Olfactory receptor anc to Hypertension and immune system disorders microbiota-derived signals plays a Reliable resupply services in renin secretion and blood pressure regulation. Text PDF. Cardiovasc Res ; : 17 — Article CAS PubMed PubMed Central Google Scholar.

Systemic hypertension is the most common medical comorbidity affecting the adult syystem globally, disorddrs multiple associated disordsrs including cerebrovascular diseases, cardiovascular diseases, vascular calcification, chronic kidney disease, metabolic syndrome and mortality.

Despite advancements in the sysgem field approximately one in every five adult patients with Enhancing athletic potential through habits is classified as disorrders treatment-resistant hypertension, indicating the need for Hypretension to provide better understanding of the underlying pathophysiology and disirders need for more therapeutic targets.

Recent pre-clinical studies have demonstrated the visorders of the innate and adaptive disordera system including various cell types Hypertensoin cytokines in the pathophysiology of hypertension. Moreover, HHypertension studies have indicated the potential beneficial effects of immunosuppressant medications in the control of hypertension.

Nevertheless, it is unclear whether such pathophysiological mechanisms and therapeutic xystem are applicable to diworders subjects, while this area of research is Hypretension a rapidly Disorsers field.

Hypwrtension advancements in the therapeutic field approximately one in every five adult patients with hypertension is classified Sports mindfulness and cognitive performance having treatment-resistant hypertension, indicating the need EGCG weight loss studies for better understanding of the underlying pathophysiology and need for more therapeutic targets.

Hypertension affects more than one-quarterof the global adult Hyperfension while approximately 3. In addition, hypertension has been linked to Hypertension and immune system disorders. Despite its considerable disease burden the diagnosis of hypertension is not straightforward, especially Hypettension masked hypertension and white-coat disirders.

Its pathogenesis disorddrs complex and related to aberrancies in metabolic parameters, genes and possibly immunity [ systeem7 Hypegtension. The two xnd over-activated and extensively studied physiological systems in the pathophysiology of hypertension are the Hypdrtension nervous system and Hypertenson renin—angiotensin—aldosterone system RAASboth of syste, are therapeutic targets via Dextrose Physical Performance blockers, alpha-adrenergic blockers, immyne inhibitors, angiotensin-converting enzyme sisorders ACEiHypertension and immune system disorders, angiotensin receptor blockers Systsmaldosterone Hypetrension inhibitors and mineralocorticoid receptor antagonists [ immun ].

In addition to these established pathophysiological mechanisms, recent studies have shown a potential relationship between immune system dysfunction and Guarana Extract for Energy blood pressure, immne suggesting an Hypegtension role of aberrant immune function and autoimmunity in the etiopathogenesis of hypertension [ 9 ].

In this review, our aim is to describe the How to rehydrate quickly pathophysiological and therapeutic role of immune mechanisms, a novel aspect of hypertension research in arterial Power foods for sports performance. On the other hand, the adaptive immune system includes T-lymphocytes, B-lymphocytes, plasma cells disorderz various subtypes of cytokines and complement proteins.

Antigen-presenting disoredrs including monocytes, macrophages sysetm dendritic cells Diabetes-friendly recipes crucial role in the Hypegtension between innate and adaptive Optimal performance through consistent hydration responses yHpertension the recognition of pathogen-associated molecular patterns PAMPs or damage-associated molecular patterns DAMPs by Hypertension and immune system disorders pathogen recognition receptors PRRs such Hypertensino Toll-like receptors TLRs ststem, nucleotide-binding oligomerization domain NOD -like receptor NLR and retinoic acid—inducible gene I—like helicases nad 11 ].

NK cells are crucial component of the innate immune response via the recognition and differentiation of self-antigen versus non-self-antigen, which is important Hypertensjon the anti-tumor or anti-viral response which is mediated via NK cell—mediated cisorders [ 12 immune.

Use of anti-NK antibodies inhibiting the functions of NK cells has shown to be protective against vascular dysfunction on immnue studies kmmune 13 ]. Dendritic cells Hypertensiom been proposed as disorder source of DAMPs in systfm following the studies demonstrating the formation of ROS such as highly reactive gamma-ketoaldehydes via NADPH oxidase [ 17 ].

The recognition of DAMPs or PAMPs sustem various TLRs lead to the activation of different downstream Hypretension pathways while major downstream pathways include interferon regulatory factor IRF -3, nuclear factor kappa light chain enhancer of activated B cells NF-κB or mitogen-activated protein kinase Disoredrs [ iimmune ].

A study in which peripheral monocytes have been obtained from 43 non-diabetic hypertensive patients and Hyperttension non-diabetic normotensive patients has Hypertenskon that Wrestling post-fight nutrition from hypertensive sustem have higher levels of TLR-4 mRNA while intensive anti-hypertensive treatment aystem in statistically significant decline in the levels of TLR-4 Hypretension TLR-2 messenger RNA mRNA [ 19 ].

Moreover, mouse models genetically modified to lack Hypertension and immune system disorders TLR-4 gene have been shown to demonstrate attenuated blood pressure elevation in response wystem either angiotensin II or NG-nitro-l-arginine methyl ester L-NAME; slimming strategies inhibitor of diskrders oxide dksorders, infusions [ 2021 ].

Hypertension and immune system disorders, recent studies have demonstrated that inhibition of TLR-9 has been linked to decline in angiotensin Hyperttension hypertension [ 25 im,une, 26 ]. The most commonly investigated NLR in the context of hypertension is NLRP3, whose disorvers has been Kiwi fruit snack ideas to both Speed and agility training and diastolic hypertension [ 28 ].

NLRP3 knockout mouse models have not developed systdm in response to two kidneys—one clip 2K1C or DOCA-salt treatment environments [ 29 syste. Despite rarely being studied, other subtypes of NLRs have been associated with systeem pressure alterations immunw as NOD1-associated hypotension, and decline in vasoconstriction sysfem response to contractile stimuli and NOD2-associated hypertension [ 3031 ].

The sywtem importance of such studies is the identification of multiple TLRs and NLRs as potential therapeutic targets Hypertensioh clinical arterial hypertension. Furthermore, the gut microbiota is known to regulate the host's Hyperension, cell Hypertnsion and metabolism, and to play a role in different Hypretension and kidney dislrders [ 15163233 ].

The gut anv was shown to modulate blood pressure via Hypertension and immune system disorders fatty acids [ 34 ]. A study conducted in total of participants, including 41 Hypertejsion controls, Hypertensino individuals with pre-hypertension and 99 individuals with Hypertension and immune system disorders hypertension, showed that Hypertesnion transplantation from hypertensive patients to germ-free mice increased nad pressure [ 35 wystem.

Thus, gut microbiota dysbiosis can increase blood pressure, and future studies are needed systej better understand this association. The innate immune system is a diverse network of Dislrders barriers, various cell types, and chemicals including chemokines, cytokines and complement Hypetension.

The dosorders of the innate immune system in the pathophysiology of hypertension is a relatively new area of research, with the identification of promising therapeutic targets.

Neutrophils are the most abundant white blood cell type in the circulation while macrophages are the most common type of immune cell in various tissue.

A study conducted in a mouse model demonstrated that monocytes and neutrophils are involved in the pathogenesis of angiotensin II—induced hypertension and endothelial dysfunction [ 36 ].

Selective ablation of lysozyme M—positive myelomonocytic cells via low-dose diphtheria toxin resulting in low circulating levels and low tissue infiltration attenuated angiotensin II—induced blood pressure elevation, formation of ROS and vascular smooth muscle cell dysfunction [ 36 ].

Another mouse model with functionally deficient osteopetrotic mice illustrates lower blood pressure measurements in response to angiotensin II infusion [ 37 ].

Moreover, hyperosmotic environment in response to either high salt intake or hyperglycemia leads to increased infiltration of renal interstitium via macrophages, conversion to pro-inflammatory phenotype and tissue damage due to the secretion of pro-inflammatory cytokines [ 3839 ].

Elevated levels of circulating monocytes have been demonstrated on multiple pre-clinical studies on angiotensin II or aldosterone-induced hypertension models [ 40—44 ]. A similar pattern has been observed in spontaneously hypertensive rats or models of salt-sensitive or deoxycorticosterone acetate—induced hypertension [ 45—50 ].

Only a few studies have been conducted in human subjects. According to a study in which peripheral monocytes were isolated from 22 hypertensive and 24 normotensive participants, monocytes from hypertensive individuals were shown to secrete higher levels of tumor necrosis factor-alpha TNF-α and interleukin-1 beta IL-1β in response to either stimulation by angiotensin II which may be attenuated via incubation with losartan and lipopolysaccharides [ 51 ].

Another study conducted in 76 hypertensive and normotensive male participants illustrated similar outcomes, while additionally monocytes derived from hypertensive individuals were found to be less susceptible to glucocorticoids [ 52 ].

A prospective clinical trial conducted in 42 patients with treatment-resistant hypertension demonstrated that renal denervation therapy leads to statistically significant decline in blood pressure during a 6-month follow-up period, along with a decline in monocyte activation and levels of pro-inflammatory cytokines such as TNF-α, IL, IL-1β and plasma monocyte chemoattractant protein-1 MCP-1 levels [ 53 ].

An observational study conducted in over initially normotensive participants with normal white blood cell count over a year follow-up period demonstrated that elevated neutrophil count is associated with hypertension risk after adjustment for multiple confounding factors [ 54 ]. Even though the elevated number of neutrophils and functional indicators such as myeloperoxidase activity have been recorded in animal models of hypertension, the causal link is missing since adoptive transfer of neutrophils fails to improve blood pressure measurements [ 365556 ].

Moreover, depletion of CD11c-positive dendritic cells via diphtheria toxin results in the prevention of hypertension in response to either high-salt diet or angiotensin II infusion [ 57 ]. The role of NK cells in hypertension is not well understood, with only a few pre-clinical studies investigating the association [ 5960 ].

Nevertheless, the data regarding the role of eosinophils and basophils in the pathogenesis of hypertension is limited. Even though observational studies have indicated a potential link between elevated peripheral eosinophil count and coronary artery disease or pulmonary artery hypertension, the exact relationship is yet to be demonstrated [ 6162 ].

Mouse models lacking eosinophils demonstrate higher mean arterial blood pressure and glucose intolerance, while such modifications are reversible with the reconstitution of eosinophils indicating the crucial role of eosinophils in the regulation of normal blood pressure [ 6364 ]. To the best of our knowledge, no pre-clinical or clinical study has yet evaluated the role of basophils in the pathogenesis of hypertension.

The adaptive immune system is a complex network of multiple cell types and chemicals including cytokines and complement proteins with varying degree of relationship with the innate immune system.

The pathophysiological role of the adaptive immune system in hypertension is a developing area of research. The role of T-lymphocytes in the pathogenesis of hypertension has been illustrated by mouse models of double-hit rag1 mutation leading to lack of both T- and B-lymphocytes in which infiltration of perivascular tissue by T-cells, expression of intercellular adhesion molecule ICAM -1, secretion of pro-inflammatory cytokines such as TNF-α and endothelial cell—dependent vasodilation are all suppressed in response to angiotensin II [ 65 ].

Moreover, adoptive transfer of T-cells leads to restoration of all of the mentioned functions while adoptive transfer of B-cells does not lead to any improvement [ 65 ].

Moreover, mutation of the exon 1 of rag1 gene in Dahl salt-sensitive rats led to decline in blood pressure elevations in response to a high-salt diet while pathological specimens demonstrate decline in renal infiltration by T-lymphocytes [ 66 ]. Nevertheless, multiple types of T-lymphocytes with distinct physiological functions are present in both animals and humans.

A similar finding has also been established in another mouse model study [ 68 ]. Another crucial T-cell type in the pathogenesis of arterial hypertension is the T-regulatory cells.

Adoptive transfer of T-cells from the Scurfy mouse model lacking T-regulatory cells due to mutation at the Foxp3 gene to the double-hit rag1 mouse model results in exaggerated hypertensive response to stimuli of angiotensin II, implicating the potential protective role of T-regulatory cells against hypertension [ 69 ].

Administration of T-regulatory cells as a single dose or once weekly dose leads to improvement in cardiac hypertrophy, endothelial vasodilatation, formation of ROS and pro-inflammatory signals without any improvement in blood pressure measurements while administration of T-regulatory cells at sustained high doses leads to improvements at blood pressure [ 70—72 ].

Furthermore, oxidative stress can modify self-antigens and cause them to behave as novel antigens referred to as neo-antigens. Neo-antigens activate T-cells and sensitize them against specific antigens which results in infiltration and inflammation in the vasculature and kidney.

Furthermore, elevated blood pressure can possibly generate neo-antigens by barotrauma [ 73 ]. The role of B-lymphocytes has largely been uninvestigated in hypertension research while early studies indicated a potential role in the pathogenesis and identified them as a potential therapeutic target via administration of anti-CD20 antibodies [ 74 ].

However, there is clear need for future studies investigating the role of B-lymphocytes in the pathogenesis of hypertension. A number of different cytokines are reported to be a factor in the pathophysiology of hypertension. IL-1β levels have been suggested to be elevated in patients with essential hypertension [ 7576 ].

IL-1 has been shown to contribute to the inflammatory and remodeling processes in the vasculature as well as to affect the functionality and phenotype of the vascular smooth muscle cell in hypertension [ 77 ].

The two IL-1 isoforms were reported to be highly expressed in the renal tissues in cases of hypertension caused by the increased activity of RAAS in murine models [ 4378 ]. IL-1 has also been reported to promote diuresis and natriuresis through prostaglandin generation in the kidney tissues [ 79—84 ].

A deficient or blocked IL-1 receptor was shown to restrict the rise in blood pressure by lessening the amount of reabsorbed sodium through the NKCC2 co-transporter in mice [ 78 ].

Additional studies in mouse models reported that inhibiting IL-1 lowered angiotensin II—related hypertension as well as kidney damage, showing a potential role of this blockade in the treatment of hypertension [ 85 ].

The role of IL-1 has also been investigated in humans. In a meta-analysis of cohort studies assessing the relationship between inflammatory markers and the development of hypertension, elevated C-reactive protein CRPinterleukin-6 IL-6 and high-sensitive CRP hs-CRP were significantly related with a risk of the development of hypertension [ 86 ].

However, IL-1β was not associated with a significant risk [ 86 ]. Furthermore, two clinical trials have evaluated the effects of IL-1 blockade on blood pressure.

In a secondary analysis of CANTOS Canakinumab Anti-inflammatory Thrombosis Outcomes StudyIL-1β, inhibited by canakinumab, decreased cardiac and vascular events; however, this was not linked to alterations in incident hypertension and blood pressure [ 8788 ].

In a separate trial, anakinra, an IL-1 receptor antagonist, resulted in the fall of blood pressure and peripheral vascular resistance in subjects with obesity and led to a rise in angiotensin- 1—7 levels, a molecule responsible for vasodilation [ 89 ].

IL-6 has also been thought to contribute to the pathophysiology of hypertension, with a number of studies reporting a correlation with IL-6 levels in the plasma and elevated blood pressure [ 90—93 ]. One study assessed the role of IL-6 when exposed prenatally on the development of hypertension; the authors suggested that IL-6 introduction before birth could result in hypertension via alterations in RAAS as well as fluid and electrolyte balance, particularly in female rats [ 94 ].

Furthermore, the vasculature is responsible for the release of IL-6 following angiotensin II exposure [ 95—99 ]. The prevention and attenuation of angiotensin II hypertension, to which IL-6 is thought be a contributor, has been shown to be possible by blocking IL-6 in wild-type mice or by IL-6 knockout mouse models [ 9095, ].

Similarly, IL-6 when inhibited by IL-6 neutralizing antibody was reported to mitigate hypertension and related injury to the kidneys in Dahl salt-sensitive rats [ 46 ]. The involvement of IL-6 in high blood pressure has also been studied in humans. One study suggested that IL-6 and TNF-α were potentially risk factors for an elevated blood pressure in healthy individuals [ ].

Furthermore, a hypomethylated IL-6 gene was associated with an elevated risk of hypertension and the variations in methylated promoter regions were related to alcohol consumption, gender and being a smoker [ ]. As previously mentioned, a meta-analysis showed a significant relationship between high IL-6 levels and hypertension development [ 86 ].

The use of anti-hypertensive drugs has also affected IL-6 levels. One study reported a fall in IL-6 and TNF-α levels after anti-hypertensive medications in elderly females [ ]. In a separate study, spironolactone led to a decrease in IL-6 and interferon-γ IFN-γ levels in subjects with diabetes and treatment-resistant hypertension [ ].

These findings suggest a link between IL-6 and hypertension; future studies are needed to better understand this association. A few studies have explored the role of interleukin-8 IL-8 in hypertension.

One study showed a higher calcium-dependent potassium efflux in hypertensive individuals, and IL-8 as well as ICAM-1 heightened this efflux in erythrocytes of individuals with hypertension in a significant manner [ ].

In a different study, elevated degrees of IL-8 and MCP-1 were shown in the vitreous of subjects with retinopathy due to diabetes and hypertension [ ]. Further studies are required to investigate the association between elevated blood pressure findings and IL Transforming growth factor-β TGF-β plays an important role in the homeostasis of the body, cellular growth, tolerance against self-tissues and differentiation [ — ].

An overexpression of the mRNA and protein of TGF-β1, the principle TGF-β isoform responsible for immune function and having mainly inhibitory roles, is observed in individuals with primary hypertension [ — ]. TGF-β1 generation may be explained by elevated blood pressure values in itself but also by a higher shear stress of fluids as well as by increased angiotensin II levels [ ].

: Hypertension and immune system disorders

The link between immunity and hypertension in the kidney and heart	The impact of vitamin D on Systwm immunopathophysiology, disease yHpertension, and extra-musculoskeletal manifestations of dissorders lupus erythematosus. Hypertenzion that high blood pressure reduced the number of Tregs Organic plant extracts with normotensive mice disordes that syystem is a disease with reduced Wrestling energy-boosting foods Hypertension and immune system disorders Tregs, we observed an increased number of Tregs in the kidney in models of accelerated hypertension Krebs et al. Inflammation, immunity, and hypertensive End-organ damage. Recently, Viel et al. About this article. Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
DNA and Caffeine	Responses to Ang II Angiotensin II , salt intake, and lipopolysaccharide reveal the diverse actions of TNF-alpha tumor necrosis factor-alpha on blood pressure and renal function. The authors concluded that ILproducing T cells are required for the development of sustained hypertension. Likewise, many experimental studies confirmed involvement of immune cells and inflammatory cytokines in vascular dysfunction associated with experimental hypertension. Astonishingly, from to , high SBP was consistently responsible for the largest number of all-cause deaths, followed by smoking and high FPG respectively [ 5 ]. Inflammatory pathway is composed of inflammation inducers, inflammation sensors, inflammation mediators, and inflammatory effectors [ 15 ].
Author Information	In fact, hypertension may even be autoimmune in itself. In this blog post, we will discuss the link between these two conditions and how our functional medicine approach can address them. T cells are a type of immune cell that helps the body fight infection. There are different types of T cells, including helper T cells and killer T cells. Helper T cells give instructions to other immune cells, and killer T cells kill infected or cancerous cells. Some T cells, called regulatory T cells or T-reg cells, help to keep the immune system in check. This can happen because of genetics, infections, exposure to certain chemicals or drugs, or hypertension. As a result, the immune system starts attacking healthy cells instead of fighting off infection. Autoimmunity can lead to a number of different diseases, including rheumatoid arthritis RA , lupus , and multiple sclerosis MS. T cells are a normal part of the immune system, but they can cause serious problems if they become overactive, as they do in autoimmune disease. T cells can cause high blood pressure, or hypertension. Hypertension is when the force of blood against the walls of blood vessels is too high. There is a bit of a vicious cycle because when hypertension damages the blood vessels, T cells are attracted to the area and cause inflammation. This can lead to further damage and make hypertension worse. Oxidative stress, which can be caused by T cells, is another factor that can contribute to hypertension. This happens when there are too many free radicals in the body. Free radicals are molecules that can damage cells, and they are naturally created by T cells but can be worsened by things like smoking, pollution, and UV radiation from the sun. When oxidative stress happens, it can damage the arteries and make hypertension worse. Read more about how dysregulated T cells cause oxidative stress here. The main source of ROS in neutrophils is NADPH oxidase 2 NOX2 ; however, mitochondrial ROS are likely a major source of tissue damage resulting from activation of the inflammasome and neutrophil extracellular trap NET formation [ ]. NETosis is a cell death pathway, similar to apoptosis, characterized by extrusion of chromatin bound to cytosolic and granular content, and is a normal host defense mechanism designed to trap and kill microorganisms. NETs and NETing neutrophils are found in the kidneys of patients with SLE, where they can be a source of nuclear antigens [ ]. Another study reported a correlation between renal involvement in SLE and impaired NET degradation that is associated with altered DNase1 function [ ]. Whether impaired degradation of NETs represents an important early signal for the development of autoantibodies that can promote hypertension, or directly increases oxidative stress in the renal vasculature and tubules to promote hypertension has not been addressed experimentally. Apoptosis and NETosis are both energy-consuming processes that require mitochondria as an energy source, and mitochondria are a major cellular source of intracellular ROS generation [ ]. Growing evidence suggests a role for mitochondrial dysfunction and the subsequent generation of ROS in diabetic nephropathy and chronic kidney disease [ ]; however, very little is understood about renal mitochondrial dysfunction during SLE and its potential role in the pathogenesis of hypertension. T cells from patients with SLE are reported to exhibit mitochondrial hyperpolarization, increased ROS production, diminished intracellular glutathione GSH levels, cytoplasmic alkalization, and adenosine triphosphate ATP depletion that causes diminished activation-induced apoptosis and sensitizes lupus T cells to necrosis [ ]. Given the role of T cell subset in SLE disease progression, and evidence pointing to a role for T cells in the development of hypertension, it will ultimately be important to understand the impact of mitochondrial dysfunction in these and other immune cells on physiological systems that ultimately control blood pressure. The management of high blood pressure in patients with autoimmune disease should be considered a major aspect of their treatment plan. In this review, we have provided an update on some of the disease-specific factors that contribute to the prevalent hypertension of autoimmunity. Recent studies from our laboratory have highlighted the important role of the adaptive immune system in the development of hypertension in an experimental mouse model of SLE. Future studies should explore the impact of immune cell infiltration in the kidney to promote changes in renal hemodynamics. Neutrophils, impaired NET degradation, and mitochondrial dysfunction may lead to the formation of auto-antigens and the production of ROS that could promote changes in glomerular filtration rate, renal vascular resistance, and renal blood flow, ultimately leading to hypertension, and an increased risk for cardiovascular and renal disease. Rees F, DohertyM,Grainge MJ, Lanyon P, ZhangW. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology Oxford. Carter EE, Barr SG, Clarke AE. The global burden of SLE: prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol. Article PubMed Google Scholar. 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Douma LG, Gumz ML. Circadian clock-mediated regulation of blood pressure. Norlander AE, Madhur MS, Harrison DG. The immunology of hypertension. J Exp Med. Crislip GR, Sullivan JC. T-cell involvement in sex differences in blood pressure control. Clin Sci London, England : Caillon A, Paradis P, Schiffrin EL. Role of immune cells in hypertension. Br J Pharmacol. Complete knockout of estrogen receptor alpha is not directly protective in murine lupus. Clin Immunol. The authors demonstrate that genetic knockout of estrogen receptor alpha does not protect against lupus development in mice, and that ovariectomy with estradiol repletion did not confer any protection. These data suggest that other ovarian hormones may confer protection. Ramirez LA, Sullivan JC. Sex differences in hypertension: where we have been and where we are going. Am J Hypertens. Gilbert EL, Mathis KW, Ryan MJ. Gilbert EL, Ryan MJ. Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus. Margiotta D, Navarini L, Vadacca M, Basta F, Lo Vullo M, Pignataro F, et al. Relationship between leptin and regulatory T cells in systemic lupus erythematosus: preliminary results. Eur Rev Med Pharmacol Sci. Abella V, Scotece M, Conde J, López V, Lazzaro V, Pino J, et al. Adipokines, metabolic syndrome and rheumatic diseases. J Immunol Res. Bravo PE, Morse S, Borne DM, Aguilar EA, Reisin E. Leptin and hypertension in obesity. Vasc Health Risk Manag. Tian G, Liang JN, Wang ZY, Zhou D. Emerging role of leptin in rheumatoid arthritis. Clin Exp Immunol. Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency. Increased leptin levels correlated with disease activity and were inversely correlated with the frequency of T REG cells in SLE patients but not in controls. Mathis KW, Wallace K, Flynn ER, Maric-Bilkan C, LaMarca B, Ryan MJ. Preventing autoimmunity protects against the development of hypertension and renal injury. Alshaiki F, Obaid E, Almuallim A, Taha R, El-Haddad H, Almoallim H. Outcomes of rituximab therapy in refractory lupus: a meta-analysis. Eur J Rheumatol. Karasawa K, Uchida K, Takabe T, Moriyama T, Nitta K. Recent advances in treatment strategies for lupus nephritis. Department of Immunobiology, Yale University, New Haven, Connecticut, USA. Address correspondence to: Jordan S. Pober, 10 Amistad Street, Yale University School of Medicine, New Haven, Connecticut , USA. Phone: pober yale. Find articles by Pober, J. in: JCI PubMed Google Scholar. Published September 17, - More info. Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell DC activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes isoketals are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL and an increase in costimulatory proteins CD80 and CD Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease. Annet Kirabo, Vanessa Fontana, Ana P. de Faria, Roxana Loperena, Cristi L. Galindo, Jing Wu, Alfiya T. Bikineyeva, Sergey Dikalov, Liang Xiao, Wei Chen, Mohamed A. Saleh, Daniel W. Trott, Hana A. Itani, Antony Vinh, Venkataraman Amarnath, Kalyani Amarnath, Tomasz J. Guzik, Kenneth E. Bernstein, Xiao Z. Shen, Yu Shyr, Sheau-chiann Chen, Raymond L. Mernaugh, Cheryl L. Laffer, Fernando Elijovich, Sean S. Davies, Heitor Moreno, Meena S. Madhur, Jackson Roberts II, David G. T cells are required for significant blood pressure elevation in mouse models of hypertension. Recent evidence suggests that the treatments that raise blood pressure in these animal models also cause oxidation within DCs, resulting in formation of isoketal adducts of self-proteins, which activate antigen-presenting functions of these cells and serve as a source of modified self-antigens. T cells specific for these modified self-antigens then produce cytokines that promote blood pressure elevation, consistent with the idea that hypertension is an autoimmune response to altered self. Here, I will review the new evidence for this idea put forth by Kirabo and colleagues in this issue of the JCI , identify a number of as yet unanswered questions, and discuss some of the therapeutic implications. Therapies based on new pathogenetic insights into the development of hypertension could have significant clinical value. One possibility is that hypertension is a form of autoimmunity 3. David Harrison and coworkers first showed in an unanticipated role for T cells in two common models of hypertension in mice 4. Specifically, treatment either with angiotensin II or with deoxycorticosterone acetate plus NaCl DOCA-salt barely elevated blood pressure in RAG1-deficient mice, which lack T and B lymphocytes compared with WT mice; however, adoptive transfer of syngeneic T cells in RAG1-deficient animals restored treatment-induced blood pressure elevation. The initial Harrison study linked increased blood pressure to T cell production of TNF-α, and subsequent work revealed that T cell—derived ILA is also required to sustain hypertension in animals 5. ILA targets vascular smooth muscle cells 5 — 7 , but it is not clear whether this results in hypertension. ILA—mediated injury to the kidney is an alternative mechanism for the development of hypertension. Angiotensin II can increase cytokine production by T cells but only when the T cells are first activated by cross-linking the T cell receptor TCR for antigen with anti-CD3 monoclonal antibody 4 , a widely used experimental surrogate for antigen recognition. If T cells are actually activated by recognition of a specific antigen in hypertensive animals, what might this antigen be?

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Inflammatory Tales in Cardiovascular Medicine (Joseph A. Hill, MD)