Molecular mechanisms of the hyper IgE syndrome

The autosomal dominant hyper IgE syndrome (AD-HIES) is a rare primary immunodeficiency, caused mainly by heterozygous missense mutations in the signal transducer and activator of transcription 3 (STAT3) gene (1). STAT3 is activated after cytokine-induced signaling, and therefore is relevant in many lymphocyte functions and development like the differentiation of the T helper (Th)17 cells (2).

In our group, we investigate the mutations in STAT3 causing AD-HIES and how others transcription factors that interact or regulate STAT3 are involved in this process. By using a broad range of biochemical and molecular techniques, together with the development of mouse models, we evaluate the different mechanisms in which these mutations can affect the survival and differentiation of specific immune cells.

In particular, we are interested in evaluating different STAT3 mutations causing AD-HIES, and discovering new mechanisms that will explain the phenotype observed in patients, from having a dominant negative or haploinsufficient effect, to analyzing the heterodimer formation of STAT3 with other STAT molecule, and in evaluating how IgE+ plasma cells are generated in these patients. At the same time, we are studying how mutations in the transcription factor ZNF341, which produces a similar phenotype to AD-HIES (3), is regulating STAT3 and vice versa. Finally, we are developing humanized mouse models with patient’s derived cells that were modified by using gene therapy (4), to have a Wildtype STAT3 gene. This study in particular, and all in general, will give us new understanding of how STAT3 functions and will open new perspectives for the development of future therapies for AD-HIES patients.