma chain) upregulation, induction of CD40-ligand and interferon-γ production by intracellular cytokine analysis in response to either the bacterial superantigen SEB or anti-CD3/anti-CD28 mAb stimulation were normal, suggesting that STAT5b is not necessary for these functions. Importantly, perforin expression in response to IL-2 was decreased in CD8 T cells suggesting that both decreased CD8 number and function contribute to this immunodeficiency. Interestingly, NK cells failed to increase adhesion molecules CD54 or CD58 in response to IL-2 suggesting impaired NK cell function. Lastly, EBV transformed B cell lines were unable to phosphorylate STAT5b in response to IL-2 and IL-7 suggesting an intrinsic B cell defect that may affect immunoglobulin production. Thus, the STAT5b −/ − mutation appears to limit the effects of important γc-containing cytokines on CD4, CD8, NK and B cells, resulting in increased susceptibility to infection.