Divergent Characteristics of T-Cell Receptor Repertoire Between Essential Hypertension and Aldosterone-Producing Adenoma

Abstract

Aldosterone-producing adenoma (APA) is a benign adrenal tumor that results in persistent hyperaldosteronism. As one major subtype of primary aldosteronism, APA leads to secondary hypertension that is associated with immune dysregulation. However, how the adaptive immune system, particularly the T-cell population, is altered in APA patients remains largely unknown. Here, we performed TCR sequencing to characterize the TCR repertoire between two age-matched groups of patients: one with APA and the other one with essential hypertension (EH). Strikingly, we found a significant reduction of TCR repertoire diversity in the APA group. Analyses on TCR clustering and antigen annotation further showed that the APA group possessed lower diversity in TCR clonotypes with non-common antigen-specific features, compared with the EH group. In addition, our results indicated that the strength of correlation between generation probabilities and frequencies of TCR clonotypes was significantly higher in the APA group than that in the EH group. Finally, we observed that clinical features, including plasma aldosterone level, aldosterone–renin ratio, and blood sodium level, were positively associated with the strength of correlation between generation and abundance of TCR clonotypes in the APA group. Our findings unveiled the correlation between T-cell immune repertoire and APA, suggesting a critical role of such adrenal adenoma in the T-cell immunity of patients with hypertension.

Re: comment from Ladak et al. to JH-D-23-00692, entitled ‘Analyzing eGFR-Dip after medical target therapy in primary aldosteronism’

“…Confronting the issues they have artfully delineated, we duly acknowledge the significance of nutritional variables, notably caffeine and salt intake, and their potential repercussions on the renin-angiotensin-aldosterone system (RAAS) [2]. We wholeheartedly concur with their recommendation to incorporate these variables into our future analytical framework.…”

“…While the study accounted for effects of hypertensive medications on the renin-angiotensin-aldosterone system (RAAS) by discontinuing these medications before primary aldosteronism diagnosis, some nutritional factors that affect RAAS that were not considered. Robertson et al [2] demonstrated that acute caffeine consumption increased serum renin levels significantly, which would cause an increase in downstream plasma aldosterone concentrations. In addition, a large body of research demonstrated that salt intake has an inverse relationship with renin production/RAAS activation, though the exact mechanism remains unknown [3].…”

TCR-Sequencing Provides a Barcode of Immune Activation and Target Organ Damage in Human Hypertension

“…As a further example, it has been shown that patients with EH or hypertension due to secondary causes like aldosterone-producing adenoma display a different type of TCR repertoire. 15 Ma et al 13 found a positive correlation between reduced T cell clone diversity and the number of antihypertensive drugs taken. This information could be related to the fact that patients with enhanced immune activation might have severe hypertension and, consequently, assume more drugs.…”

“…As a further example, it has been shown that patients with EH or hypertension due to secondary causes like aldosterone-producing adenoma display a different type of TCR repertoire. 15…”