Inhibition of immunoglobulin E attenuates pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by pathological vascular remodeling in the lung. Immunoglobulin E (IgE) is known to participate in aortic vascular remodeling, but whether IgE mediates pulmonary vascular remodeling in PH is unknown. Here, we found serum IgE elevation in PAH patients, hypoxia-induced PH mice and monocrotaline (MCT)-induced PH rats.Combining animal model of PH with single-cell RNA sequencing, we found IgE production in the lung tissues of PH mice. Neutralizing IgE with an anti-IgE antibody was effective in preventing PH development in mice and rat models. The IgE receptor FcεRIα was also upregulated in PH lung tissues and Fcer1a de ciency prevented the development of PH in mice. Single-cell RNA-seq revealed that FcεRIα was mostly expressed in mast cells, and mast cell-speci c Fcer1a knockout protected against PH in mice.Further mechanistic experiments revealed that IgE-activated mast cells produced interleukins IL6 and IL13, which subsequently promoted vascular muscularization. Clinically approved IgE antibody Omalizumab alleviated the progression of established PH in rats. Using genetic and pharmacological approaches, we have demonstrated that blocking IgE-FcεRIα signaling may hold potential for the treatment of PAH.

B-cells in pulmonary arterial hypertension: friend, foe or bystander?

“…Here, higher expression was associated with better survival [ 12 ]. Although not measured in this cohort, previous studies reported elevated IgE levels in iPAH patients, due to skewed isotype switching induced by Th2 cytokines [ 25 , 26 ]. Few data are available regarding patients with CTD-PAH, with conflicting reports of elevated IgA [ 64 ] and decreased IgG [ 45 ] levels in SSc-PAH (compared to SSc without pulmonary hypertension).…”

“…Preferential class-switching towards IgE, a hallmark of Th2 stimulation, is frequently noted in PAH. Increased IgE serum levels and IgE + B-cells are observed in the blood of PAH patients and the lungs of several experimental models [ 25 , 26 ].…”

“…Single-cell RNA sequencing performed on the lungs of hypoxia-induced pulmonary hypertension (HPH) mice reveals a significant infiltration of Th2 cells with upregulated genes involved in the IL-4 pathway, an increased expression of costimulatory receptors in both T-cells (CD28) and B-cells (CD86 and CD40), as well as differential expression of genes involved in B-cell activation and IgE class-switching (GLε) [ 26 ]. In a similar model induced by combined hypoxia and ovalbumin exposure, Th2 inhibition due to CD294 deficiency or IL-4/IL-13 neutralisation decreases lung infiltration by IgE + B-cells and attenuated pulmonary hypertension [ 25 ].…”

“…Increased IgE production leads to mast cell priming and activation through binding of FcεRI receptors [ 27 ]. Interestingly, lung infiltration by mast cells is a prominent feature of the disease in human and experimental PAH, and IL-4, IL-6 and IL-13 were identified as the main mediators produced by mast cells after IgE stimulation in animal models [ 26 , 28 – 32 ]. Mast cell inhibition in MCT rats results in lower B-cell lung infiltration, lower circulating autoantibodies and normalised serum IgG levels [ 30 ].…”

“…Another recent work demonstrated the importance of IgE-induced mast cell activation in the pathogenesis of PAH [ 26 ]. In HPH mice and MCT rats, treatment with anti-IgE antibodies or mast cell-specific FcεRI deletion normalises haemodynamics, pulmonary vascular thickening and muscularisation, as well as IL-6 and IL-13 expression in lung tissues.…”