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1.
Preprint in English | bioRxiv | ID: ppbiorxiv-500987

ABSTRACT

CD4 T-cells require T-cell receptor (TCR) signalling for their activation and differentiation. Foxp3+ regulatory T-cells (Treg) are dependent on TCR signals for their differentiation and suppressive function. However, it is not fully known how TCR signalling controls the differentiation of polyclonal CD4 T-cells upon antigen recognition at the single-cell level in vivo. In this study, using Nr4a3-Tocky (Timer-of-cell-kinetics-and-activity), which analyses temporal changes of antigen-reactive T-cells following TCR signalling, we investigated T-cell response to Spike protein fragments (S1a, S1b, S2a, and S2b) upon immunisation. We show that S1a and S2a induced the differentiation of PD1hiCXCR5+ T follicular helper (Tfh) cells, which is related to CD4 T-cell immunogenicity. In contrast, S1b induced CD25hiGITRhiPD-1int Treg, which intermittently received TCR signalling. Using Foxp3-Tocky, which analyses Foxp3 transcriptional dynamics, the S1b-reactive Treg sustained Foxp3 transcription over time, which is a hallmark of activated Treg. Foxp3 fate-mapping showed that the S1b-reactive Treg were derived not from pre-existing thymic Treg, suggesting Foxp3 induction in non-Treg cells. Thus, the current study reveals temporally dynamic differentiation of CD4 T-cells and Treg upon immunisation in the polyclonal TCR repertoire.

2.
Preprint in English | bioRxiv | ID: ppbiorxiv-115923

ABSTRACT

Severe COVID-19 patients can show respiratory failure, T-cell reduction, and cytokine release syndrome (CRS), which can be fatal in both young and aged patients and is a major concern of the pandemic. However, the pathogenetic mechanisms of CRS in COVID-19 are poorly understood. Here we show single cell-level mechanisms for T-cell dysregulation in severe SARS-CoV-2 infection, and thereby demonstrate the mechanisms underlying T-cell hyperactivation and paralysis in severe COVID-19 patients. By in silico sorting CD4+ T-cells from a single cell RNA-seq dataset, we found that CD4+ T-cells were highly activated and showed unique differentiation pathways in the lung of severe COVID-19 patients. Notably, those T-cells in severe COVID-19 patients highly expressed immunoregulatory receptors and CD25, whilst repressing the expression of the transcription factor FOXP3 and interestingly, both the differentiation of regulatory T-cells (Tregs) and Th17 was inhibited. Meanwhile, highly activated CD4+ T-cells express PD-1 alongside macrophages that express PD-1 ligands in severe patients, suggesting that PD-1-mediated immunoregulation was partially operating. Furthermore, we show that CD25+ hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly, we show that CD4+ T-cells, particularly CD25-expressing hyperactivated T-cells, produce the protease Furin, which facilitates the viral entry of SARS-CoV-2. Collectively, CD4+ T-cells from severe COVID-19 patients are hyperactivated and FOXP3-mediated negative feedback mechanisms are impaired in the lung, while activated CD4+ T-cells continue to promote further viral infection through the production of Furin. Therefore, our study proposes a new model of T-cell hyperactivation and paralysis that drives pulmonary damage, systemic CRS and organ failure in severe COVID-19 patients.

3.
Article in Japanese | WPRIM (Western Pacific) | ID: wpr-377852

ABSTRACT

Magnetic acupuncture achieved by plastering is a particular type of acupuncture whose “pressure stimulation effect” deriving from a needle type minor process produces a synergetic effect due to “magnetic stimulation effect” originating in the magnetism concentrated on and discharged from the process. This magnetic acupuncture charged with low frequency is called “low frequency magnetic acupuncture.” The major factors in effective non-needle electro-stimulus anesthesia (T. N. S.) are the shape and condition of electrodes in their contact with the skin. Since the electrode utilizing a magnetic needle fully meets these conditions, “acupuncture sensation, ” which is clinically considered important, can be adequately expected. The following are the results obtained from our studies on the objective evaluation of a stimulation property and therapeutic effects of low frequency magnetic acupuncture.<br>The subjects involved in the study were 15 healthy adults and 5 patients with various symptoms at Naka Izu Rehabilitation Center. The method adopted was the measure of MV as an index of a comfortable sense of stimulation. An MV pick-up was attached to the subject's thum ball —if right-handed, attached to left thumb, if left-handed, attached to right thumb— with cellophane tape and was recorded by 13ch multi-purpose electro-encephalograph and DTR manufactured by Sanei Sokki K. K. before the results were analyzed by a signal processor.<br>Results:<br>1) In 10 healthy adults whose MV bands before and after T. N. S. of a general type were compared, a decrease of theta band and an increase of alpha band were recognized. When stimulation effects noted in 5 healthy adults given T. N. S. of a general type and low frequency magnetic acupuncture were compared in terms of MV pattern, a generally increasing trend of alpha band was observed in magnetic acupuncture electrodes.<br>2) MV patterns noted in 5 patients with various symptoms who were given low frequency magnetic acupuncture showed a decrease of theta and beta bands as well as an increase of alpha band, while MV amplitude showed a decrease depending on the patient. From the above results, the magnetic acupuncture electrode was found to have a more comfortable sense of stimulation than that of an electrode of an ordinary type.

4.
Article in Japanese | WPRIM (Western Pacific) | ID: wpr-377809

ABSTRACT

From old times, Oriental medicine has had a double layer structure comprising therapeutic medicine and constructive medicine, and therapists of Oriental medicine have believed that the best treatment for us is to take care of our health. The problem of the usual therapeutic system used only by acupuncturists is that clinical field is limited to an acupuncture clinic and the number of patients is also limited. In view of the above and with the goal of solving these problems, we devised a new magnetic acupuncture methol which is applicable to our home treatment in the early stages of disease and examined, from both the viewpoints of Oriental medicine and health medicine, whether or not this magnetic acupuncture is a useful means for systematically performing the treatments of therapeutic medicine and of constructive medicine.<br>(1) Magnetic acupuncture treatment<br>In this treatment, it is mainly expected that slight clincal symptom (stiffness, pain) will be relieved owing to the synergistic effect of the needle pressure stimulation and the magnetic action exercised by the needle plastered on the reaction acupuncture points of living body's skin. Compared with the intracutaneous needle which acupuncturists use as a rule, it is easier to operate. In addition, it is superior in rapidity and durability of effect to the commercially available magnetic pellet and acupuncture pellet.<br>(2) Magnetic acupuncture<br>The magnet is made of isotropic barium ferrite and has a diameter of 5mm and a thickness of 2.3mm. It has a shape of a disc having a small projection located at the center of the disc on the side which comes into contact with skin (N pole side). The magnetism emanating from the projection has a magnetic flux density of about 952 gauss which is approximately 1.8 times as great as the magnetic flux density of the magnetisms emanating from the flat part of the plate other than the projection. There are two kinds of magnetic acupunctures: one is gold magnetic acupuncture for PU (weak stimulation) and the other is silver magnetic acupuncture Xie (strong stimulation).<br>(3) Clinical application<br>In Ling-Shu (Rei Su) which is a volume in the earliest known text on acupuncture, the Nei Ching or Classic of Internal Medicine, or Da-Ging (Dai Kei), it is mentioned that the basic therapeutic point lies in the pain. On these grounds, one magnetic acupuncture disc is plastered on the point at which the response was greatest according to the acupuncture point phenomena (pressure pain, stiffness, depression, hypersensit iveness, trigger-point, etc.) and some additional magnetic acupuncture discs are appropriately plastered on the points surrounding the most sensible point, as well as on the main acupuncture points having a relation to the relief of clinical signs.<br>A clinical test was performed in order to prove the clinical effects of magnetic acupuncture. Thus, 401 subjects who usually complained of stiffness and pain in shoulder without any objective findings were picked out and clinically tested. These subjects were classified into magnetic acupuncture therapy group (120 subjects) and its placebo therapy group (281 subjects), and the clinical test was performed to compare both the groups. Here is reported a part of the test results.

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