Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Abstract

Background Gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired T helper (TH) 17 cell differentiation and exaggerated responsiveness to types I and II interferon. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor. Objective We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations. Methods We used in vitro polarization assays as well as phenotypic and functional analysis of STAT1-mutated patient cells. Results We report on a child with a novel mutation in the linker domain of STAT1 who suffered from life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naïve patient lymphocytes displayed increased TH1 and T follicular helper (TFH) cell as well as suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase (JAK) 1/2 inhibitor ruxolitinib reduced hyper-responsiveness to types I and II interferon, normalized TH1 and TFH cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis and maintained remission of immune mediated cytopenias. Conclusions Autoimmunity and infection due to STAT1 GOF mutations is caused by dysregulated T helper cell responses. JAK inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

“…Knowledge of both these variants in P26 has improved pulmonary and autoimmune monitoring, allowing proactive rather than reactive medicine, and confidence in the need to continue iatrogenic immunosuppression in an immunodeficient individual. Precision medicine is available with the janus kinase inhibitor ruxolitinib for STAT1 GOF patients …”

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

“…Further reports have further broadened the phenotype of STAT1 GOF to include ‘IPEX‐like’ presentations with multisystem AI/I 22 . The janus kinase inhibitor ruxolitinib has shown promise in targeted AI/I in STAT1 GOF patients as a targeted immunosuppressive, as well as having benefits on chronic mucocandidasis 23 …”

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

“…In STAT1 and STAT3 ‐GOF, treatment with JAK inhibitors (i.e., ruxolitinib, tofacitinib, and baricitinib) may reduce the burden of autoimmune disease (e.g., immune cytopenias) and IL‐6 R antagonists (i.e., tocilizumab) used alone or in combination with JAK inhibitors in STAT3 ‐GOF reduces the burden of autoimmune disease, lymphoproliferation, and hyperinflammation . Increased risk of invasive fungal infections needs to be considered when considering addition of JAK inhibitors for the management of immune dysregulation …”