Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder

Abstract

Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated by blood counts and other analyses over the course of 1-2 months. Surface marker expression was assessed on T cells by flow cytometry and clonality by polymerase chain reaction. Intracellular cytokine evaluation, bone marrow and skin biopsies were performed during different parts of the cycle. Cycling of multiple cell lineages, including neutrophils, lymphocytes and eosinophils, was observed in the four subjects with the disorder with a periodicity of 25-35 days. An aberrant CD3(-)CD4(+) T-cell population was detected in all four subjects, and T-cell receptor rearrangement studies showed a clonal pattern in three subjects. A peak of type II cytokines was detected in the serum of subjects prior to the onset of symptoms and eosinophil cycling and corresponded to ex-vivo type II cytokines detected intracellularly in CD3(+)CD4(+)CD154(+) T cells. Although the etiology of episodic angioedema with eosinophilia is not yet known, multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. All subjects gave informed consent and were evaluated under an Institutional Review Board-approved protocol (NCT00001406).

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Cyclic variation in eosinophils, neutrophils and lymphocytes in subjects with EAE. Absolute numbers of eosinophils, neutrophils and lymphocytes are shown as a function of time during an entire cycle for four subjects.

Figure 2.

Cyclic variation in bone marrow and skin eosinophils and skin lymphocytes, but not mast cells in the skin of a subject. (A) and (B) bone marrow aspirates (500× magnification), (C)–(F) bone marrow biopsies (500× magnification) and (G)–(P) skin biopsies [(G)–(H), (K)–(L); 100× original magnification, insets 600× magnification, (I)–(J), (M)–(N), (O)–(P); 200× original magnification] during the asymptomatic (top) and symptomatic (bottom) phases of the cycle. (A)–(D), (G) and (H) are stained with hematoxylin and eosin, panels (E), (F), (I) and (J) with tryptase, and panels (K) and (I) with anti-eosinophil peroxidase antibody, (M) and (N) with anti-CD3, and (O) and (P) with anti-CD4.

Figure 3.

Cyclic variation in serum cytokine levels in subjects with EAE. Serum levels of IL-5 and IL-13 (panel 1), CCl17/TARC and eotaxin (panel 2) and IL-9 and IL-10 (panel 3) are shown as a function of time during an entire cycle for four subjects. Symbols represent individual measurements, and an arrow indicates the peak eosinophil count during a cycle.

Figure 4.

Variation in intracellular production of IL-4, IL-5, IL-13 and IFN-γ by activated CD4+ lymphocytes in a subject with EAE. After gating on viable CD3+CD4+CD154+ cells, side scatter versus intracellular cytokine (% cells positive) dot plots were generated. Intracellular IL-4, IL-5, IL-13 and IFN-γ levels are shown for subject 1 before and during symptoms (nadir and cycle, respectively) and for a normal control.

Figure 5.

Cyclic variation of serum tryptase and SCF (limit of detection 9 pg/mL) levels in EAE. Serum levels of tryptase and SCF are shown as a function of time during an entire cycle for three subjects. Symbols represent individual measurements, and an arrow indicates the peak eosinophil count during a cycle.