The immunology of hypertension

Abstract

Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined. Emerging evidence supports the concept that immune cells become activated and enter target organs, including the vasculature and the kidney, in this disease. Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage. In vessels, these factors enhance constriction, remodeling, and rarefaction. In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury. Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension. Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation. Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases.

Figure 1.

Changes in cardiac output and renal function in hypertension. (A) Relationship between cardiac output (liters/min) and age (yr) in 110 male individuals diagnosed with essential hypertension. Measurements were taken while subjects were at rest in a seated position, from Fagard and Staessen (1991). (B) Guytonian pressure–natriuresis curve relationship. Normotensive individuals undergo a brisk diuresis, excretion of sodium and water, in response to elevations in blood volume and blood pressure, allowing for maintenance of a normal mean arterial pressure. In order for sustainment of hypertension, this curve must be shifted. The shifting of the curve results from changes that occur within the kidney that decrease its capacity to excrete sodium and water. Thus, the mean arterial pressure over which sodium and water are excreted increases to compensate for these deficits in kidney function.

Figure 2.

Innate and adaptive immune cells that have been shown to play a critical role in hypertension. Adaptive immune cells: CD8⁺ T cells, CD4⁺ cells (Th1, Th17, and T reg cells), T cells, and B cells produce factors that promote or inhibit hypertension. Innate immune cells: Macrophages, microglia, monocytes, DCs, and MDSCs also produce cytokines and ROS, which promote or inhibit hypertension. The NLRP3 inflammasome in monocytes and DCs plays a key role in hypertension. γδ T cells function on the border of innate and adaptive immunity.

Figure 3.

Working hypothesis for activation of renal DCs by sympathetic activation in hypertension. Hypertension enhances sympathetic outflow to the kidney, where DCs become activated, accumulate isoLG-adducts, and transmigrate to secondary lymphoid organs. T cells activated by DCs return to the kidney to promote renal dysfunction and damage. From Xiao et al. (2015).

Figure 4.

Inflammation in the kidney, aorta, brain, and heart promote hypertension and end-organ damage. Kidney: CD4⁺ Th1 and Th17 cells as well as γδ T cells and DCs infiltrate the kidney and produce cytokines such as IL-1β, TNF-α, IFN-γ, and IL-17A. Mediators from these cells up-regulate sodium transporter expression and activity, resulting in sodium and water retention; damage kidney tissue, resulting in albuminuria and nephrinuria; alter/damage kidney vasculature, resulting in rarefaction and remodeling; and increase ROS production within the kidney. Blood vessels: CD4⁺ Th1 and Th17 cells, CD8⁺ T cells, γδ T cells, macrophages, and DCs infiltrate the blood vessels and produce IFN-γ and IL-17A. As a result, there is increased ROS production, increased matrix metalloproteinase production, and decreased NO bioavailability, which leads to vasoconstriction and increased collagen synthesis, resulting in stiffening of the vessels within the vasculature. Brain/CNS: Microglia, which are resident in the brain, become activated and produce IL-1β, TNF-α, and IL-6. These cytokines increase sympathetic outflow and promote the infiltration of T cells. Heart: CD4⁺ Th1 and Th17 cells as well as CD8⁺ T cells infiltrate and produce IFN-γ and IL-17A. This increases cardiac hypertrophy and fibrosis within the heart.