© Borgis - Postępy Nauk Medycznych 11/2015, s. 779-786
*Jacek Michałkiewicz1, 2
Udział mechanizmów odpornościowych w patogenezie pierwotnego nadciśnienia tętniczego
The role of immune system in pathogenesis of primary hypertension**
1Department of Microbiology and Immunology, The Children’s Memorial Health Institute, Warszawa
2Chair of Immunology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń
Streszczenie
Większość badań układu odpornościowego u ludzi z pierwotnym nadciśnieniem tętniczym wykonano u osób dorosłych, stąd ich znaczenie patogenetyczne jest wątpliwe z powodu licznych obciążeń, niezwiązanych bezpośrednio z chorobą pierwotną, takich jak stosowanie używek, leków, obecność zaburzeń metabolicznych i innych uwarunkowań, powodujących zwiększoną aktywację mechanizmów odpornościowych, manifestujących się przewagą limfocytów o fenotypie komórek efektorowych i pamięci immunologicznej (profil prozapalny), a mniejszą populacją limfocytów dziewiczych (profil niezapalny).
Dziecięca postać PN (nadciśnienie pierwotne) stanowi najbardziej przydatny model badawczy chorób sercowo-naczyniowych z powodu nieznacznego tylko obciążonia innymi czynnikami współistniejącymi. Zwiększenie ciśnienia tętniczego oraz zapalenie naczyń u dzieci z PN związane są z obecnością wykładników chronicznego, podostrego zapalenia systemowego, którego aktywność korelowała: a) ze zmianami aktywności metabolicznej tkanki tłuszczowej manifestującymi się wzrostem poziomu leptyny i spadkiem adiponektyny, b) ze zmianami w zakresie dystrybucji tkanki tłuszczowej, c) ze wzrostem stężenia surowiczych komponent stresu oksydacyjnego oraz niektórych cytokin prozapalnych.
Dzieci z PN charakteryzują się także: a) przyspieszeniem wieku biologicznego, wyrażonego jako różnica pomiędzy wiekiem kostnym a wiekiem chronologicznym, b) zaburzeniami w zakresie ekspresji genów systemu renina-angiotensyna oraz genów kontrolujących ekspresję receptorów dla adipokin i metaloproteinaz w leukocytach krwi obwodowej, c) zmianami w zakresie ekspresji szeregu receptorów komórkowych leukocytów takich jak AdipoR1, wzrostem populacji limfocytów o fenotypie komórek T-reg (regulatorowych) i ekspresją interleukiny 17.
Wyniki te wskazują, że PN u dzieci i dorosłych jest silnie związane z wieloma parametrami aktywacji układu odpornościowego, lecz pochodzenie czynnikow stymulujących ciągle pozostaje niewyjaśnione.
Summary
Most of human studies on immunity in hypertension have been performed in adults so their pathogenic significance still remains obscure because of the numerous confounders such as smoking, drugs use, metabolic disorders as well as generally high inflammatory background created by overall excess of the effector/memory lymphocyte populations over the naïve ones. PH children are regarded as the best clinical model of development of cardiovascular disease not influenced by other factors. Both blood pressure elevation and vascular inflammation in the PH children were associated with a systemic low-grade inflammation that correlated with: a) the changes in the metabolism of adipose tissue: increase in leptin and decline in adiponectin serum levels, b) altered distribution of fat tissue with relative increase of visceral fat over subcutaneous fat, c) serum elevation of oxidative stress components and certain pro-inflammatory cytokines. The PH children were also characterized by: a) accelerated biological maturation expressed as the difference between bone age and chronological age, b) changes in expression profile of genes of renin-angiotensin system and metalloproteinases as well as leukocyte surface markers such as AdipoR1 receptors, c) elevation of T-reg cell numbers and increase in transition of T-reg into Th17 cells. Altogether, these results strongly suggest that PH in both children and adults is strongly associated with immune cells activation but the origin of the stimulating agents still remain unknown.
Introduction
The role of immune mechanisms in pathogenesis of hypertension was suggested by several early findings including: a) a functional thymus requirement for hypertension development, b) a presence of markers of systemic inflammation as well as agonistic antibodies against angiotensin II receptors and adrenergic receptors in the serum of hypertensive patients, c) a correction, amelioration or prevention of experimental hypertension by suppression of T cell driven inflammation in the target organs.
At present, primary hypertension (PH) both in humans and animal models is considered as a condition of low-grade, chronic, systemic inflammation often associated with metabolic syndrome components (dyslipidemia, insulin resistance, obesity, etc.), and acute phase response manifested by elevation of cytokines (IL-6, TNF-alfa) and C-reactive protein serum levels (1-4). Blood pressure elevation in the course of hypertension depends on innate and adaptive immune immune responses that result in inflammation in the kidney, arteries and central nervous system.
Innate immunity in hypertension
The innate immune system is responsible for fast and non-specific immediate inflammatory response recruited to eliminate infection or in response to tissue injury. The system consists of cells (granulocytes, monocytes, macrophages, dendritic cells, mast cells, NK lymphocytes) and many soluble factors (interferons, acute phase proteins, cytokines, chemokines, defensins, and complement fragments).
The cells of innate immune system express pattern recognition receptors (PRRs) which recognize pathogen associated molecular patterns (PAMPs) that are expressed and shared by large groups of pathogens or damage associated molecular patterns (DAMPs) that represent structures of damaged cells.
Dendritic cells (DCs) infiltrate the kidney and arterial walls in many hypertension models. Their numbers increase in perivascular tissue and adventitia in large vessels (aorta) and in medium sized vessels (mesenteric arteries) together with other immune cells including CD4+ and CD8+ T cells and macrophages. In the kidney, immune cells are located preferentially around renal arteries. The reason why DCs and other immune cells accumulate in peri-vascular space are unknown but possibly sympathetic nerve endings present in these areas play some role in this phenomenon (5). DCs are the most efficient antigen-presenting cells and promote a differentiation of T cells towards many different functional phenotypes (6). The number of activated DCs in perivascular space increased in angiotensin II and DOCA-salt hypertension. They expressed high levels of several co-stimulatory molecules engaged in antigen presentation to T cells (7).
Co-stimulators are the molecules that are engaged in providing the second signals necessary for optimal T cells activation following their stimulation by the first signals (the ones generated by recognition of antigens presented to T cells by DCs, macrophages and B cells which act as antigen-presenting cells – APCs). One of the best characterized co-stimulatory pathway is the CD28/B7 in which CD28 represents a surface protein constitutively expressed by over 90% of mature CD4+ T cells and about 50-70% of CD8+ T cells. The CD28 molecule interacts with its B7 ligands (CD80 and CD86) expressed by activated and/or resting APCs, respectively). Pharmacological inhibition of CD28/CD80 pathway, lack of this pathway in CD80/CD86 knock-out mice or engrafting wild type bone marrow in CD80/CD86 deficient mice restored the hypertensive response to angiotensin II (7).
It has recently been found that DCs played a causal role in hypertension development by increased formation of ROS and oxidative modifications of proteins by highly reactive gamma-ketoaldehydes (isoketals). DCs from angiotensin II infused mice produced increased amounts of O2-, accumulated isoketal protein adducts, and released cytokines such as IL-6, IL-1 beta and IL-23 and had elevated expression of costimulators such as CD80, CD86. They promoted T cell proliferation, especially CD8+, and polarized T cells to an inflammatory phenotype involving production of IL-17, IFN-gamma and TNF-alfa. DCs from hypertensive mice primed a hypertensive response in recipient mice to low-dose of angiotensin II.
Scavenging isoketals prevented these parameters of DCs activation and ameliorated hypertension. Exposure of DCs to the prooxidant agent tert-butyl hydroperoxide (t-BHP) promoted their ability to suport CD8+ T cell proliferation and hypertension, thus mimicking the effect of angiotensin II in vivo. Likewise, DCs pulsed with isoketal-modified proteins from renal homogenates potently stimulated T cell proliferation, while DCs pulsed with other oxidized lipid products did not. The authors also noted that plasma F-2 izoprostanes which are formed in concert with isoketals are elevated in humans with treated hypertension and very markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also elevated in circulating monocytes and DCs from human with hypertension and that these increased with severity of hypertension. The authors conclude that hypertensive stimuli activates DCs by promoting the formation of isoketals and suggest that reducing isoketals has potential as a treatment strategy for this disease (8).
These observations directly suport the earlier assumption that vascular inflammation that results in hypertension is initiated by neo-antigens formation in the target tissues such as vasculature and kidney. These antigens are subsequently recognized by macrophages and dendritic cells via PRRs. Antigen presentation to responder T cells (in draining lymph nodes) results in their further activation, proliferation and differentiation into numerous types of different effectors, responsible for vascular inflammation (9).
This scheme implies the role of both innate (macrophages, dendritic cells) and adaptive immunity (T cells) in hypertension development. These data also imply the development of memory adaptive immune responses to vascular neoantigens (autantigens) that develop in the onset of the disease that support the idea of autoimmune reactivities against certain vascular antigens, e.g. HSP-70 proteins (10, 11).
Macrophages and monocytes
Macrophages like DCs infiltrate the kidney and periadventitial areas of the peripheral vessels (aorta and medium sized arteries). Hypertension induced infiltration of monocytes/macrophages into the vessel wall, brain, heart and kidney represents the main component of vascular inflammation and inflammation-induced organ damage in many experimental models including polygenic, monogenic, renovascular and mineralocorticoid hypertension. Macrophage infiltration in the kidney appears to be most prominent in forms of hypertension associated with an activated renin-angiotensin-aldosteron system.
On the contrary, a reduction in macrophage infiltration is associated with improvement of hypertension in several animal models including spontaneously hypertensive rats (SHRs) (12), Dahl salt-sensitive rats (13), hypertension induced by angiotensin II (14) and aldosteron (15), salt-dependent hypertension (16) and autoimmune hypertensive renal disease (17).
Elimination of circulating monocytes in mouse model by action of diphtheria toxin (18), deficiency in macrophage population in osteopetrotic mice with mutation in colony – stimulating factor gene (19) and treatment of mice with the CCR2 or MCP-1 antagonists that blocks chemokine receptors (CCR-2) or chemokine itself (MCP-1), protected mice from angiotensin II or DOCA induced hypertension (20, 21).
Macrophages are also main targets for adrenergic and cholinergic regulations of the immune reactions in course of hypertension. The spleen macrophages of spontaneously hypertensive rats (SHRs) primed with nicotine (cholinergic, anti-inflammatory signal) or angiotensin II (pro-inflammatory signal) remain highly reactive in response to pro-inflammatory activities induced by second stimulation via certain TLRs (TLR-7,8) as measured by IL-6, and TNF-alfa production. These effects are observed only in the hypertensive rats but not in the control, normotensive rats, and appeared before the onset of hypertension indicating on impaired response to cholinergic signals in the pre-hypertension stage (22).
There is still unclear if macrophage infiltration into vessel walls or target organs represents “primary” or “secondary” alterations in the immune system. So far unidentified “primary” changes of the immune system may result in subsequent inflammatory response in the vessel wall and/or the kidney vasculature leading then to blood pressure elevation. There are some data suggesting that certain immune defects may preceed hypertension development in SHRs (23) but this remains difficult to confirm in human.
“Secondary” leukocyte alterations induced either by hypertension per se (via mechanical stress) and/or by factors that cause hypertension (e.g. angiotensin II) may also lead to the infiltration and/or activation of leukocytes, particularly macrophages, in target tissues where these cells contribute to the development of organ injury by realeasing pro-inflammatory agents including soluble mediators (cytokines, chemokines, oxygen radicals, etc.) and acting as cytotoxic cells for many vascular targets or other toxic mediators (24, 25).
From the practical reasons, the pathological diagnosis of hypertensive kidney disease is difficult to study in patients with hypertension. Macrophage analysis in atherectomy speciments is often confounded by the presence of atherosclerosis. Kidney biopsies may not be representative if the infiltration is as focal as it is in experimental hypertension (26). Diagnosis is often doubted by pathologists and a marked macrophage infiltration may even suggest the presence of other primary immunological kidney disease. A true “control” tissue without hypertension or atherosclerosis is hard to obtain. Therefore studies in human patients have been performed with the use of peripheral blood monocytes. There is a lot of data concerning this issue. In general, they indicated that hypertension was associated with the presence of activated monocytes in periphery, which showed: a) decreased sensitivity to blocking action of glucorticosteroids in vitro (27), b) increased adherence to endothelium in vitro and elevated production of IL-1 and TNF-alfa (28), TGF-beta (29), MCP-1 as well as TF (30) upon stimulation, c) elevated expression of some surface receptors related to endothelial adhesion and transmigration, CD11b, CD11c, ICAM-1, CCR2 and CCR-5 (31), d) increased expression of TLR-4 but not TLR-2 (32), e) increase in ROS production (33), f) increased expression of transient receptor potential canonical type 3 channels (TRPC3) that was associated with increased monocyte migration (34), g) up-regulation of bradykinine receptors 1 and 2 (35).
In addition, monocytes have some phenotype and functional characteristics which are strictly related to their role in blood pressure regulation. They inlude: a) expression of AT1 receptor for angiotensin II (36); it enables monocyte activation by this peptide that results in high production of several pro-inflammatory cytokines and has an influence on several monocyte functions related to their endothelial transmigration and differentiation to tissue macrophages, b) expression of renin angiotensinogen, and aldosteron (37), c) expression of adrenergic and cholinergic receptors which enable monocyte interaction with neurotransmitters (acetylocholina, noradrenaline, dopamine) that are engaged in blood pressure regulation (38) as well as abilities for their production (39) d) expression of leptin, and adiponectin receptors that enable monocytes to interact with these adipokines (40, 41).
The latter point is especially interesting. Fat mass is linked mechanistically to the cardiovascular system through adipokines action, including leptin. Leptin increases blood pressure via hypothalmic-sympathetic pathways and also stimulates many pro-inflammatory activities such as monocyte migration through extracellular matrix, up-regulation of monocyte scavenger receptor expression, increased uptake of oxidized low-density lipoprotein (LDL), cytokines secretion, adhesion to endothelium and other immune functions that contribute to vascular inflammation.
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