Germline RUNX1 Deficiency Predisposes to Allergy and Autoimmunity

Abstract

RATIONALE: The Runx1 transcription factor decreases GATA3 and IL-4 expression and Th2 skewing and promotes Th1/Th17/Tregulatory (Treg) cell development and function. We hypothesized that patients with germline RUNX1 deficiency would be predisposed to allergic and/or autoimmune disease. METHODS: Thirty-one patients (17 female; median age 42 years, range 2-74) with confirmed RUNX1 mutations were evaluated. Peripheral blood was obtained to evaluate hematologic variables, total and allergen specific IgE, and lymphocyte immune phenotypes. RESULTS: 29/31 patients had a positive allergic history; 21 had allergic rhinitis, 16 allergic conjunctivitis, and 20 mild-moderate eczema controlled with topical glucocorticoids and emollients. Seven patients had doctordiagnosed asthma with 1 patient receiving mepolizumab for eosinophilic asthma. Four reported oral allergy syndrome. Two patients had IgEmediated food allergy to flounder and egg, respectively, and two had biopsy-proven eosinophilic esophagitis. Five patients reported autoimmune disorders including mixed connective tissue disease, Hashimoto's thyroiditis, Sjogren's syndrome, alopecia universalis and systemic Juvenile idiopathic arthritis. Median total IgE and eosinophil counts were within the normal range (73.35 IU/mL; range 16 -635 IU/mL and 215/mcL; range 0-1000/mcL, respectively). Median CD4 and CD8 T cells counts were within the normal range, although patients exhibited an increased frequency of memory CD4+ T cells, decreased CD4:CD8 ratios, and decreased Tregs in peripheral blood when compared to healthy controls. CONCLUSIONS: Patients with germline RUNX1 deficiency exhibit an increased prevalence of atopic and autoimmune disorders, demonstrating an important role for Runx1 in tolerance development in humans.

RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition

“…Of note, human plasmacytoid DCs (pDCs) are in part defined by their expression of the high-affinity IL-3RA, whereas mouse pDCs do not express the IL-3 receptor ( 33 ). Further, pDCs are associated with skin autoimmune conditions, which raises the possibility that the aberrant activation of pDCs may be contributing to the high incidence of eczema and psoriasis observed in RUNX1-FPD patients ( 8 ). Last, IL-3 is upregulated during infection, autoimmune disease, allergies, and AML ( 34 – 38 ), and the chronic inflammatory conditions in germline RUNX1 disease may elevate basal IL-3 levels.…”

Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies

“…There may also be autoimmune or inflammatory manifestations of germline predisposition conditions that are actively being studied. These include thyroid disease [ GATA2 deficiency ( 9 )], eczema and allergies [ RUNX1- FPD ( 10 , 65 )], psoriasis [ RUNX1- FPD ( 10 )], panniculitis, and lupus-like arthritis [ GATA2 deficiency ( 103 , 108 )], and others listed in Table 1 . Laboratory screening of immunological abnormalities is recommended below and should be considered in the workup of MDS patients.…”

RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils

“…The inflammatory disease eczema was reported in an FPDMM pedigree 5 , and since then has been documented in up to 50% of families 2,3 . FPDMM patients also have an increased incidence of asthma, reactive airway disease, rosacea, and allergies 6 . Chronic inflammation is a driver of leukemia 7,8 , therefore inflammatory disorders in FPDMM patients may contribute to the elevated incidence of hematologic malignancies 1 .…”

“…The inflammatory disease eczema was reported in an FPDMM pedigree 5 , and since then has been documented in up to 50% of families 2,3 . FPDMM patients also have an increased incidence of asthma, reactive airway disease, rosacea, and allergies 6 .…”