Finding 1: In collaboration with James Thaventhiran at Cambridge and Kaan Boztug in Austria, we identified two patients with recessive loss of function mutations in interleukin 6 receptor (IL6R) leading to absent Il-6 receptor signaling, severe atopic dermatitis, bacterial skin and lung infections, elevated immunoglobulin E (IgE) and markedly abnormal inflammatory responses. The findings were important for several reasons. First, they contextualized the role for IL-6 signaling in diseases of high IgE and infection, such as STAT3DN, gp130 deficiency and ZNF341 deficiency; they showed that IL6R is the likely binding partner for gp130 that is required to prevent elevated IgE. The second reason is that it demonstrates the potential consequences of IL-6R blockade, as is now commonly in use, highlighting the differences between inborn IL6R deletion and blockade later in life. The fact that most treated adults do not develop allergy (but can develop infection) suggests that IL6R signaling is necessary only early in life to prevent IgE elevation and severe dermatitis. The results were published in the Journal of Experimental Medicine. Finding 2: In collaboration with multiple groups throughout the world, we showed the experience of treated patients with STAT1 or STAT3GOF mutations with JAK inhibitors. We found that these inhibitors can be effective in the pathway specific treatment of these disorders, but that they tend to be more effective in combination with IL-6R blockade (mentioned in finding 1) and when initiated earlier in the disease course. The results were published in the Journal of Allergy and Clinical Immunology.
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