The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension

Abstract

Over past years, a critical role for the immune system and, in particular, for mast cells in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B cells and autoimmunity. Experiments were performed in Sprague-Dawley rats and B cell-deficient JH-KO rats in the monocrotaline, Sugen/hypoxia, and the aortic banding model of PH. Hemodynamics, cell infiltration, IL-6 expression, and vascular remodeling were analyzed. Gene array analyses revealed constituents of immunoglobulins as most prominently regulated mast cell-dependent genes in the lung in experimental PH. IL-6 was shown to link mast cells to B cells, as 1) IL-6 was upregulated and colocalized with mast cells and was reduced by mast-cell stabilizers and 2) IL-6 or mast cell blockade reduced B cells in lungs of monocrotaline-treated rats. A functional role for B cells in PH was demonstrated in that either blocking B cells by an anti-CD20 antibody or B-cell deficiency in JH-KO rats attenuated right ventricular systolic pressure and vascular remodeling in experimental PH. We here identify a mast cell–B cell axis driven by IL-6 as a critical immune pathway in the pathophysiology of PH. Our results provide novel insights into the role of the immune system in PH, which may be therapeutically exploited by targeted immunotherapy.

Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover Conference Series)

“… 24 and Colvin et al. 25 as well as from our own laboratory 26 has identified the formation of characteristic tertiary lymphoid tissue comprising B- and T-cell areas with high endothelial venules and dendritic cells in the vicinity of remodeled pulmonary arteri(ol)es and bronchi(oles) in iPAH patients as well as animal models of PH.

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“…The functional relevance of immune responses in the initiation and/or progression of PH has recently become evident, in that pharmacological inhibition, depletion, or genetic deficiency in specific cell subsets such as mast cells 4 , 13 , 15 or B cells 26 , 56 has been shown to confer protection from the development of PH in a variety of animal models. Furthermore, IL-6 has been identified as a critical link between mast cells and B cells and, hence, between the innate and adaptive immune system in that mast cell-derived IL-6 promotes the formation of tertiary lymphoid tissue in PH lungs 26 in line with previous data demonstrating that mast cells synthesize and release IL-6. 57 , 58 Originally identified as a B cell stimulatory factor that induces differentiation into antibody-producing plasma cells, 59 IL-6 production has also been linked to increased Ig secretion and production of autoantibodies.…”

“… 96 The functional relevance of these autoantibodies was recently elegantly demonstrated, in that passive transfer of either autoantibody-rich plasma or purified immunoglobulin (Ig) G from rats with monocrotaline-induced PH was sufficient to induce the de novo formation of lung ectopic lymphoid tissue and the development of PH in naïve rats. 97 Notably, increased production of autoantibodies does not seem to be restricted to PAH patients or the monocrotaline model of PH, as increased levels of circulating immunoglobulin G were similarly detected in a rat model of PH with left heart disease, 26 in which moreover immunoglobulin-encoding genes were found to be the most mast cell-dependent regulated genes in lung tissue. 26 While these findings point to an overarching relevance of pathogenic autoantibodies in the development of PH that is not restricted to CTDs, the mechanisms that drive this acquired autoimmunity remain unclear.…”

“… 97 Notably, increased production of autoantibodies does not seem to be restricted to PAH patients or the monocrotaline model of PH, as increased levels of circulating immunoglobulin G were similarly detected in a rat model of PH with left heart disease, 26 in which moreover immunoglobulin-encoding genes were found to be the most mast cell-dependent regulated genes in lung tissue. 26 While these findings point to an overarching relevance of pathogenic autoantibodies in the development of PH that is not restricted to CTDs, the mechanisms that drive this acquired autoimmunity remain unclear.…”

Targeting inflammation and immunity in pulmonary arterial hypertension: any easier after the CANTOS proof‐of‐concept that anti‐inflammation cuts cardiovascular events?

“…Recently, a mast cell–B cell axis driven by IL-6 as a critical immune pathway has been implicated in the pathophysiology of pulmonary hypertension (PH). 2 IL-6 is secreted by T cells and macrophages in response to specific microbial agents, referred to as pathogen-associated molecular patterns (PAMPs) to stimulate immune responses, e.g. during infection and mechanical trauma.…”