A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis Melody C. Carter, MD, Avanti Desai,

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A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis Melody C. Carter, MD, Avanti Desai, MSc, Hirsh D. Komarow, MD, Yun Bai, MS, Sarah T. Clayton, DO, Alicia S. Clark, BA, Karina N. Ruiz-Esteves, BS, Lauren M. Long, BSN, Daly Cantave, MSN, Todd M. Wilson, DO, Linda M. Scott, CRNP, Olga Simakova, PhD, Mi- Yeon Jung, PhD, Jamie Hahn, BS, Irina Maric, MD, Dean D. Metcalfe, MD Journal of Allergy and Clinical Immunology Volume 141, Issue 1, Pages 180-188.e3 (January 2018) DOI: 10.1016/j.jaci.2017.05.036 Copyright © 2017 Terms and Conditions

Fig 1 Bone marrow mast cell flow cytometry and immunohistochemistry in patients with IA (A), patients with MMAS (B), and patients with ISM (C). Flow cytometric results show that CD117+ mast cells gain CD25 surface expression in patients with clonal disease, as shown by no abnormal CD25+ mast cells in patients with IA (Fig 1, A), 2 populations of mast cells in patients with MMAS (CD25+ and CD25− cells; Fig 1, B), and abnormal CD25+ mast cells in patients with ISM (Fig 1, C). Bone marrow biopsy specimens showed no mast cell clusters in patients with IA and those with MMAS, with multiple clusters in patients with ISM. APC, Allophycocyanin; FITC, fluorescein isothiocyanate. Journal of Allergy and Clinical Immunology 2018 141, 180-188.e3DOI: (10.1016/j.jaci.2017.05.036) Copyright © 2017 Terms and Conditions

Fig 2 Immunophenotypic mast cell markers expressed by bone marrow mast cells, mast cell growth, and degranulation of cultured human mast cells. The mast cell markers CD63 and CD203c are compared in nonclonal (HVs and patients with IA) and clonal (patients with MMAS and those with ISM; A and B) patient populations. Patients with ISM demonstrated the highest expression of CD63 and CD203c, which were both significantly higher than in both nonclonal populations. Nonclonal populations were similar. Mast cell proliferation from CD34+ progenitor cells produced more mast cells from patients with IA or those with ISM (C). Degranulation of mast cells through the IgE receptor was similar among groups (D). Fig 2, A: *P = .02 and ***P < .0001; Fig 2, B: *P = .04 and **P = .002; Fig 2, C: *P = .01 and ***P = .0002. Journal of Allergy and Clinical Immunology 2018 141, 180-188.e3DOI: (10.1016/j.jaci.2017.05.036) Copyright © 2017 Terms and Conditions

Fig 3 Pre-event/postevent serum tryptase (A and B) and bST (C and D) levels over time in patients with nonclonal and clonal mast cell disease. When compared with baseline values, both patients with IA (P = .001; Fig 3, A) and those with clonal disease (MMAS and ISM; P = .002; Fig 3, B) had a significant increase in serum tryptase levels with an anaphylactic event. However, the average increase was 502 versus 25 ng/mL for patients with clonal disease versus those with IA, respectively. In most patients with IA, the bST level remained stable over time (Fig 3, C), whereas the majority of patients with clonal disease experienced a gradual increase over time (Fig 3, D). Circles, Patients with IA; triangles, patients with ISM; squares, patients with MMAS. Journal of Allergy and Clinical Immunology 2018 141, 180-188.e3DOI: (10.1016/j.jaci.2017.05.036) Copyright © 2017 Terms and Conditions

Fig E1 Residential demographics of patients. Patients were enrolled mainly from the East Coast but also included Western states and Canada. Fifty-six patients were enrolled from 22 states, the District of Columbia, and 1 Canadian province over a period of 6 years. Journal of Allergy and Clinical Immunology 2018 141, 180-188.e3DOI: (10.1016/j.jaci.2017.05.036) Copyright © 2017 Terms and Conditions