Acute and Chronic Systemic Inflammation: Features and Differences in the Pathogenesis, and Integral Criteria for Verification and Differentiation.

Currently, there is rationale for separating the systemic manifestations of classical inflammation from systemic inflammation (SI) itself as an independent form of the general pathological process underlying the pathogenesis of the most severe acute and chronic diseases. With this aim in view, we used integral scales of acute and chronic SI (ChSI), including the following blood plasma parameters: interleukins 6, 8, 10; tumor necrosis factor alpha; C-reactive protein; D-dimer; cortisol; troponin I; myoglobin. The presence of multiple organ dysfunction according to the SOFA score was also taken into account. The effectiveness of the scales was tested in groups of intensive care patients during different periods of acute trauma, sepsis, and septic shock. The ChSI scale was applicable under systemic autoimmune diseases, chronic purulent infections, chronic limb threatening ischemia, and end-stage renal disease of various genesis. The number of examined patients was 764 in total. The scales allowed us to verify specific phases of acute SI and identify pathogenetic risk factors of lethal outcomes, as well as the most severe variants of the chronic pathologies course. These scales are open adaptable systems (in terms of the nomenclature and choice of indicators). They are primarily intended for scientific research. However, the SI verification methodology presented in this paper may be useful for developing advanced criteria for assessing both the typical links in the pathogenesis of many diseases and the severity of the overall condition of patients for clinical practice.

SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19.

The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection. These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus's protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19. The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors. The presence of a diverse repertoire of receptors allows SARS-CoV-2 to infect various types of cells, including those not expressing ACE2. During the second stage, the majority of the polyfunctional structural, non-structural, and extra proteins SARS-CoV-2 synthesizes in infected cells are involved in the primary blockage of antiviral innate immunity. A high degree of redundancy and systemic action characterizing these pathogenic factors allows SARS-CoV-2 to overcome antiviral mechanisms at the initial stages of invasion. The third stage includes passive and active protection of the virus from factors of adaptive immunity, overcoming of the barrier function at the focus of inflammation, and generalization of SARS-CoV-2 in the body. The fourth stage is associated with the deployment of variants of acute and long-term complications of COVID-19. SARS-CoV-2's ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperergic mechanisms of systemic inflammation is critical at this stage of infection.

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes).

The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of "inflammatory systemic microcirculation". The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19.

Antinuclear Autoantibodies in Health: Autoimmunity Is Not a Synonym of Autoimmune Disease.

The incidence of autoimmune diseases is increasing. Antinuclear antibody (ANA) testing is a critical tool for their diagnosis. However, ANA prevalence in healthy persons has increased over the last decades, especially among young people. ANA in health occurs in low concentrations, with a prevalence up to 50% in some populations, which demands a cutoff revision. This review deals with the origin and probable physiological or compensatory function of ANA in health, according to the concept of immunological clearance, theory of autoimmune regulation of cell functions, and the concept of functional autoantibodies. Considering ANA titers ≤1:320 as a serological marker of autoimmune diseases seems inappropriate. The role of anti-DFS70/LEDGFp75 autoantibodies is highlighted as a possible anti-risk biomarker for autoimmune rheumatic disorders. ANA prevalence in health is different in various regions due to several underlying causes discussed in the review, all influencing additive combinations according to the concept of the mosaic of autoimmunity. Not only are titers, but also HEp-2 IFA) staining patterns, such as AC-2, important. Accepting autoantibodies as a kind of bioregulator, not only the upper, but also the lower borders of their normal range should be determined; not only their excess, but also a lack of them or "autoimmunodeficiency" could be the reason for disorders.

Pathogenesis of Autoimmune Male Infertility: Juxtacrine, Paracrine, and Endocrine Dysregulation.

According to global data, there is a male reproductive potential decrease. Pathogenesis of male infertility is often associated with autoimmunity towards sperm antigens essential for fertilization. Antisperm autoantibodies (ASAs) have immobilizing and cytotoxic properties, impairing spermatogenesis, causing sperm agglutination, altering spermatozoa motility and acrosomal reaction, and thus preventing ovum fertilization. Infertility diagnosis requires a mandatory check for the ASAs. The concept of the blood-testis barrier is currently re-formulated, with an emphasis on informational paracrine and juxtacrine effects, rather than simple anatomical separation. The etiology of male infertility includes both autoimmune and non-autoimmune diseases but equally develops through autoimmune links of pathogenesis. Varicocele commonly leads to infertility due to testicular ischemic damage, venous stasis, local hyperthermia, and hypoandrogenism. However, varicocelectomy can alter the blood-testis barrier, facilitating ASAs production as well. There are contradictory data on the role of ASAs in the pathogenesis of varicocele-related infertility. Infection and inflammation both promote ASAs production due to "danger concept" mechanisms and because of antigen mimicry. Systemic pro-autoimmune influences like hyperprolactinemia, hypoandrogenism, and hypothyroidism also facilitate ASAs production. The diagnostic value of various ASAs has not yet been clearly attributed, and their cut-levels have not been determined in sera nor in ejaculate. The assessment of the autoimmunity role in the pathogenesis of male infertility is ambiguous, so the purpose of this review is to show the effects of ASAs on the pathogenesis of male infertility.

The global response to the COVID-19 pandemic: how have immunology societies contributed?

The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Scope and new horizons for implementation of m-Health/e-Health services in pulmonology in 2019.

The reason for this review based on the results of many meta- analyses is the great assessed difference in the methods of most studies in e-Health, telemedicine and tele-rehabilitation. It consists of different understanding of new terms, using different hard- and software, including criteria, different methodology of patient's treatment and its evaluation. This status suggests that first of all m-Health/e-Health requires a unique ontology of terms using and methodology of studies comparing. In this review we try to describe shortly the most significant points of modern e-Health field of medicine. The basic parts include methodology of review formation, tele-communication implementation results, tele-education, interactive questioning, tele-consultation, telemedicine diagnosis, tele-monitoring, rehabilitation and tele-rehabilitation, gamification, acceptability of mobile electronic devices and software in e-Health and planning studies. At the end of the review the new ontological structure of digital medicine is presented.

Lymphopenia-induced proliferation of CD4 T-cells is associated with CD4 T-lymphocyte exhaustion in treated HIV-infected patients.

Background & objectives: Under the lymphopenic condition, T-cells divide to maintain their peripheral pool size. Profound chronic lymphopenia in some treated HIV-infected patients, characterized by poor T-cell recovery, might result in intensive homeostatic proliferation and can cause T-cell exhaustion and/or senescence. The present study was undertaken to evaluate the homeostatic proliferation of CD4+T-cells in treated HIV-infected individuals, and to determine the amount of phenotypically exhausted and senescent CD4 T-lymphocytes. Methods: Thirty seven treated HIV-infected patients with suppressed HIV viral load (<50 copies/ml) were studied. Patients were divided into two groups: immunological non-responders (INRs) with CD4+T-cells <350/µl (n=16) and immunological responders (IRs) with CD4+T-cells >350/µl (n=21). T-cell subsets [naïve, central memory (CM), and effector memory (EM)] and proportions of cycling (Ki-67+), senescent (CD57+) and exhausted (PD-1+) T-lymphocytes were assessed using flow cytometry. Results: CD4+T-cell cycling rate was higher in INRs than in IRs due to more extensive proliferation of CM, 4.7 vs 2.7 per cent (P <0.01) and EM, 4.8 vs 3.2 per cent (P <0.05). The percentages of CD4+Ki-67+ CM and EM T-lymphocytes were inversely related to the CD4+T-cell counts in the appropriate subset, r=-0.584 (P <0.001) and r=-0.556, (P <0.001), respectively. Exhaustion [24.2 vs 16.7% (P <0.01)], but not senescence [7.1 vs 10.8% (P>0.05)] was more pronounced in the INR group than in the IR group. The frequency of CD4+Ki-67+ CM T-cells was related to the proportion of CD4+PD-1+ cells of the same subset, r=0.789 (P <0.001). The numbers of CD4+Ki-67+PD-1+ CM and EM T-cells were substantially higher in INRs than in IRs. Interpretation & conclusions: The present data indicated that intensive homeostatic proliferation contributed to the T-cell exhaustion in HIV-infection.

Influence of hepatitis C virus coinfection on CD4⁺ T cells of HIV-infected patients receiving HAART.

OBJECTIVE: The effects of hepatitis C virus (HCV) coinfection on immune homeostasis and immune restoration in treated HIV infection are not well understood. METHODS: We studied 79 HIV-infected patients who had been receiving HAART for more than 2 years and who had HIV viral load below 50 copies/ml. Four patient groups were studied: HIV/HCV, CD4⁺ cells above 350/µl; HIV/HCV, CD4 cells below 350/µl; HIV/HCV, CD4 cells above 350/µl; HIV/HCV, CD4⁺ cells below 350/µl. Controls comprised 20 healthy volunteers. Naive, central memory, effector memory, and terminal effector CD4⁺ T cells were enumerated. Naive CD4CD31 T cells were counted as recent thymic emigrants (RTEs). Activation state and ex-vivo apoptosis of CD4⁺ T cells, levels of liver enzymes, and aspartate aminotransferase-to-platelet ratio index were evaluated. RESULTS: CD4⁺ T-cell counts and the numbers of all circulating CD4 T-cell maturation subsets were diminished in HIV infection; CD4⁺ T-cell activation and apoptosis were increased in HIV infection, but none of these indices was affected by HCV coinfection. RTE numbers were diminished in HIV infection, were inversely related to age, and were increased in women and lower in HIV/HCV patients than in singly HIV-infected patients. In coinfected patients, RTE numbers were inversely related to levels of liver enzymes, but not to HCV viral load. CONCLUSION: Whereas we could find no relationship between HCV infection and most indices of CD4⁺ T-cell homeostasis or activation, CD4⁺ RTEs are diminished in the circulation of HCV coinfected persons and appear to be related to indices of ongoing hepatic damage or inflammation.