Certain Immune Cells May Increase, Decrease PAH Risk

Nine different immune cells, out of a possible 731, have been shown in novel research to have a connection with the risk of pulmonary arterial hypertension (PAH). Five immunophenotypes were linked to increased risk (false discovery rate [FDR] < 0.05; OR > 1.0), while 4 had a negative correlation with PAH (FDR < 0.05; OR < 1.0).

This is the first time evidence has revealed a causal link between circulating immune cell phenotypes and PAH through genetic mechanisms, stated the authors of the work, published in Medicine (Baltimore).¹ Also novel was using Mendelian randomization (MR) analysis to explore this link.

Researchers found evidence that 2 small groups of immunophenotypes are linked to either greater or lesser odds of developing PAH. | Image Credit: © Orawan - stock.adobe.com

Clearly, additional studies should further investigate how immunophenotypes may impact the development of PAH, they said. For now, though, the outcomes underscore the significance of immune cells in PAH’s pathogenesis. Crucially, the results expand the field of identifying potential protein targets for drug development, thus laying a foundation for future therapeutic approaches, they said.

A Winnowing Process

The authors began with 731 different types of immune phenotypes available in the most recent genome-wide association studies data, an approach that bolsters the findings’ reliability, the authors declared. Initially, using bidirectional MR analysis, they found that 9 were potentially positively connected (inverse variance weighted P < .05) with an increased risk of PAH, while 19 had a possible negative link to decreased risk. After FDR adjustment, those were reduced to 5 and 4, respectively.

The 5 immune cells that seem to be involved with increased PAH risk are CD11b on basophil, CD20– CD38– AC, CD4 Treg AC, FSC-A on T cells, and native double negative (CD4– CD8–) %T cell. Describing some of the cells individually, the authors noted that in previous research, myeloid inhibitory cells marked by CD11b in the peripheral blood of patients with PAH was significantly elevated and was implicated in the process of vascular remodeling, which aligned with their findings.²

And, although CD4 Treg AC has not yet been specifically investigated in relation to PAH, other research results have shown an increase in Treg levels in the peripheral blood of patients with PAH.³ This increase “could be due to immune biomarkers, with the ratio of regulatory T cells within CD4 (+) T cells being notably higher in the PAH group compared to the non-PAH group,” the authors speculated.¹

CD20-marked B cells may play a role in pulmonary vascular remodeling, and the authors noted that their results found a positive correlation between CD20– CD38– AC and PAH. Abnormalities in the B-cell immune response in individuals with idiopathic PAH and connective tissue disease–associated PAH could have survival-rate implications in patients with hereditary and idiopathic PAH, they pointed out. However, whether B cells directly contribute to endothelial cell damage, amplify vascular inflammation, or suppress vascular inflammation is unclear.

The 4 immune cells found to potentially reduce the risk of PAH are CD86 on myeloid dendritic cells (DC), HLA DR on HLA DR+ T cells, IgD– CD38– %lymphocyte, and CD62L plasmacytoid DC AC. Regarding these, the authors noted that antigen-presenting DC are involved in stimulating and propagating primary T cells, while mature DC demonstrate proficient recognition and presentation of antigens. Consequently, circulating conventional DC (cDC) is reduced in patients with idiopathic PAH, indicating that cDC has beneficial impact, they stated.

A link their results suggested between natural killer (NK) cells and PAH is particularly significant, the authors declared, as it aligns with outcomes of previous research.⁴ “These findings suggest that NK cells may have an inhibitory role in PAH, indicating their potential as a target for therapy,” they noted.¹

References

1.Du D, Qiu J-Y, Zhao J, Yuan Y-D. Causal relationship between immune cells and pulmonary arterial hypertension: Mendelian randomization analysis. Medicine (Baltimore). 2024;103(37):e39670. doi:10.1097/MD.0000000000039670

2. Yeager ME, Nguyen CM, Belchenko DD, et al. Circulating myeloid-derived suppressor cells are increased and activated in pulmonary hypertension. Chest. 2012;141(4):944-952. doi:10.1378/chest.11-0205

3. Austin ED, Rock MT, Mosse CA, et al. T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension. Respir Med. 2010;104(3):454-462. doi:10.1016/j.rmed.2009.10.004

4. Funk-Hilsdorf TC, Behrens F, Grune J, Simmons S. Dysregulated immunity in pulmonary hypertension: from companion to composer. Front Physiol. 2022;13:819145. doi:10.3389/fphys.2022.819145