Autosomal dominant STAT6 gain of function causes severe atopy associated with lymphoma

Abstract

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.

Atopic manifestations of inborn errors of immunity

“…Autosomal dominant STAT6 GOF variants associated with early-onset (<12 months) severe atopy have been reported by multiple groups [2 ▪▪ ,3,43–45]. Treatment-resistant atopic dermatitis and food allergies were most common, followed by asthma, eosinophilic gastrointestinal disease and anaphylaxis.…”

“…Elevated IgE levels and eosinophilia were noted [2 ▪▪ ]. STAT6 is an intracellular transcription factor downstream of IL4 and IL4R/JAK-kinase signalling cascade and a central node of immune polarization and a key modulator for the risk of allergic disease in humans and mice [3,46]. Translocation of STAT6 to the nucleus, activates a pattern of gene expression mediating Th2 cell differentiation, M2 macrophage polarization, promotion of B cell survival and IgE class switching [47–50].…”

“…Given atopy-related manifestations of these diseases may present to a range of clinical specialists across infancy to adulthood, we set out to summarise recent developments in this field. We highlight novel genetic conditions that may present at this interface, including gain of function mutations in the IKAROS transcription factor [1 ▪▪ ], and autosomal dominant gain of functions (GOF) in signal transducer and activator of transcription 6 (STAT6) [2 ▪▪ ,3]. Finally, we propose an updated mechanistic framework for the development of atopy at the interface of IEI whilst highlighting pitfalls for associated complications, and opportunities for precision therapy…”

The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

“…Core clinical presentations associated with STAT6 GOF are early onset, severe allergic immune dysregulation including atopic dermatitis, multiple allergies and serial anaphylaxis, hypereosinophilia, and high serum IgE levels (>5000 U/mL). [144][145][146][147][148][149]217 Thus, IEI causing STAT6 GOF establishes that STAT6 activation, downstream of IL-4 and IL-13, is the central driver of IgE production by human B cells. [144][145][146][147][148][149]217 It remains to be determined how or whether IL-6/ STAT3 signaling directly or indirectly antagonizes IL-4:IL-13/STAT6 signaling in B cells to rein in IgE production.…”

“…Core clinical presentations associated with STAT6 GOF are early onset, severe allergic immune dysregulation including atopic dermatitis, multiple allergies and serial anaphylaxis, hypereosinophilia, and high serum IgE levels (>5000 U/mL) 144–149,217 . Thus, IEI causing STAT6 GOF establishes that STAT6 activation, downstream of IL‐4 and IL‐13, is the central driver of IgE production by human B cells 144–149,217 .…”