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      Peer Review of “Angiotensin Converting Enzyme 1 Expression in the Leukocytes of Adults Aged 64 to 67 Years”

      reviewer-report
      , MD 1
      JMIRx Med
      JMIR Publications
      aging, angiotensin converting enzyme, lymphocytes, immunosenescence, inflammaging

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          Abstract

          This is a peer-review report submitted for the paper “Angiotensin Converting Enzyme 1 Expression in the Leukocytes of Adults Aged 64 to 67 Years.” [1] Round 1 Review General Comments The paper is essentially anecdotal because it studies the cells of 6 subjects without any comparison with other age groups. There is also a serious limitation because beyond the age and sex, there is no information on the donors (how and why they were recruited, what drugs they took, etc). To infer that chronological and biological ages do not match is inappropriate in the absence of the above information. However, the paper is of some interest because there are few studies on the topic. Specific Comments Essential revisions that are required to verify the manuscript Although we do not have data on donors, placing an age and gender column in all tables adds a minimum of useful information for the reader. Inflammaging means low grade of inflammation. The CRP value of 23.1 suggests acute inflammation (also because albumin has high values, while in chronic inflammation its values decrease). Therefore the averages do not have to take this subject into account. Other suggestions to improve the manuscript The authors write that their findings suggest that ACE1 could play a role in several processes linked to aging including the generation and activation of autoimmune cells, due to the experimental evidence that inhibitors of ACE suppress the autoimmune process in a number of autoimmune diseases such as EAE, arthritis, autoimmune myocarditis [2]. They do not appear to have these findings in their paper. So, they need to change the sentence. Decision Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and major revisions are suggested. Decision Changed Verified manuscript: The content is scientifically sound, only minor amendments (if any) are suggested. Round 2 Review Decision Changed Verified manuscript: The content is scientifically sound, and only minor amendments (if any) are suggested.

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          Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity.

          The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-kappaB1 transcription factor complex and activation of the alternative NF-kappaB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.
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            Angiotensin Converting Enzyme 1 Expression in the Leukocytes of Adults Aged 64 to 67 Years

            The renin angiotensin system is composed of several enzymes and substrates on which angiotensin converting enzyme (ACE) 1 and renin act to produce angiotensin II. ACE1 and its substrates control blood pressure, affect cardiovascular and renal function, hematopoiesis, reproduction, and immunity. The increased expression of ACE1 has been observed in human monocytes during congestive heart failure and abdominal aortic aneurysm. Moreover, T lymphocytes from individuals with hypertension presented increased expression of ACE1 after in vitro stimulation with angiotensin II (ATII) with the highest ACE1 expression observed in individuals with hypertension with low-grade inflammation. Our group and others have shown that aging is associated with comorbidities, chronic inflammation, and immunosenescence, but there is a lack of data about ACE1 expression on immune cells during the aging process. Therefore, our aim was to evaluate the levels of ACE1 expression in nonlymphoid cells compared to lymphoid that in cells in association with the immunosenescence profile in adults older than 60 years. Cryopreserved peripheral blood mononuclear cells obtained from blood samples were used. Cells were stained with monoclonal antibodies and evaluated via flow cytometry. We found that ACE1 was expressed in 56.9% of nonlymphocytes and in more than 90% of lymphocytes (all phenotypes). All donors exhibited characteristics of immunosenescence, as evaluated by low frequencies of naïve CD4+ and CD8+ T cells, high frequencies of effector memory re-expressing CD45RA CD8+ T cells, and double-negative memory B cells. These findings, in addition to the increased C-reactive protein levels, are intriguing questions for the study of ACE1, inflammaging, immunosenescence, and perspectives for drug development or repurposing (Reviewed by the Plan P #PeerRef Community).

              Author and article information

              Journal
              JMIRx Med
              JMIRx Med
              JMIRxMed
              JMIRx Med
              JMIR Publications (Toronto, Canada )
              2563-6316
              2023
              20 January 2023
              : 4
              : e45279
              Affiliations
              [1 ] University of Palermo Palermo Italy
              Author information
              https://orcid.org/0000-0001-8004-2363
              Article
              v4i1e45279
              10.2196/45279
              10414234
              bd064c2c-f2e5-4b3a-adfa-3613904da747
              ©Calogero Caruso. Originally published in JMIRx Med (https://med.jmirx.org), 20.01.2023.

              This is an open-access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIRx Med, is properly cited. The complete bibliographic information, a link to the original publication on https://med.jmirx.org/, as well as this copyright and license information must be included.

              History
              : 22 December 2022
              : 22 December 2022
              Categories
              Peer-Review Report
              Peer-Review Report

              aging,angiotensin converting enzyme,lymphocytes,immunosenescence,inflammaging

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