Metabolic Glutamine and tissue repair Autoimmune Hypertension and immune system disorders like SLE didorders commonly associated with metabolic changes aystem insulin resistance and dyslipidemia [ 55 ]. In sytsem to these established pathophysiological mechanisms, recent studies have shown a potential relationship between immune system dysfunction and high blood pressure, therefore suggesting an important role of aberrant immune function and autoimmunity in the etiopathogenesis of hypertension [ 9 ]. x CrossRef Full Text Google Scholar. Benson LN, Liu Y, Deck KS, Mora C, Mu S. Lawes CMVander Hoorn SRodgers A.

Hypertension and immune system disorders -

Asagami T , Reaven GM , Tsao PS. Enhanced monocyte adherence to thoracic aortae from rats with two forms of experimental hypertension. Am J Hypertens ; 12 : — 3.

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Leukocyte counts and activation in spontaneously hypertensive and normotensive rats. Hypertension ; 17 : — Dörffel Y , Lätsch C , Stuhlmüller B et al. Preactivated peripheral blood monocytes in patients with essential hypertension.

Hypertension ; 34 : — 7. Wirtz PH , von Känel R , Frey K et al. Glucocorticoid sensitivity of circulating monocytes in essential hypertension.

Am J Hypertens ; 17 : — Zaldivia MT , Rivera J , Hering D et al. Renal denervation reduces monocyte activation and monocyte-platelet aggregate formation: an anti-inflammatory effect relevant for cardiovascular risk.

Hypertension ; 69 : — Tatsukawa Y , Hsu WL , Yamada M et al. White blood cell count, especially neutrophil count, as a predictor of hypertension in a Japanese population. Hypertens Res ; 31 : — 7. Lu X , Rudemiller NP , Privratsky JR et al. Classical dendritic cells mediate hypertension by promoting renal oxidative stress and fluid retention.

Hypertension ; 75 : — 8. Zhang R , Inagawa H , Kazumura K et al. Evaluation of a hypertensive rat model using peripheral blood neutrophil activity, phagocytic activity and oxidized LDL evaluation.

Anticancer Res ; 38 : — Hevia D , Araos P , Prado C et al. Hypertension ; 71 : — Van Beusecum JP , Barbaro NR , McDowell Z et al. Hypertension ; 74 : — Angiotensin II—induced vascular dysfunction depends on interferon-γ—driven immune cell recruitment and mutual activation of monocytes and NK-cells.

Taherzadeh Z , VanBavel E , de Vos J et al. Strain-dependent susceptibility for hypertension in mice resides in the natural killer gene complex. Am J Physiol Heart Circ Physiol ; : H — Weng M , Baron DM , Bloch KD et al. Eosinophils are necessary for pulmonary arterial remodeling in a mouse model of eosinophilic inflammation-induced pulmonary hypertension.

Am J Physiol Lung Cell Mol Physiol ; : L — Tanaka M , Fukui M , Tomiyasu K et al. Eosinophil count is positively correlated with coronary artery calcification. Hypertens Res ; 35 : — 8. Withers SB , Forman R , Meza-Perez S et al. Eosinophils are key regulators of perivascular adipose tissue and vascular functionality.

Wu D , Molofsky AB , Liang HE et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.

Science ; : — 7. Guzik TJ , Hoch NE , Brown KA et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med ; : — Mattson DL , Lund H , Guo C et al. Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage.

Am J Physiol Regul Integr Comp Physiol ; : R — Crowley SD , Song YS , Lin EE et al. Lymphocyte responses exacerbate angiotensin II-dependent hypertension.

Trott DW , Thabet SR , Kirabo A et al. Hypertension ; 64 : — Mian MO , Barhoumi T , Briet M et al. Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses.

J Hypertens ; 34 : 97 — Matrougui K , Abd Elmageed Z , Kassan M et al. Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice. Am J Pathol ; : — Kvakan H , Kleinewietfeld M , Qadri F et al.

Regulatory T cells ameliorate angiotensin II-induced cardiac damage. Kasal DA , Barhoumi T , Li MW et al. T regulatory lymphocytes prevent aldosterone-induced vascular injury. Hypertension ; 59 : — Trott DW , Harrison DG. The immune system in hypertension. Adv Physiol Educ ; 38 : 20 — 4. Chan CT , Sobey CG , Lieu M et al.

Obligatory role for B cells in the development of Angiotensin II-dependent hypertension. Hypertension ; 66 : — Dalekos GN , Elisaf MS , Papagalanis N et al. Elevated interleukin-1 beta in the circulation of patients with essential hypertension before any drug therapy: a pilot study.

Eur J Clin Invest ; 26 : — 9. Dalekos GN , Elisaf M , Bairaktari E et al. Increased serum levels of interleukin-1beta in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients?

J Lab Clin Med ; : — 8. Melton E , Qiu H. Interleukin-1β in multifactorial hypertension: inflammation, vascular smooth muscle cell and extracellular matrix remodeling, and non-coding RNA regulation.

Int J Mol Sci ; 22 : Zhang J , Rudemiller NP , Patel MB et al. Interleukin-1 receptor activation potentiates salt reabsorption in Angiotensin II-induced hypertension via the NKCC2 co-transporter in the nephron.

Cell Metab ; 23 : — 8. Crorkin P , Hao S , Ferreri NR. 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.

Hypertension ; 79 : — Beasley D , Dinarello CA , Cannon JG. Interleukin-1 induces natriuresis in conscious rats: role of renal prostaglandins. Kidney Int ; 33 : — Kohan DE , Schreiner GF.

Interleukin 1 modulation of renal epithelial glucose and amino acid transport. Am J Physiol ; : F — Boesen EI. Chronic elevation of IL-1beta induces diuresis via a cyclooxygenase 2-mediated mechanism.

Am J Physiol Renal Physiol ; : F — Kohan DE , Merli CA , Simon EE. Micropuncture localization of the natriuretic effect of interleukin 1. Kohan DE. Interleukin-1 regulation of prostaglandin E2 synthesis by the papillary collecting duct. J Lab Clin Med ; : — Akita K , Isoda K , Ohtomo F et al.

Blocking of interleukin-1 suppresses angiotensin II-induced renal injury. Jayedi A , Rahimi K , Bautista LE et al. Inflammation markers and risk of developing hypertension: a meta-analysis of cohort studies. Heart ; : — Rothman AM , MacFadyen J , Thuren T et al.

Effects of interleukin-1beta inhibition on blood pressure, incident hypertension, and residual inflammatory risk: a secondary analysis of CANTOS.

Hypertension ; 75 : — Ridker PM , Everett BM , Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med ; : — Urwyler SA , Ebrahimi F , Burkard T et al. IL interleukin -1 receptor antagonist increases Ang Angiotensin [] and decreases blood pressure in obese individuals.

Lee DL , Sturgis LC , Labazi H et al. Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Chae CU , Lee RT , Rifai N et al. Blood pressure and inflammation in apparently healthy men.

Hypertension ; 38 : — Ridker PM , Rifai N , Stampfer MJ et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.

Chamarthi B , Williams GH , Ricchiuti V et al. Inflammation and hypertension: the interplay of interleukin-6, dietary sodium, and the renin-angiotensin system in humans. Am J Hypertens ; 24 : — 8. Samuelsson AM , Alexanderson C , Molne J et al.

Prenatal exposure to interleukin-6 results in hypertension and alterations in the renin-angiotensin system of the rat.

J Physiol ; : — Brands MW , Banes-Berceli AK , Inscho EW et al. Hypertension ; 56 : — Kranzhofer R , Schmidt J , Pfeiffer CA et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol ; 19 : — 9. Funakoshi Y , Ichiki T , Ito K et al.

Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells. Hypertension ; 34 : — Han Y , Runge MS , Brasier AR. Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors.

Circ Res ; 84 : — Moriyama T , Fujibayashi M , Fujiwara Y et al. Angiotensin II stimulates interleukin-6 release from cultured mouse mesangial cells. J Am Soc Nephrol ; 6 : 95 — Lee DL , Leite R , Fleming C et al. Hypertensive response to acute stress is attenuated in interleukin-6 knockout mice.

Hypertension ; 44 : — Coles B , Fielding CA , Rose-John S et al. Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo.

Bautista LE , Vera LM , Arenas IA et al. Independent association between inflammatory markers C-reactive protein, interleukin-6, and TNF-alpha and essential hypertension. J Hum Hypertens ; 19 : — Hypomethylation of interleukin-6 IL-6 gene increases the risk of essential hypertension: a matched case-control study.

J Hum Hypertens ; 31 : — 6. Toledo JO , Moraes CF , Souza VC et al. Tailored antihypertensive drug therapy prescribed to older women attenuates circulating levels of interleukin-6 and tumor necrosis factor-α.

Clin Interv Aging ; 10 : — Thangaraj SS , Oxlund CS , Fonseca MPD et al. The mineralocorticoid receptor blocker spironolactone lowers plasma interferon-gamma and interleukin-6 in patients with type 2 diabetes and treatment-resistant hypertension.

J Hypertens ; 40 : — Buemi M , Marino D , Floccari F et al. Curr Med Res Opin ; 20 : 19 — Wakabayashi Y , Usui Y , Okunuki Y et al. Increases of vitreous monocyte chemotactic protein 1 and interleukin 8 levels in patients with concurrent hypertension and diabetic retinopathy.

Retina ; 31 : — 7. Letterio JJ , Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol ; 16 : — Li MO , Flavell RA. TGF-beta: a master of all T cell trades. Cell ; : — Kim HS , Kim HY.

Hypertensive effects of transforming growth factor-beta1 in vascular smooth muscles cells from spontaneously hypertensive rats are mediated by sulfatase 2. Cytokine ; : Zhang Q , Liu H , Yang J. Regulation of TGF-beta1 on PI3KC3 and its role in hypertension-induced vascular injuries.

Exp Ther Med ; 17 : — Biomed Pharmacother ; : 64 — Laviades C , Varo N , Diez J. Transforming growth factor beta in hypertensives with cardiorenal damage. Hypertension ; 36 : — Li B , Khanna A , Sharma V et al. TGF-beta1 DNA polymorphisms, protein levels, and blood pressure.

Hypertension ; 33 : — 5. Lijnen PJ , Petrov VV , Fagard RH. Association between transforming growth factor-beta and hypertension.

Am J Hypertens ; 16 : — Wolf G. Link between angiotensin II and TGF-beta in the kidney. Miner Electrolyte Metab ; 24 : — Nephrol Dial Transplant ; 23 : — 6. Houlihan CA , Akdeniz A , Tsalamandris C et al.

Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate: effects of angiotensin receptor blockade and sodium restriction. Diabetes Care ; 25 : — 7. Praga M , Andrade CF , Luno J et al.

Antiproteinuric efficacy of losartan in comparison with amlodipine in non-diabetic proteinuric renal diseases: a double-blind, randomized clinical trial.

Nephrol Dial Transplant ; 18 : — Ramseyer VD , Garvin JL. Tumor necrosis factor-alpha: regulation of renal function and blood pressure. Kobayashi R , Wakui H , Azushima K et al.

An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model. Kidney Int ; 91 : — Elmarakby AA , Quigley JE , Imig JD et al.

TNF-alpha inhibition reduces renal injury in DOCA-salt hypertensive rats. Am J Physiol Regul Integr Comp Physiol ; : R76 — Verma MK , Jaiswal A , Sharma P et al. Oxidative stress and biomarker of TNF-alpha, MDA and FRAP in hypertension.

JMedLife ; 12 : — 9. Puszkarska A , Niklas A , Gluszek J et al. The concentration of tumor necrosis factor in the blood serum and in the urine and selected early organ damages in patients with primary systemic arterial hypertension.

Medicine Baltimore ; 98 : e Naya M , Tsukamoto T , Morita K et al. Plasma interleukin-6 and tumor necrosis factor-alpha can predict coronary endothelial dysfunction in hypertensive patients. Hypertens Res ; 30 : — 8.

Yoshida S , Takeuchi T , Kotani T et al. Infliximab, a TNF-alpha inhibitor, reduces h ambulatory blood pressure in rheumatoid arthritis patients. J Hum Hypertens ; 28 : — 9. Zhao Q , Hong D , Zhang Y et al.

Association between anti-TNF therapy for rheumatoid arthritis and hypertension: a meta-analysis of randomized controlled trials. Medicine Baltimore ; 94 : e Lamb FS , Choi H , Miller MR et al. TNFalpha and reactive oxygen signaling in vascular smooth muscle cells in hypertension and atherosclerosis.

Am J Hypertens ; 33 : — Ma Y , He FJ , MacGregor GA. High salt intake: independent risk factor for obesity? Hypertension ; 66 : — 9. Afsar B , Kuwabara M , Ortiz A et al. Salt intake and immunity. Hypertension ; 72 : 19 — Rucker AJ , Rudemiller NP , Crowley SD.

Salt, hypertension, and immunity. Annu Rev Physiol ; 80 : — Takahashi H , Nakagawa S , Wu Y et al. A high-salt diet enhances leukocyte adhesion in association with kidney injury in young Dahl salt-sensitive rats. Hypertens Res ; 40 : — Dmitrieva NI , Burg MB. Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis.

Proc Natl Acad Sci USA ; : — Krieglstein CF , Granger DN. Adhesion molecules and their role in vascular disease.

Am J Hypertens ; 14 : S44 — Evans LC , Petrova G , Kurth T et al. Increased perfusion pressure drives renal T-cell infiltration in the Dahl salt-sensitive rat.

Hypertension ; 70 : — Hashmat S , Rudemiller N , Lund H et al. Interleukin-6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats. Norlander AE , Saleh MA , Pandey AK et al.

A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage. JCI Insight ; 2 : e Norlander AE , Saleh MA , Kamat NV et al. InterleukinA regulates renal sodium transporters and renal injury in angiotensin II-induced hypertension.

Hypertension ; 68 : — Junger WG , Hoyt DB , Hamreus M et al. Hypertonic saline activates protein tyrosine kinases and mitogen-activated protein kinase p38 in T-cells.

J Trauma ; 42 : — 45 ; discussion —5. Hernandez AL , Kitz A , Wu C et al. Zhang WC , Zheng XJ , Du LJ et al. High salt primes a specific activation state of macrophages, M Na.

Cell Res ; 25 : — Barbaro NR , Foss JD , Kryshtal DO et al. Dendritic cell amiloride-sensitive channels mediate sodium-induced inflammation and hypertension. Cell Rep ; 21 : — Guyton AC , Coleman TG , Cowley AV et al. Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension.

Rodríguez-Iturbe B , Quiroz Y , Ferrebuz A et al. Evolution of renal interstitial inflammation and NF-kappaB activation in spontaneously hypertensive rats. Am J Nephrol ; 24 : — Rodríguez-Iturbe B , Quiroz Y , Nava M et al.

Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats. Franco M , Martínez F , Quiroz Y et al.

Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension. Am J Physiol Regul Integr Comp Physiol ; : R — 6. Franco M , Tapia E , Bautista R et al.

Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney. Johnson RJ , Schreiner GF.

Hypothesis: the role of acquired tubulointerstitial disease in the pathogenesis of salt-dependent hypertension.

Kidney Int ; 52 : — Asghar M , Chugh G , Lokhandwala MF. Inflammation compromises renal dopamine D1 receptor function in rats. Am J Physiol Renal Physiol ; : F — 9. Gonzalez-Villalobos RA , Janjoulia T , Fletcher NK et al.

The absence of intrarenal ACE protects against hypertension. Giani JF , Bernstein KE , Janjulia T et al. Salt sensitivity in response to renal injury requires renal angiotensin-converting enzyme. Zhang RM , McNerney KP , Riek AE et al.

Immunity and hypertension. Acta Physiol ; : e Lima VV , Zemse SM , Chiao CW et al. Giannelou M , Mavragani CP. Cardiovascular disease in systemic lupus erythematosus: a comprehensive update. J Autoimmun ; 82 : 1 — Panoulas VF , Douglas KM , Milionis HJ et al.

Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology Oxford ; 46 : — Neimann AL , Shin DB , Wang X et al. Prevalence of cardiovascular risk factors in patients with psoriasis.

J Am Acad Dermatol ; 55 : — Both PAMPs and DAMPs function to localize DC activation to sites of infection or tissue injury, at which DCs acquire antigens prior to migrating to secondary lymphoid organs, in which the antigen is presented to naive T cells that express a relevant TCR.

Antigen-activated T cells proliferate, producing a clone of daughter cells specific for the relevant antigen, and these differentiate into effector cells of various types. While there are very few naive T cells that can recognize a particular antigen, proliferation creates many effector cells that can do so.

If the eliciting antigen is eliminated, most effector cells die off, but some become long-lived memory cells that can rapidly redifferentiate into new effector cells if the same antigen reappears, such as occurs during reinfection or in response to primary infection following vaccination.

This expanded pool of memory T cells is the basis of immunological memory This background provides context for the current findings of Kirabo and colleagues. First, infusion of angiotensin II or DOCA-salt to produce hypertension generated ROS in DCs through phagocyte oxidase.

Importantly, it is the mediators of hypertension, not hypertension per se, that stimulates ROS production, as normalizing blood pressure with hydralazine did not prevent ROS formation. Second, ROS in DCs caused lipid oxidation, resulting in formation of isoketal adducts of various self-proteins.

These isoketal-modified proteins were detectable by immunostaining, and the specific scavenger 2-hydroxybenzylamine prevented their formation.

Third, isoketal-modified proteins behaved like DAMPs, activating DCs to upregulate MHC molecules, costimulators CD80 and CD86, and cytokines IL-1, IL-6, and IL, all of which was preventable by 2-hydroxybenzylamine. It should be noted that Kirabo and colleagues found that isoketal adducts unexpectedly reduce rather than activate the ability of DCs to present a model antigen, an unexplained observation.

Fourth, DCs pulsed with isoketal-modified self-proteins were able to activate in vitro proliferation and cytokine production of memory T cells from hypertensive but not control animals.

Finally, transfer of isoketal-activated DCs raised blood pressure in WT animals that have T cells but not in those lacking them. Cumulatively, the findings of Kirabo and colleagues 8 suggest that peptides derived from isoketal adducts of proteins behave as modified self-antigens, activating naive T cells to become ILA—producing effector cells.

Thus, hypertension, like RA, may be an autoimmune disease to modified self. While the report by Kirabo et al. greatly advances the understanding of how hypertension-inducing stimuli may activate T cells to produce ILA, several questions remain unanswered. First, what type s of DCs are relevant for initiating this T cell response?

This issue is complicated, as monocytes, macrophages, and DCs are heterogeneous and plastic, and their relationship to each other is disputed Still, this question could be addressed by separation of activated DCs prior to adoptive transfer.

Second, which DC receptors recognize isoketal adducts as DAMPs? Most if not all of the relevant receptors for PAMPs and DAMPs are known, and mice are available in which these receptors and their adaptor molecules have been knocked out; therefore, this question should be readily addressable. Third, what is the actual antigen recognized by the activated T cells?

Not all citrullinated peptides activate T cells of patients with RA. Fourth, do these observations in mouse models apply to hypertensive humans?

Kirabo et al. found that circulating myeloid cells in hypertensive individuals both controlled and uncontrolled have measurable levels of isoketal protein adducts, which are not present in normotensive individuals.

Fifth, are these myeloid cells activated to present antigens, and do hypertensive individuals have circulating memory T cells that are responsive to isoketal-modified proteins or peptides? Finally, if human hypertension is an autoimmune disease, is there a link to a specific MHC allele?

Remarkably, although the MHC was not identified in initial GWAS of hypertension, the most recent GWAS report noted an association between hypertension and the HLA-DQB1 allele; however, this must be independently validated Future studies should be able to test the hypothesis that antigen-presenting cells expressing HLA-DQB1 may be especially effective at presenting isoketal peptide adducts to T cells that share this allele.

The most important implications of the study by Kirabo and colleagues relate to the possibility of potential therapies for hypertension. If the isoketal-stimulated adaptive immune response contributes to human hypertension, could targeting this pathway reduce the blood pressure of patients refractory to current antihypertensive drug therapies?

Antioxidants have failed to provide clinical benefit in heart disease 17 , but this may reflect the fact that ROS mediate both beneficial and pathological effects. The mouse data presented by Kirabo et al. suggest that a specific scavenger of isoketals could be protective without interfering with beneficial ROS functions.

While global immunosuppression may be far too high a price to pay for reducing blood pressure, observational studies of blood pressure in patients on immunosuppression therapy for other reasons may be highly informative. Specific ILA or IL receptor blockades with monoclonal antibodies have shown positive effects in clinical trials for psoriasis Some of these patients were undoubtedly hypertensive, and the effects of inhibition of ILA and IL on blood pressure could be examined.

Interestingly, high dietary salt intake, which increases sodium ion concentration in the interstitium of the secondary lymphoid organs without increasing plasma concentration, favors the differentiation of autoreactive ILA—producing T cells Thus, salt restriction, already recommended for hypertensive patients for hemodynamic effects, may also be an effective immunomodulatory strategy.

Finally, tolerogenic therapies for autoimmunity 20 , such as stimulating regulatory T cells with self-antigen plus low-dose IL-2, appear to be on the horizon. Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux J, Hupperts R. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis.

PLoS One ; 4 : e Burgaz A, Byberg L, Rautiainen S, Orsini N, Håkansson N, Arnlöv J, Sundström J, Lind L, Melhus H, Michaëlsson K, Wolk A. Confirmed hypertension and plasma 25 OH D concentrations amongst elderly men. J Intern Med ; : — Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM.

Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med ; : — Download references. Department of Internal Medicine, Division of Clinical and Experimental Immunology, Maastricht University Medical Center, PO box , Maastricht, , MD, The Netherlands. You can also search for this author in PubMed Google Scholar.

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References Stumpf C, Auer C, Yilmaz A, Lewczuk P, Klinghammer L, Schneider M, Daniel WG, Schmieder RE, Garlichs CD. Article CAS Google Scholar Blake GJ, Rifai N, Buring JE, Ridker PM. Article CAS Google Scholar Svendsen UG. CAS Google Scholar Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG.

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Article CAS Google Scholar Shao J, Nangaku M, Miyata T, Inagi R, Yamada K, Kurokawa K, Fujita T. Article CAS Google Scholar Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Romagnani P, Ghiadoni L, Serio M, Taddei S, Ferrannini E. Article CAS Google Scholar Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, Baggiolini M, Moser B.

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Article CAS Google Scholar Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux J, Hupperts R. Article Google Scholar Burgaz A, Byberg L, Rautiainen S, Orsini N, Håkansson N, Arnlöv J, Sundström J, Lind L, Melhus H, Michaëlsson K, Wolk A. Article CAS Google Scholar Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM.

Article Google Scholar Download references. Author information Authors and Affiliations Department of Internal Medicine, Division of Clinical and Experimental Immunology, Maastricht University Medical Center, PO box , Maastricht, , MD, The Netherlands Jan Willem Cohen Tervaert Authors Jan Willem Cohen Tervaert View author publications.

Thank you for visiting iimmune. You are using a browser version with syshem support for CSS. To obtain the Hypertension and immune system disorders Cellulite reduction diet, stress reduction methods for parents recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. In the current issue of Hypertension ResearchStumpf et al. After diworders a heart attack, people with autoimmune disease disorderw more Hypertenson than others to die disprders experience further serious heart problems, including a second heart attack, new research finds. Hypeetension study, published Wednesday Diabetic neuropathy and pregnancy the Journal of the American Heart Associationstress reduction methods for parents fill Noninvasive glucose monitoring gap in what's known about the long-term cardiovascular health of people with autoimmune diseases such as rheumatoid arthritis, psoriasis and lupus, researchers say. Amgad Mentias said in a news release. He is an assistant professor of medicine at the Cleveland Clinic Lerner College of Medicine in Ohio. have an autoimmune disease, in which the immune system attacks the body's own organs, tissues and cells. The study used data for people 65 and older from a government database of all inpatient Medicare hospital bills in the U. The researchers matched records for 59, heart attack patients who had inflammation-causing autoimmune disorders with records ofheart attack patients without the autoimmune conditions.

Hypertension and immune system disorders -

This recognition of modified self can result in rheumatoid arthritis RA 10 , explaining why there is a much stronger risk for developing RA in individuals who have inherited an HLA-DR4 allele. In general, a link to specific MHC alleles is a common feature of autoimmunity To initiate a T cell response, naive T cells must receive three distinct signals: specific antigen the peptide bound to the MHC molecule that is recognized by its TCR ; one or more antigen-independent boosters costimulators of T cell responses such as CD80 or CD86, which engage CD28 on the T cell ; and secreted cytokines that promote T cell expansion and differentiation Specialized antigen-presenting cells, known as DCs, provide all three signals, but DCs must first be activated in order to elicit a response from naive T cells DC-activating signals include molecules expressed by microbes, such as pathogen-associated molecular patterns PAMPs , or molecules released from injured cells, known as damage-associated molecular patterns DAMPs.

Both PAMPs and DAMPs function to localize DC activation to sites of infection or tissue injury, at which DCs acquire antigens prior to migrating to secondary lymphoid organs, in which the antigen is presented to naive T cells that express a relevant TCR. Antigen-activated T cells proliferate, producing a clone of daughter cells specific for the relevant antigen, and these differentiate into effector cells of various types.

While there are very few naive T cells that can recognize a particular antigen, proliferation creates many effector cells that can do so. If the eliciting antigen is eliminated, most effector cells die off, but some become long-lived memory cells that can rapidly redifferentiate into new effector cells if the same antigen reappears, such as occurs during reinfection or in response to primary infection following vaccination.

This expanded pool of memory T cells is the basis of immunological memory This background provides context for the current findings of Kirabo and colleagues.

First, infusion of angiotensin II or DOCA-salt to produce hypertension generated ROS in DCs through phagocyte oxidase. Importantly, it is the mediators of hypertension, not hypertension per se, that stimulates ROS production, as normalizing blood pressure with hydralazine did not prevent ROS formation.

Second, ROS in DCs caused lipid oxidation, resulting in formation of isoketal adducts of various self-proteins. These isoketal-modified proteins were detectable by immunostaining, and the specific scavenger 2-hydroxybenzylamine prevented their formation. Third, isoketal-modified proteins behaved like DAMPs, activating DCs to upregulate MHC molecules, costimulators CD80 and CD86, and cytokines IL-1, IL-6, and IL, all of which was preventable by 2-hydroxybenzylamine.

It should be noted that Kirabo and colleagues found that isoketal adducts unexpectedly reduce rather than activate the ability of DCs to present a model antigen, an unexplained observation.

Fourth, DCs pulsed with isoketal-modified self-proteins were able to activate in vitro proliferation and cytokine production of memory T cells from hypertensive but not control animals. Finally, transfer of isoketal-activated DCs raised blood pressure in WT animals that have T cells but not in those lacking them.

Cumulatively, the findings of Kirabo and colleagues 8 suggest that peptides derived from isoketal adducts of proteins behave as modified self-antigens, activating naive T cells to become ILA—producing effector cells.

Thus, hypertension, like RA, may be an autoimmune disease to modified self. While the report by Kirabo et al. greatly advances the understanding of how hypertension-inducing stimuli may activate T cells to produce ILA, several questions remain unanswered.

First, what type s of DCs are relevant for initiating this T cell response? This issue is complicated, as monocytes, macrophages, and DCs are heterogeneous and plastic, and their relationship to each other is disputed Still, this question could be addressed by separation of activated DCs prior to adoptive transfer.

Second, which DC receptors recognize isoketal adducts as DAMPs? Most if not all of the relevant receptors for PAMPs and DAMPs are known, and mice are available in which these receptors and their adaptor molecules have been knocked out; therefore, this question should be readily addressable.

Third, what is the actual antigen recognized by the activated T cells? Not all citrullinated peptides activate T cells of patients with RA. Fourth, do these observations in mouse models apply to hypertensive humans?

Kirabo et al. found that circulating myeloid cells in hypertensive individuals both controlled and uncontrolled have measurable levels of isoketal protein adducts, which are not present in normotensive individuals. Fifth, are these myeloid cells activated to present antigens, and do hypertensive individuals have circulating memory T cells that are responsive to isoketal-modified proteins or peptides?

Finally, if human hypertension is an autoimmune disease, is there a link to a specific MHC allele? Remarkably, although the MHC was not identified in initial GWAS of hypertension, the most recent GWAS report noted an association between hypertension and the HLA-DQB1 allele; however, this must be independently validated Future studies should be able to test the hypothesis that antigen-presenting cells expressing HLA-DQB1 may be especially effective at presenting isoketal peptide adducts to T cells that share this allele.

The most important implications of the study by Kirabo and colleagues relate to the possibility of potential therapies for hypertension. If the isoketal-stimulated adaptive immune response contributes to human hypertension, could targeting this pathway reduce the blood pressure of patients refractory to current antihypertensive drug therapies?

Antioxidants have failed to provide clinical benefit in heart disease 17 , but this may reflect the fact that ROS mediate both beneficial and pathological effects. The mouse data presented by Kirabo et al. suggest that a specific scavenger of isoketals could be protective without interfering with beneficial ROS functions.

While global immunosuppression may be far too high a price to pay for reducing blood pressure, observational studies of blood pressure in patients on immunosuppression therapy for other reasons may be highly informative.

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Science ; : — Zhang W , Zhou Y , Ding Y. J Intern Med ; : — Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med ; : — Download references. Department of Internal Medicine, Division of Clinical and Experimental Immunology, Maastricht University Medical Center, PO box , Maastricht, , MD, The Netherlands.

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The contribution of Holistic healing cells in the initiation Hypertensiion maintenance of hypertension is undeniable. Several studies Hypertensioon established the association between hypertension, inflammation, and immune cells from Dissorders innate and i,mune immune systems. Here, we provide an update to disroders American Journal Noninvasive glucose monitoring Hypertension review stress reduction methods for parents the overview of the cellular immune responses involved in hypertension. Further, we discuss the activation of immune cells and their contribution to the pathogenesis of hypertension in different in vivo models. We also highlight existing gaps in the field of hypertension that need attention. The main goal of this review is to provide a knowledge base for translational research to develop therapeutic strategies that can improve cardiovascular health in humans. The immune system plays a fundamental role in the intricacies of the human body with varying responses dependent on daily attributions.