Role of the Immune System in Hypertension

Abstract

High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system. Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation. Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance. Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease.

FIGURE 1.

Participation of the NLRP3 inflammasome in the pathogenesis of experimental hypertension. 1) Suppression or deficiency of TLR4 ameliorates or prevents hypertension (20, 46, 247). 2) Inactivation or deficiency of the P2x7 receptor ameliorates hypertension in the Dahl SS rat (120). 3) Suppression of NFκB activation ameliorates hypertension in SHR (218), Fawn Hooded rat (137), and the dTGF rat (185). 4) Deficiency of ASC ameliorates DOCA-salt hypertension (140). 5) NLRP3 inflammasome components overexpressed in the SHR (see FIGURE 2) and inhibition of inflammasome activation ameliorate DOCA-salt hypertension (140).

FIGURE 2.

NLRP3 inflammasome components are increased in the kidney of SHR. Relative abundance of NLRP3, ASC, procaspase, caspase, IL-1β, and IL-18 in 40-wk-old SHR and normotensive WKY rats. See text for definitions.

FIGURE 3.

Adaptive immunity in experimental hypertension. Investigations demonstrating involvement of adaptive immunity in experimental models of hypertension include evidence that isoketal–modified proteins (135) and overexpression of HSP70 (25, 111, 211) are potential antigens in hypertension-associated immune reactivity (1). Dendritic cells process the antigen (135) (2), travel to lymphoid organs (135) (3), and present it to the TCR in T cells (90, 175) in the context of the MHC (225) in association with costimulatory signals (294) (4). Memory T cells (5) are developed and stored for inducing accelerated responses to subsequent antigenic challenge (114, 205) and activation and expansion of effector T cells (6) that result in proinflammatory cytokine responses (see TABLE 2) and regulatory T cells (7, 126, 146, 161, 182, 241) (7). B-cell activation (8) is necessary for the development of hypertension when the immune system is intact (32). The CNS-SNS axis is recruited by oxidative stress (154, 155, 251, 333) involving angiotensin II receptors (100, 244, 251) and results in SNS-induced stimulation of the release of activated T cells from the spleen (9) (27, 28) and stimulation of target organ immune infiltration and reactivity (314) (10). APC, antigen presenting cells; MHC, major histocompatibility complex; TCR, T cell receptor; CNS, central nervous system; SNS, sympathetic nervous system.

FIGURE 4.

Relative content of HSP70 and HSP72 in SHR and WKY at 4 and 40 wk of age. SHR are normotensive at 4 wk of age and have overexpression of HSP72. At 40 wk of age, HSP70 and HSP72 are overexpressed in the SHR. Histology corresponds to immunoperoxidase staining for HSP70 in WKY and SHR 40 wks of age.

FIGURE 5.

Lymphocytes staining positive for angiotensin II in tubulointerstitial areas of the SHR. Double staining methodology used to demonstrate by indirect immunofluorescence (A) lymphocytes (fluorescein-labeled CD5 positive cells) expressing angiotensin II (rhodamine-labeled angiotensin II positive cells) (B). [From Rodriguez-Iturbe et al. (222).]

FIGURE 6.

Immune cell infiltration in tubulointerstitial areas impairs pressure natriuresis. A: salt-sensitive hypertension following l-NAME administration (SSHBP) is associated with immune cell infiltration and angiotensin positive cells in tubulointerstitial areas that are suppressed with mofetil mycophenolate (MMF) treatment. B: the severity of salt-induced hypertension is directly related to the intensity of immune cells (CD68+ and CD3+ cells) infiltration. C: pressure natriuresis is impaired in SSHBP. MMF treatment increases pressure natriuresis in l-NAME-treated rats to the values found in control rats on a high (C-HSD) and normal (C-NSD) sodium diet. SBP, systolic blood pressure; F_NaE, fractional sodium excretion. [Data from Franco et al. (72).]

FIGURE 7.

Participation of the sympathetic nervous system in the immune responses (key references in parentheses). Most of the immune-related effects of the sympathetic nervous system have been identified using angiotensin infusions. Hemodynamic actions of the sympathetic nervous system favoring hypertension are included in a box. PVP, peripheral vascular resistance; PIGF, placental growth factor.

FIGURE 8.

Innate and adaptive immune system in clinical hypertension. The innate and adaptive immunity play a role in establishing inflammation in the kidney, arteries (perivascular), and central nervous system (CNS)/sympathetic nervous system (SNS). Danger-associated molecular patterns (DAMPs) recognized by pattern recognition receptors (PRR), specifically, Toll-like receptors (TLR), activate the inflammasome and drive an innate immune response with the participation of monocytes (Mo), macrophages (M¢), dendritic cells (DC), neutrophils (N), and natural killer cells (NK). Neoantigens generated (isoketal-modified proteins) and overexpressed immunodominant molecules (HSP70) are taken up by antigen presenting cells (APCs), presented for recognition to the naive T lymphocytes in the context of the MHC to the specific T cell receptor. Stimulation of antibody producing B cells and of helper (CD4+) and cytotoxic (CD8+) T cells takes place. CD4+ T cells generate a proinflammatory Th1, Th2, and IL-17 cytokine responses and T regulatory cells (Tregs), required for limiting inflammation. Numbers in parentheses indicate the references that support the finding in human hypertension (*data for isoketal-modified proteins, **data for HSP70).

FIGURE 9.

Activation of the immune system and the natural history of essential hypertension. Prehypertension is associated with irregular generation of stimulatory signals associated with rise in blood pressure. Transient episodes of hypertension are associated with episodic generation of danger-associated molecular patterns (DAMPs) and expression of Toll-like receptors (TLRs) that activate intermittently the innate immune system with episodic inflammatory infiltration in target organs. Established hypertension results from the activation of both the innate and the adaptive immunity that support one another and drive a permanent renal and vascular inflammation that is, nevertheless, in a state of unsteady equilibrium with the suppressive (anti-inflammatory) responses. This balance is capable of maintaining a well-preserved renal function. The development of chronic renal damage and arteriosclerosis, resulting from persistent and increasing inflammation fueled by the unchecked generation of neoantigens, is manifested by hypertension of increased severity and resistance to treatment.