Physiological Induction of Regulatory Qa-1-Restricted CD8+ T Cells Triggered by Endogenous CD4+ T Cell Responses

T cell-dependent autoimmune diseases are characterized by the expansion of T cell clones that recognize immunodominant epitopes on the target antigen. As a consequence, for a given autoimmune disorder, pathogenic T cell clones express T cell receptors with a limited number of variable regions that define antigenic specificity. Qa-1, a MHC class I-like molecule, presents peptides from the variable region of TCRs to Qa-1-restricted CD8+ T cells. The induction of Vß-specific CD8+ T cells has been harnessed in an immunotherapeutic strategy known as the “T cell vaccination” (TCV) that comprises the injection of activated and attenuated CD4+ T cell clones so as to induce protective CD8+ T cells. We hypothesized that Qa-1-restricted CD8+ regulatory T cells could also constitute a physiologic regulatory arm of lymphocyte responses upon expansion of endogenous CD4+ T cells, in the absence of deliberate exogenous T cell vaccination. We immunized mice with two types of antigenic challenges in order to sequentially expand antigen-specific endogenous CD4+ T cells with distinct antigenic specificities but characterized by a common Vß chain in their TCR. The first immunization was performed with a non-self antigen while the second challenge was performed with a myelin-derived peptide known to drive experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that regulatory Vß-specific Qa-1-restricted CD8+ T cells induced during the first endogenous CD4+ T cell responses are able to control the expansion of subsequently mobilized pathogenic autoreactive CD4+ T cells. In conclusion, apart from the immunotherapeutic TCV, Qa-1-restricted specialized CD8+ regulatory T cells can also be induced during endogenous CD4+ T cell responses. At variance with other regulatory T cell subsets, the action of these Qa-1-restricted T cells seems to be restricted to the immediate re-activation of CD4+ T cells

Results of thrombectomy in lower-extremity ischemia in patients with COVID-19 and respiratory failure of different severity

Aim. To analyze the results of thrombectomy in lower-extremity ischemia in patients with coronavirus disease 2019 (COVID-19) and respiratory failure of different severity.Material and methods. This retrospective, cohort, comparative study for the period from May 1, 2020 to March 1, 2022 included 305 patients with acute lower-extremity ischemia and COVID-19. Depending on the type of oxygen support, three groups of patients were formed: group 1 (n=168) — nasal oxygen insufflation; group 2 (n=92) — non-invasive ventilation (NIV); group 3 (n=45) — artificial ventilation (AV). Thrombectomy was carried out according to the standard technique using Fogarty catheters (3F-6F — depending on the vessel size). After the diagnosis was established before and after the start of surgical treatment, all patients received the following therapy: Unfractionated IV heparin infusion at an initial rate of 1000 U/r, adjusted to maintain the activated partial thromboplastin time at 2-3 times the normal value; 2. Oral acetylsalicylic acid 125 mg; 3. Analgesics.Results. Myocardial infarction and ischemic stroke were not detected in the total sample. The highest number of deaths (group 1: 5,3%, n=9; group 2: 72,8%, n=67; group 3: 100%, n=45; p<0,0001), retrombosis (group 1 : 18,4%, n=31; group 2: 69,5%, n=64; group 3: 91,1%, n=41; p<0,0001) and limb amputations (group 1: 9,5%, n=16; group 2: 56,5%, n=52; group 3: 91,1%, n=41; p<0,0001) was recorded in group 3 patients.Conclusion. In patients receiving mechanical ventilation, COVID-19 have more aggressive course, which is expressed in an increase in laboratory para- meters (C-reactive protein, ferritin, interleukin-6, D-dimer), the severity of pneumonia and location of thrombosis in the tibial arteries. Among patients with COVID-19 receiving mechanical ventilation, the greatest number of rethromboses (91,1%), limb amputations (91,1%), and deaths (100%) are noted, which suggests the expediency of abandoning open thrombectomy in favor of anticoagulant/antiplatelet therapy in this cohort of patients. The development of arterial thrombosis in patients with COVID-19 receiving mechanical ventilation is an indicator of a high risk of death. Open thrombectomy in combination with anticoagulant/antiplatelet therapy is most effective in patients on nasal oxygen insufflation or NIV

Carotid endarterectomy in Russia. What if current guidelines do not answer difficult questions?

This literature review covers the publications of Russian vascular surgeons in recent years and deals with debatable issues of carotid surgery, including: 1. What is the best technique for carotid endarterectomy (CEA)? 2. Why does restenosis of the internal carotid artery (ICA) develop and how to eliminate it? 3. How to operate on bilateral ICA stenosis? 4. Should carotid glomus be preserved? 5. Is CEA safe in the acute phase of cerebrovascular accident (CVA)? 6. Is CEA safe in elderly patients? 7. How to operate on patients with combined internal carotid and coronary artery involvement? The evidence presented in this publication makes it possible to draw the following conclusions: 1. When choosing a CEA technique, the classical technique with patch angioplasty should be avoided due to the high risk of ICA restenosis. 2. To eliminate ICA restenosis, carotid angioplasty with stenting (CAS) should be used. When performing primary CEA with ICA transposition over the hypoglossal nerve, reCEA can be used 3. In the absence of contraindications, bilateral ICA stenosis can be operated at the same time using CEA. 4. CEA with carotid glomus preservation is the operation of choice in the treatment of patients with hemodynamically significant ICA stenosis due to the elimination of the risks of postoperative hypertension and the formation of hemorrhagic transformation. 5. If there are indications for cerebral revascularization in the most acute period of stroke, CEA should be abandoned in favor of CAS. 6. In old age, CAS is the safest treatment strategy. 7. In the presence of a combined ICA and coronary involvement, the choice of treatment tactics should be carried out only by a multidisciplinary commission, taking into account the risk stratification of adverse cardiovascular events

Predictors of rethrombosis and death in patients with COVID-19 after lower limb arterial thrombectomy for acute ischemia

Aim. To identify predictors of rethrombosis and death in patients with coronavirus disease (COVID-19) after thrombectomy for acute lower limb ischemia.Material and methods. For the period from April 2020 to January 2022, 189 pa tients with acute arterial lower limb thrombosis and acute lower limb ischemia were included in this study. In all cases, a positive polymerase chain reaction test for SARS-CoV-2 was obtained. According to chest multislice computed tomography, bilateral multisegmental pneumonia was identified as follows: 76 patients — grade 2 (25-50% of lung tissue involvement); 52 patients — grade 3 (50-75%); 61 patients — grade 4 (>75%). Breathing was carried out as follows: in 88 patients — spontaneous; in 42 — with oxygen administration by nasal cannula; 26 — non-invasive ventilation; 33 had artificial ventilation. All acute arterial thromboses developed within the hospital at 4,5±1,5 days after hospitalization. The time between the onset to diagnosis verification was 27,8±5,0 min. The revascularization strategy was established by a multidisciplinary team meeting. The interval between the development of acute ischemia symptoms and surgery was 45,9±6,3 minutes. Thrombectomy was performed according to the standard technique, under local and/or intravenous anesthesia, using 3F-7F Fogarty catheters.Results. Retrombosis developed in 80,4% of cases 6,4±5,1 hours after surgery. In 59,8% of cases, retrombectomy turned out to be ineffective and the patient underwent limb amputation. In 65,6% of patients, a death was established due to multiple organ dysfunction. Among them, limb amputation was performed in 103 patients. Binary logistic regression identified following predictors of retrombosis/ death: age over 70 years (odds ratio (OR), 30,73; 95% confidence interval (CI), 11,52-33,7), obesity (OR, 15,53; 95% CI, 6,41-78,19), diabetes (OR 14,21; 95% CI, 5,86-49,21), vasopressor support (OR 8,55; 95% CI, 4,94-17,93), mechanical ventilation (OR 7,39; 95% CI, 4,81-16,52).Conclusion. Predictors of retrombosis and death in patients with COVID-19 after lower limb arterial thrombectomy are age over 70 years, obesity, diabetes, vasopressor support, and mechanical ventilation

NK Cells Promote Th-17 Mediated Corneal Barrier Disruption in Dry Eye

The conjunctiva contains a specialized population of lymphocytes that reside in the epithelium, named intraepithelial lymphocytes (IEL).Here we characterized the IEL population prior to and after experimental desiccating stress (DS) for 5 or 10 days (DS5, DS10) and evaluated the effect of NK depletion on DS. The frequency of IELs in normal murine conjunctiva was CD3(+)CD103(+) (~22%), CD3(+)γδ(+) (~9.6%), CD3(+)NK(+) (2%), CD3(-)NK(+) (~4.4%), CD3(+)CD8α (~0.9%), and CD4 (~0.6%). Systemic depletion of NK cells prior and during DS led to a decrease in the frequency of total and activated DCs, a decrease in T helper-17(+) cells in the cervical lymph nodes and generation of less pathogenic CD4(+)T cells. B6.nude recipient mice of adoptively transferred CD4(+)T cells isolated from NK-depleted DS5 donor mice showed significantly less corneal barrier disruption, lower levels of IL-17A, CCL20 and MMP-3 in the cornea epithelia compared to recipients of control CD4(+)T cells.Taken together, these results show that the NK IELs are involved in the acute immune response to desiccation-induced dry eye by activating DC, which in turn coordinate generation of the pathogenic Th-17 response

‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides

Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases

CarotidSCORE.RU — risk stratification for complications after carotid endarterectomy

Aim. To demonstrate the first Russian computer program (carotidscore.ru) for risk stratification of postoperative complications of carotid endarterectomy (CE).Material and methods. The present study is based on the analysis of a multicenter Russian database including 25812 patients after CE operated on from January 1, 2010 to April 1, 2022. The following types of CE were implemented: conventional CE with patch angioplasty — 6814 patients; eversion CE — 18998 patients. Following postoperative complications were assessed during the study: death, stroke, myocardial infarction (MI), composite endpoint (death + stroke + MI).Results. During inhospital postoperative period, 0,18% of participants died, while 0,14% had MI, 0,35% — stroke. The composite endpoint was recorded in 0,68%. For each factor present in patients, a predictive coefficient was estimated. The predictive coefficient was considered as a numerical parameter reflecting the strength of the effect of each factor on the development of postoperative complications. Based on this equation, predictive coefficients were calculated for each factor present in patients in our study. The total contribution of these factors was reflected as a percentage and denoted the risk of postoperative complications with a minimum of 0% and a maximum of 100%. On the basis of obtained calculations, a CarotidSCORE program was created. Its graphical interface is based on the QT framework. It is possible not only to estimate the risk of a complication, but also to save all data about a patient in JSON format. The CarotidSCORE program contains 47 patient parameters, including clinical, demographic, anamnestic and angiographic characteristics. It makes it possible to choose one of the four CE types, which will provide an accurate stratification of the complication risk for each of them.Conclusion. CarotidSCORE (carotidscore.ru) may determine the probability of postoperative complications in patients undergoing CE

Streptococcus pneumoniae Serotype 1 Capsular Polysaccharide Induces CD8+CD28− Regulatory T Lymphocytes by TCR Crosslinking

Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an α-helix configuration. In this paper we look at the immune response of CD8+ T cells to ZPSs. Intraperitoneal application of the ZPS Sp1 from Streptococcus pneumoniae serotype 1 induces CD8+CD28− T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Sp1 (mSp1) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD8+CD28− T lymphocytes. The Sp1-induced CD8+CD28− T lymphocytes are CD122lowCTLA-4+CD39+. They synthesize IL-10 and TGF-β. The Sp1-induced CD8+CD28− T cells exhibit immunosuppressive properties on CD4+ T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD8+ T cell activation by Sp1 demonstrate in a dimeric MHC class I-Ig model that Sp1 induces CD8+ T cell activation by enhancing crosslinking of TCR. The expansion of CD8+CD28− T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD8+CD28− T cells, Sp1 enhances Zap-70 phosphorylation and increasingly involves NF-κB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD8+CD28− population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD8+CD28− T lymphocytes in vivo and in vitro. The underlying mechanism of CD8+ T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system