In a review article David Harrison and colleagues from the Department of Medicine, Vanderbilt University, Nashville, TN, summarize recent animal and human studies suggesting that inflammation and adaptive immunity responses are implicated in the pathogenesis of hypertension.
As stated by the authors, quote: “A prominent pathology textbook used in the United States includes an image illustrating the renal histopathology caused by malignant hypertension. Curiously, a sea of mononuclear inflammatory cells surrounding this arteriole is overlooked both in the legend and in the related text. Moreover, nothing regarding inflammation or immune reactions is discussed”.
In the review that was published in the American Heart Association’s journal Hypertension, Harrison et al. provide a brief but comprehensive overview of the major immune and inflammatory mechanisms contributing to the development of hypertension, and a working hypothesis of how signals from the central nervous system may trigger an immune response that causes hypertension.
The authors also highlight the importance of the clinical condition referred to as “prehypertension,” which may represent a condition in which inflammation initiates a more severe hypertensive state.
A few examples from this excellent review.
Relationship Between Oxidation and Inflammation
Many factors common to the hypertensive milieu, including angiotensin II, aldosterone, cytokines, and altered mechanical forces, such as stretch and shear stress, stimulate enzyme sources such as the NADPH oxidases, uncoupled nitric oxide synthase, and the mitochondria to produce reactive oxygen species (ROS) that contribute to hypertension. In the central nervous system, ROS promote sympathetic outflow. In the vessel, ROS induce vasoconstriction, whereas in the kidney, they cause sodium and volume retention.
Oxidized lipoproteins can interact with TLRs, in particular TLR4, to promote vascular disease. ROS can affect T cell polarization and cytokine secretion. Inflammatory cells, such as macrophages and granulocytes, can release ROS, further amplifying an oxidative environment.
Neoantigens and Their Potential Role in Cardiovascular Diseases
The term “neoantigens” was first used in the cancer literature to refer to proteins detected by the presence of antibodies against tumor-associated epitopes. Molecules suggested to elicit immune responses in atherosclerosis include oxidized low-density lipoprotein, heat shock proteins, platelet glycoproteins, and others, although no specific antigen has been identified with certainty.
Figure: Proposed role of T cells and inflammation in hypertension. Hypertensive stimuli such as angiotensin II and salt cause a modest elevation in pressure (prehypertension), in large part because of central stimuli and via direct effects on the kidney and vasculature. We hypothesize that this leads to neoantigen formation, promoting T cell activation as shown in Figure 1. Activated T cells enter the kidney and vasculature. T cell–derived signals such as IL-17 promote entry of other inflammatory cells such as macrophages.
These inflammatory cells release cytokines that cause vasoconstriction and promote sodium and water absorption, ultimately causing severe hypertension. From: Inflammation, immunity, and hypertension, by David G Harrison, Tomasz J Guzik, Heinrich E Lob, Meena S Madhur, Paul J Marvar, Salim R Thabet, Antony Vinh, Cornelia M Weyand,Hypertension, 2011 Feb;57(2):132-40. doi: 10.1161/HYPERTENSIONAHA.110.163576.
Special mention should be made of the potential role of heat shock protein (HSP) 70 in hypertension. This molecular chaperone has been intensely studied for more than 40 years and has been implicated in the transport and delivery of antigenic peptides. Various epitopes of HSP70 are immunogenic and induce T cells with anti-inflammatory properties in a neoantigen-like fashion.
Recent Observations Regarding the Adaptive Immune Response and Hypertension
The authors of this review found that chronic angiotensin II infusion increases the percent of cells CD69 and CCR5 positive and CD44high T cells in the circulation. These are markers of activated, effector T cells. Interestingly, angiotensin II also markedly increased vascular levels of RANTES. Thus, like many inflammatory stimuli, hypertension has a dual effect: one is to promote T cell activation, and the second is to increase chemokine and adhesion molecule expression in target tissues to promote tissue entry of activated inflammatory cells.
Role of Cytokines in Hypertension
A working hypothesis has emerged in which hypertensive stimuli promote accumulation of activated T cells in perivascular fat and in the kidney. In these sites, these cells release cytokines that affect adjacent vascular cells and tubular epithelium in the kidney.
The authors of this review found that the vascular accumulation of leukocytes (including T cells) caused by angiotensin II is markedly reduced in IL-17−/− mice. Thus, IL-17might contribute to the vascular pathophysiology of hypertension not only by its direct effects, but also by recruiting other inflammatory cells to the perivascular tissue.
The studies and concepts described in this review may provide new insights into the pathogenesis of hypertension, and suggest that immunotherapy might be useful to treat severe forms of either resistant or malignant hypertension.
SOURCE: Hypertension 2011, 57:132. Epub 2010 Dec 13