Inflammation and Immunity in Hypertension

General Considerations of the Immune System

The two major arms of the immune system are innate and adaptive immunity. Innate immunity includes chemical and humoral mediators such as nitric oxide, reactive oxygen species (ROS), complement, acute phase proteins, chemokines, and cytokines. Natural immunoglobulin M (IgM) and immunoglobulin G3 (IgG3) antibodies, produced largely by B1 cells, are present in infants and adults before exposure to an antigen and confer innate protection to viruses and bacteria but can also participate in autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. Some natural antibodies target lectins, present on the surface of microbes and apoptotic cells. Cellular components of innate immunity include phagocytic cells, including granulocytes, monocytes and macrophages and natural killer (NK) cells. Other cells of the innate immune system include dendritic cells, newly identified innate γ/δ T cells and epithelial cells, which provide a barrier to invading organisms. These features of innate immunity have been reviewed in depth recently.

Several components of the innate immune system will be discussed in greater detail later, however special mention of monocytes and monocyte-derived cells is warranted. Approximately 5% to 10% of circulating leukocytes are monocytes. These survive in the circulation for approximately one to two days, and do not undergo further proliferation, but are capable of enormous phenotypic differentiation. A major impetus for this differentiation is transmigration of these cells through the endothelium which, as mentioned earlier, is triggered by various inflammatory stimuli. Upon entry of monocytes into the interstitial space, monocytes can undergo at least three fates ( Fig. 7.1 ). Most commonly recognized is their conversion to macrophages, which remain in the interstitium and can phagocytose injurious bodies and release potent mediators including reactive oxygen species (ROS), nitric oxide (NO), cytokines, and matrix metalloproteinases. It is now recognized that there is also a population of tissue resident macrophages, not derived from circulating monocytes, which participate in tissue healing. Unlike monocyte-derived macrophages, tissue resident macrophages undergo proliferation and self-renewal. A second fate of monocytes is to differentiate into dendritic cells, powerful antigen-presenting cells for T cell activation, which are discussed more fully later. A final fate of monocytes is to reemerge from the vessel wall without differentiation. It is now recognized that monocytes can enter tissues, acquire antigens and transport these to lymph nodes where they can activate T cells without becoming either dendritic cells or macrophages. These minimally differentiated monocytes are typified by their surface expression of major histocompatibility complex type II and the activation marker Ly-6C and an enhanced ability to activate T cells.

Although the innate immune system is nonspecific and provides immediate protection, it does not have the ability to augment protection upon repeated antigenic challenges. In contrast, adaptive immunity provides powerful and specific defense against previously encountered antigens. Components of the adaptive immune response include T cells, responsible for cellular immunity, and B cells, which upon activation by T cells differentiate into either short or long-lived antibody producing plasma cells.

A critical step in initiation of the adaptive immune response is uptake and processing of antigens by antigen presenting cells (APCs). Although several cells can present antigens, the major APCs are macrophages, B cells, and dendritic cells (DCs). CD4 ⁺ T cells are generally activated by peptides that have been derived from extracellular antigens presented in the context of type II major histocompatibility complexes (MHCs), whereas CD8 ⁺ T cells are activated by intracellular antigens, such as invading viruses, that are presented by type I MHCs. APCs that have acquired antigen undergo maturation, increasing expression of costimulatory molecules and production of cytokines that can direct T cell polarization. The activated APC migrates to secondary lymphoid organs and seeks a T cell with a T cell receptor that recognizes and binds the MHC/peptide complex. The subsequent immunologic synapse formed by these two cells leads to T cell activation, involving proliferation, an increase in cytokine production and a change in surface receptors that arm the cell to leave the secondary lymphoid organ and migrate to inflamed peripheral tissues. B cells also phagocytose and present antigen, and their formation of an immunologic synapse with T helper cells promoting their proliferation and formation of germinal centers in lymph nodes and tertiary sites.

T cell subsets exhibit division of duty. CD4 ⁺ T cells are conditioned or polarized by the cytokines they encounter upon initial stimulation, leading to unique T helper phenotypes. T _H 1 cells produce proinflammatory cytokines such as interferon (IFN)-γ, IL-2 and tumor necrosis factor (TNF)α. T _H 2 cells produce IL-4, IL-5 and IL-13, cytokines involved in response to allergens and helminth infections. T _H 17 cells produce the unique cytokine IL-17, and play critical roles in diseases such as psoriasis, experimental allergic encephalitis and inflammatory bowel disease. T regulatory cells represent another subset of T cells that suppress the immune response. Activated CD8 ⁺ T cells have cytolytic activity, manifested principally by their release of isoforms of granzyme and perforin, but they can also release cytokines, and in fact are major sources of IFN-γ. These features of adaptive immunity have been reviewed in depth elsewhere.

Historical Aspects Regarding Inflammation and Hypertension

It has been recognized that there is an inflammatory component in human hypertension for more than half of a century, and that immune cells contribute to blood pressure elevation in several experimental models. In 1953, Heptinstall reported that lymphocytic infiltrates were commonly observed in the kidneys of humans undergoing sympathectomy and or adrenalectomy for hypertension. In 1964 White and Olsen showed that cortisone and mercaptopurine could lower blood pressure in a rat model of hypertension caused by renal infarction. Subsequently Okuda and Grollman found that transfer of lymph node cells from these rats could passively raise blood pressure in otherwise normal recipients. In 1970, Olsen showed that chronic angiotensin II infusion in rats lead to a striking periarteriolar infiltrate of lymphocytic and monocytic cells. Soon thereafter, Dr. Olsen demonstrated a striking periarteriolar infiltration of immune cells in humans with hypertension, and pointed out that these appeared to be lymphocytes and monocytes. In 1976, Svendsen demonstrated that athymic nude mice exhibit blunted hypertension in response to deoxycorticosterone acetate (DOCA)-salt challenge but that this phenotype was normalized by grafting of thymus tissue into these animals. Subsequently, Olsen showed that transfer of splenocytes from rats with DOCA-salt hypertension conferred an increase in blood pressure in recipient rats. Antithymocyte serum was shown to reduce hypertension in spontaneously hypertensive rats. These studies among others strongly supported the idea that the immune system contributes to hypertension via mechanisms that were poorly understood at the time.

Basic Mechanisms by Which Inflammation Contributes to Hypertension

Before discussing how immune cells contribute to hypertension, it is useful to consider currently accepted mechanisms of hypertension to begin to understand how inflammatory cells might affect these processes. As discussed in the introduction, there is substantial debate as to the etiology of most cases of adult hypertension. Indeed, the origins of hypertension are probably diverse. Nonetheless, perturbations of renal function, vascular function, and central neural control are supported by extensive investigation. There is compelling evidence that some degree of renal dysfunction must be present to sustain hypertension. This is based on the concept of the pressure natriuresis curve in which an elevation of blood pressure leads to a brisk diuresis, restoring blood pressure to its initial set point. In contrast, a lowering of blood pressure leads to a reduction in urine output, leading to volume and sodium retention until blood pressure rises to the set point. Guyton pointed out that all forms of hypertension are therefore associated with a resetting of this set point to a higher level, such that the kidneys no longer respond with diuresis at this higher level of pressure. Although overt renal failure is often associated with hypertension, alterations of the pressure natriuresis curve can involve subtle alterations of renal function not manifested by reduced glomerular filtration rate or elevations of blood urea nitrogen or serum creatinine. In fact, monogenic causes of hypertension, including Liddle syndrome and pseudohyperaldosteronism type II, involve enhanced sodium resorption in the distal nephron with otherwise normal renal function. Autocrine and paracrine factors including Ang II, nitric oxide, reactive oxygen species, endothelin-1 and prostaglandins influence renal sodium transport and their actions on the nephron have been implicated in hypertension. Many extrarenal stimuli, including catecholamines, aldosterone, vasopressin and as discussed later, inflammatory cytokines, can affect the pressure natriuresis curve without causing overt changes in renal function parameters. As discussed later in this chapter, several immune cell released cytokines affect tubular and vascular function and seem to promote sodium and volume retention in hypertension ( Fig. 7.2 ).

Blood pressure is the product of cardiac output and systemic vascular resistance, and thus an increase in blood volume and cardiac output would be expected to increase blood pressure. Vascular resistance, and particularly renal vascular resistance, is elevated in many cases of human essential hypertension, suggesting a vascular etiology. Indeed hypertension is associated with several perturbations of resistance vessel function and structure ( Fig. 7.3 ). Vasodilatation, particularly that mediated by endothelial nitric oxide production, is often compromised in hypertension and vascular remodeling, involving an increase in medial thickness and a decrease in lumen diameter, is common. These effects are in part mediated by cytokine stimulation of reactive oxygen species. Vascular fibrosis occurs at both the level of the resistance circulation and as discussed later, in larger vessels. Vascular rarefaction, or disappearance of capillaries and small resistance vessels, is also a common consequence of hypertension. These processes disable proper autoregulation and result in increased systemic vascular resistance.

An emerging vascular mechanism of hypertension relates to stiffening of the central large arteries, and particularly the aorta. Although large vessels have not been considered important in regulating systemic vascular resistance, it has become clear that aortic stiffening is a common harbinger of hypertension. Central arteries expand during systole, accommodating a portion of the ejected blood, and recoil in diastole, propelling blood to the distal tissues. In this way healthy arteries maintain diastolic perfusion. Aortic stiffening is clinically detected as an increase in pulse wave velocity and becomes abnormal in a variety of conditions, including aging, diabetes, obesity, tobacco abuse and hypertension. In large population studies, aortic stiffening precedes the development of hypertension by several years. The precise mechanisms linking aortic stiffening to gradual onset of hypertension remain undefined, but likely involve alterations of pulse wave contour reaching peripheral tissues like the kidney, the microcirculation and the brain, ultimately leading to damage of these tissues. Indeed, aortic stiffening portends conditions such as renal failure, heart failure, atherosclerosis, stroke and dementia.

In addition to renal and vascular causes of hypertension, there is convincing evidence that perturbations of the central nervous system contribute to hypertension. The lamina terminalis of the forebrain is composed of the subfornical organ (SFO), the median preoptic area (MPO) and the organum vasculosum of the lateral terminalis (OVLT). The SFO and OVLT possess poorly developed blood-brain barriers, and are sensitive to circulating mediators such as angiotensin II and salt, which increase neuronal firing in these structures and have input into the hypothalamus, and in particular the paraventricular nucleus. The paraventricular nucleus (PVN) in turn provides input to the rostroventral lateral medulla of the brainstem. This latter structure integrates baroreflex input with signals arising from the higher centers to regulate blood pressure. Hypertension is associated with abnormal neuronal firing, increased angiotensin II signaling and oxidative signaling in all of these structures. Importantly, lesions within these structures and local blockade of the renin angiotensin system have profound effects on blood pressure. As an example, lesions of the anteroventral third ventricle (AV3V) region, which disrupt fibers from the SFO to the OVLT, prevent most forms of experimental hypertension. Likewise, injection of angiotensin receptor blocking agents into the rostral ventrolateral medulla (RVLM) prevents hypertension. An emerging concept is that of the neuroimmune axis, in which sympathetic outflow modulates immune cell activation ( Fig. 7.4 ), whereas afferent signals from the periphery inhibit further sympathetic outflow. There is evidence that this inhibitory loop is disrupted in hypertension.