Pulmonary hypertension (PH), a common complication of left heart diseases (LHD), negatively impacts on LHD symptoms, exercise capacity, and outcome. PH-LHD represents the most common type of PH and is diagnosed as mean pulmonary arterial pressure (mPAP) greater than 25 mmHg and a mean pulmonary arterial wedge pressure above 15 mmHg in right heart catheterization. While PH-LHD is associated with high mortality, specifically a median time from echocardiographic detection to death of only 4.1 years, no targeted treatment strategies exist so far. Recent research has stressed the importance of dysregulated immunity in the pathophysiology of pulmonary hypertension in general and changes in the B-cell homeostasis in animal models of PH-LHD specifically. During exacerbated inflammation, a hallmark of PH-LHD, autoreactive B cells can escape both central and peripheral tolerance mechanisms and, therefore, can markedly contribute to the pathogenesis of autoimmune disease. Hence, a deeper insight into the contribution of B-cell immunity to PH-LHD may provide for a better understanding of the pathophysiological processes driving this devastating disease, and as such, for the identification of novel cellular therapeutic targets. Here, we hypothesized that changes in B-cell homeostasis and autoreactivity modulate disease development and severity in PH-LHD.

To this end, we analyzed whole blood samples of patients with mitral valve replacement or repair with and without pulmonary hypertension, according to echocardiographic risk assessment. The echocardiographic assessment of PH is based on the guideline protocol of the British Society of Echocardiography taking tricuspid regurgitation velocity (TRV) and further parameters regarding the ventricles, pulmonary artery and the right atrium into account and dividing into low, intermediate and high probability to exhibit PH. Concentrations of peripheral IgA+ and IgG+ switched memory B-cells (CD27+IgD+), total plasmablasts (CD27+CD38+CD138-) and total plasma cells (CD27+CD38+CD138+) were elevated in the blood of patients with mitral valve disease compared to a group of age and sex matched healthy controls. Of note, specifically IgG+ plasmablasts (CD27+CD38+CD138-IgD-IgM-IgA-) and IgA+ plasma cells (CD27+CD38+CD138+) were elevated in this patient cohort. These results indicate an activated B- lymphocyte compartment that after stimulation with their cognate (self-) antigen, can form short-lived plasma cells, memory B cells, or long-lived plasma cells. In line with this finding, immunoglobulin isotyping analyses revealed increased concentrations of IgG4 and IgE in the patient group with high risk for PH according to echocardiographic assessment, while IgM, IgD and IgG3 levels were decreased. More than 80% of patients with mitral valve repair or replacement and high risk to develop PH carried IgG and IgA anti-nuclear or anti-cytoplasmatic autoantibodies in their plasma. However, the target antigens, the potential pathogenetic role of these antibodies and their predictive value in patients at risk to develop PH-LHD remains to be investigated.

Teresa C. Funk-Hilsdorf reports a fellowship of the BIH.
Wolfgang M. Kuebler reports grants from the Bundesministerium für Bildung und Forschung (BMBF), the Deutsche Forschungsgemeinschaft (DFG) and the DZHK.
Szandor Simmons reports grants from the DZHK and the German Foundation for Heart Research.