Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations

Abstract

• Germline gain-of-function mutations in STAT3 lead to lymphoproliferation and autoimmunity with prominent cytopenias.• Mutations in STAT3 cause altered regulatory T cells and cytokine signaling.Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-offunction mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350. (Blood. 2015;125(4):591-599)

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…Furthermore, activating STAT3 mutations may be not only associated with early-onset multi-organ autoimmune disease, but also with growth failure (68,69).…”

Recessively InheritedLRBAMutations Cause Autoimmunity Presenting as Neonatal Diabetes

“…If performed early HSCT can cure the life threatening enteropathy as well as prevent the onset of autoimmunemediated diabetes (15). In an individual with polyarthritis, scleroderma and autoimmune haemolytic anaemia resulting from an activating STAT3 mutation, treatment with tocilizumab, a monoclonal antibody against IL-6, resulted in marked improvement in their symptoms (16). Patients with Common Variable Immunodeficiency-8 (CVID-8), caused by recessively inherited mutations in Lipopolysaccharide-responsive Beige-like Anchor protein (LRBA), can be successfully treated with Abatacept, a mimetic for CTLA-4.…”

The plethora, clinical manifestations and treatment options of autoimmunity in patients with primary immunodeficiency

“…Therefore, autoimmune involvement, especially of multiple organs in the early period necessitates the suspicion of IPEX, which is one of the primary immune deficiencies even if infection has not yet developed. In STAT5b deficiency, which is defined as similar to IPEX, IL-2 receptor mutation, gain of protein function mutation of the STAT1 and STAT3 genes, CTLA4 deficiency and LRBA deficiency, disruptions in signal pathways responsible for regulatory T cell function have also been identified (12)(13)(14)(15)(16). In our patients who had LRBA deficiency and gain of protein function mutation of the STAT1 gene, hemolytic anemia, IBD/IB-like findings, alopecia, thrombocytopenia, and hypothyroidism were detected.…”