Immune Aggression Research Articles

Immunology of the “sensible world” and of the “intelligible world”: the evolutionary decline and the “constructed reality”

The term “immunity” was introduced in medicine due to Ilya Mechnikov. However, the concept of infection resistance existed in European culture long before Mechnikov in the form of s.c. “vital force”. According to holistic methodology, the history of immunology can be divided into three unequal periods: 1) vitalistic – from antiquity to the discoveries of Mechnikov and Ehrlich; 2) “Mechnikov time” (1890s – 1916); and 3) a post-Mechnikov period (1916 – present). At the beginning of 18th century, the existence of “vital force” ideas created the possibility to adapt variolation in Europe, which was based on medieval magical-mystical concepts. Without generalizing of variolation experience, Edward Jenner would hardly have been able to discover vaccination. Scientific ideas of Mechnikov were not a categorical denial of the previous period of immunology. For almost 20 years, he himself had to fend off teleological and vitalistic accusations from the side of those biologists who denied the possibility of phagocytes to act expediently. An analogy helped Mechnikov to confirm his intuition was the phenomenon of intracellular digestion of amoebas or ciliates. Besides, he experimentally proved that phagocytosis was the product of evolution and not a “god gift”. However, in his works, Mechnikov also addressed to the category of “healing forces of the body.” Modern immunology now faces a number of theoretical contradictions and methodological difficulties related to reductionists paradigm: as far as the “split” between the world of “immune objects” (immune cells receptors, antibodies, cytokines, etc.) and “subjectness” of its basic categories “self-nonself”, “immune aggression, “immune defence”, etc., Ilya Mechnikov tried to overcome this contradiction substantiating the phenomenon of phagocytosis as functional system acting in accordance with defense purpose. The construction of “holistic” subject-object models of immunity (such as the symbiosis model of plant immunity) could be a way of overcoming the aforementioned contradictions.

Autoimmune Heart Disease: A Comprehensive Summary for Forensic Practice.

Autoimmune heart disease is a non-random condition characterised by immune system-mediated aggression against cardiac tissue. Cardiac changes often exhibit nonspecific features and, if unrecognised, can result in fatal outcomes even among seemingly healthy young individuals. In the absence of reliable medical history, the primary challenge lies in differentiating between the various cardiopathies. Numerous immunohistochemical and genetic studies have endeavoured to characterise distinct types of cardiopathies, facilitating their differentiation during autopsy examinations. However, the presence of a standardised protocol that forensic pathologists can employ to guide their investigations would be beneficial. Hence, this summary aims to present the spectrum of autoimmune cardiopathies, including emerging insights such as SARS-CoV-2-induced cardiopathies, and proposes the utilisation of practical tools, such as blood markers, to aid forensic pathologists in their routine practice.

Treatment of full-layer skin defects using decellularized pig skin dermal matrix

The choice of treatment methods for complex skin defects poses certain technical and medical difficulties related to the choice of material for filling the wound defect and its antigenic compatibility. A promising direction in the treatment of skin defects is the use of decellularized (celluless) pig skin, the composition and structure of which is as close as possible to the patient's dermis.
 The aim of the study was to analyze the clinical case of a patient with a basal cell carcinoma in the right wing of the nose, who was treated with full-layer skin defects using a decellularized dermal matrix from pig skin.
 Material and methods of investigation. Patient P., 94 years old, with a basal cell carcinoma in the area of the right wing of the nose, underwent treatment. As a material applied directly to the wound, a flap of acellular dermal matrix (ADM) of pig skin with preservation of the native structure was used.
 Results. 6 weeks before the visit to the dermatologist, the patient developed a pea-sized papule on the skin in the area of ​​the wing of the nose, which increased in size and became painful on palpation. When examining the skin in the area of ​​the right wing of the nose, a tumor-like formation was observed, 1x1 cm in size, flesh-colored, with peeling on the surface and vascularization, firm consistency, painful. Regional lymph nodes are not enlarged. The formation is clearly separated from healthy skin. The oncologist made a diagnosis: basal cell carcinoma. The tumor was removed, resulting in a full-layer skin defect measuring 1x1.5 cm with connection to the nasal cavity. Acellular dermal matrix was used to close the defect on the 3rd day after surgery. The flap was placed so that it did not cover the skin around the wound. With the help of "Levomykol" ointment, a moist chamber was created over the dermal flap. The dressing was changed every 2-3 days. On the 14th day, the flap peeled off, a granulating wound with signs of marked marginal epithelization formed in its place. The bottom of the wound was located almost at the same level as the intact skin. On the 21st and 26th day, active marginal epithelization of the wound and wound healing under the scab were noted. The bandage was not used during this period. On the 32nd day, the wound closed.
 Conclusions. Decellularized dermal matrix of pig skin when closing a full-layer postoperative skin defect creates optimal conditions for reparative wound regeneration. The effectiveness of its use is due to the presence of a collagen matrix in it, from which the nuclear elements of cells have been removed, which does not lead to immune aggression. The clinical case proves the expediency of using the decellularized dermal matrix of pig skin in the treatment of full-layer skin defects of various genesis.

Features of interleukin status in patients with type 1 diabetes mellitus

A hundred years have passed since the first use of insulin as the main means of therapy for type 1 diabetes mellitus. During this time, significant progress has been made in the development of insulin therapy, including the development of new insulin formulations and methods of its delivery. At the same time, over the years, expanding knowledge about the immunopathogenesis of type 1 diabetes mellitus, doctors are trying to reach a completely new level of possibilities in the treatment of this disease. At this level, methods of immunotherapeutic effects on those links of autoimmune chains will become available, which today limit both the therapy of patients with type 1 diabetes and the development of the idea of stem-cells transplantation due to the lack of a holistic understanding of ways to overcome post-transplant immune aggression against -cells. The review summarizes the current understanding of known interleukins involved as the most important intermediaries in the phases of initiation and immuno-mediated destruction of pancreatic -cells. The achievements in the study of the role of key interleukins in the pathophysiology of autoimmune diabetes for marking potential application points of immunomodulatory targeted therapy are considered.

Isolation of Live Leukocytes from Human Inflammatory Muscles.

In inflammatory myopathies, the self-reactive immune cells involved in muscle aggression have been studied mostly using histological assessment of muscle biopsy sections; this methodology provides the advantage of visualizing and identifying cells within the tissue, but it does not allow further investigation. To gain access to live and isolated cells, many studies utilized blood samples; however, in the absence of biological tools to discriminate the leukocytes associated with the autoimmune process from those that emerged from responses against pathogens, the information observed on circulating immune cells often lacks in specificity, and thus result interpretation may prove difficult. In order to selectively retrieve self-reactive immune cells, we developed a protocol to isolate live leukocytes from human muscle biopsies, which allows for further analysis using a large range of methodologies. The protocol uses enzymatic digestion to release live leukocytes from freshly collected skeletal muscle samples, followed by filtration and separation of the leukocytes from the myocytes by density gradient centrifugation. The isolated cells can be submitted immediately to various analysis strategies to characterize ex vivo the specific cellular and molecular mechanisms responsible for self-directed immune muscle aggression or may be placed in culture for expansion.

Novel antibodies that selectively block mouse IL-12 enable the re-evaluation of the role of IL-12 in immune protection and pathology.

The dimeric cytokine IL-12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is complicated by the fact that its two subunits are present in other cytokines: p40 in IL-23 and p35 in IL-35. This has led to erroneous conclusions like the alleged implication of IL-12 in experimental autoimmune encephalomyelitis (EAE). Here, we report the development of a mouse anti-mouse IL-12 vaccine and the production of monoclonal antibodies (mAbs) that do not react with p40 or p35 (in IL-35) but specifically recognize and functionally inhibit the IL-12 heterodimer. Using one of these mAbs, MM12A1.6, that strongly inhibited IFN-γ production and LPS-induced septic shock after viral infection, we demonstrate the critical role played by IL-12 in the rejection of male skin graft by female C57BL/6 syngeneic recipients and in the clearance of an immunogenic mastocytoma tumor variant by DBA/2 mice, but not in a parent to F1 immune aggression model nor in MOG-induced EAE, which was clearly prevented by anti-p40 mAb C17.8. Given this selective inhibition of IL-12, these mAbs provide new options for reassessing IL-12 function in vivo.

The Immune Contexture and Cancer Therapy Aspects of the TIM-3 Checkpoint Pathway

The advent of immune checkpoint therapy revolutionizes the oncology field by achieving durable anti-tumor efficacy and immense clinical progress. Among the immune checkpoints, T cell immunoglobulin and mucin domain 3 (TIM-3) has been reported to express on both innate and adaptive immune cells where it accounts for immune tolerance and tumor aggression. It shows promising effects that are applicable in several cancer types. This review provides a broad overview of the main TIM-3 relative signaling pathways and its immune regulatory role to shape cancer development positively. The importance of TIM-3 inhibitors in cancer control were also summarized according to the latest reports, discussing its clinical trial data that inform the rationale for TIM-3 blockade.

CLONE OF PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA AND OTHER PREDICTORS OF THE RESPONSE TO IMMUNOSUPPRESSIVE THERAPY IN PATIENTS WITH IDIOPATHIC APLASTIC ANAEMIA

Introduction. The pathogenesis of acquired aplastic anaemia (AA) is based on immune-mediated development of bone marrow failure. The absence of clear reasons for the development of immune aggression determines the relevance of investigations aimed at studying genetic disorders in the remaining pool of hematopoietic stem cells, in the hematopoietic niche, as well as mechanisms underlying the failure of immunological tolerance.Aim. The present literature review describes the most relevant markers used for characterising AA patients on the basis of their possible response to immunosuppressive therapy (IT) and for forming groups being at risk of developing refractoriness and clonal evolution.General findings. The overall survival probability in patients with AA following program IT is comparable to the results of transplanting allogeneic hematopoietic blood stem cells (allo-HSCT) from a related donor in the first line of therapy. According to current Russian and international recommendations, the tactics for treating AA patients is determined by the patient’s age and the presence of an HLA-identical sibling. Allo-HSCT from a related HLA-identical donor is a method used for treating patients younger than 40 years; however, the possibility of performing allo-HSCT is limited by donor availability. Although the event-free survival probability during IT is inferior to the results of allo-HSCT, IT remains the main treatment method for most patients with AA. In order to minimise adverse outcomes, it is necessary to consider predictors of treatment efficacy along with the likelihood of developing late clonal evolution as early as at the AA diagnosis stage. Patient evaluation and formation of risk groups will facilitate selection of the most optimal treatment approach at the therapy planning stage, which includes either IT combination with thrombopoietin receptor agonists, or a search for an unrelated HLA-compatible donor and timely allo-HSCT.

Herpes HSV latency and apoptosis causes epilepsy and much more. Challenge - zooming in on the impossible; epilepsy and immune system auto aggression.

Herpes HSV latency and apoptosis causes epilepsy and much more. Challenge - zooming in on the impossible; epilepsy and immune system auto aggression.

Mental Health among Syrian Immigrants in Iraq

Background: The migration of Syrian citizens to many parts of the world began after civil war in Syria. Many migrants lost their homes, friends and relatives as a result of the civil war. Millions of Syrians have been refugees to European countries and especially to neighboring countries such as Libya, Turkey and Iraq. They have experienced housing, safety and cultural gap problems, which may put their mental health at risk. Many present signs of physical and mental illness, such as an insomnia, a weakened immune system, drug addiction, self-harm, and aggression, making their social adjustment more and more difficult. Despite facing the same conditions, other immigrants succeed to adjust with the new environment. It is necessary to understand factors that may optimize immigrants’ social adjustment. Objectives: The aim of the present study is to evaluate to what extend some characteristics of Syrian immigrants in Iraq, such as cultural intelligence, emotional intelligence are related to their social adjustment, and the role of mental health upon that relationship. Methods: Participants are Syrian immigrants who live in Erbil – Iraq. Data collection was held in 2017. Were randomly included 288 subjects (50% female). All participants completed 4 questionnaires translated from Persian version to Arabic language: Cultural and Emotional Intelligence Questionnaires (CI and EI), a Social Adjustment scale (SA) and a Mental Health Questionnaire (MH). Results: This study presents an empirical study into the mental health of immigrants. More specific, based on collected questionnaire data an explanatory model for mental health and social adjustment is established on the basis of emotional- and cultural intelligence. A better mental health is associated with better social adjustment. Emotional and cultural intelligence are significantly and positively and significantly and positively associated to social adjustment. Cultural intelligence is significantly and positively related to mental health, while emotional intelligence has no significant relation with mental health, when simultaneous effects are analyzed. Conclusions: The present results suggest that mental health may have an intermediate role in the relationship between cultural intelligence and social adjustment, but no intermediate role in the relationship between emotional intelligence and social adjustment. Results convey an important message to public policies, highlighting the importance of preserving both cultural and emotional intelligence among Syrian immigrant in Iraq, as a measure to assure their mental health and social adjustment.

Hepatic expression of programmed death-1 (PD-1) and its ligand, PD-L1, in children with autoimmune hepatitis: relation to treatment response.

Aim of the studyAutoimmune hepatitis (AIH) is characterized histologically by aggressive inflammation with interface hepatitis and prominent lymphoplasmacytic infiltration. Programmed death-1 (PD-1) is expressed on activated lymphocytes. Engagement of PD-1 by its ligand PD-L1 leads to cell apoptosis and death. We aimed to evaluate the immunohistochemical expression of PD-1 and PD-L1 in children with AIH, and its relation to treatment outcome.Material and methodsPre-treatment liver biopsies of 31 children with AIH were compared to 30 children with chronic hepatitis C virus (HCV) infection as a control group. PD-1 was evaluated in lymphocytes, while PD-L1 was evaluated in lymphocytes, hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells. All AIH patients received the standard treatment.ResultsThe mean PD-1 was significantly higher in AIH than HCV patients (29.19 ±18.5% vs. 15.2 ±10.1%; p = 0.002) while there was no statistically significant difference as regards PD-L1 on lymphocytes (p = 0.853). Neither PD-1 nor PD-L1 correlated with either liver fibrosis or the inflammatory activity (p > 0.05 for all). PD-1/PD-L1 ratio was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders (46.9 vs. 6.58). PD-1 expression was comparable in both responders and non-responders (p = 0.813), while PD-L1 was significantly upregulated in responders (4.17 ±3.15% vs. 0.63 ±1.3%; p = 0.046). PD-L1 expression on hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells was comparable in AIH and HCV groups.ConclusionsPD-1/PD-L1 ratio, which reflects immune aggression, was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders.

Glioblastoma Recurrence Correlates With Increased APE1 and Polarization Toward an Immuno-Suppressive Microenvironment.

While treatment with surgery, radiotherapy and/or chemotherapy may prolong life for patients with glioblastoma, recurrence is inevitable. What is still being discovered is how much these treatments and recurrence of disease affect the molecular profiles of these tumors and how these tumors adapt to withstand these treatment pressures. Understanding such changes will uncover pathways used by the tumor to evade destruction and will elucidate new targets for treatment development. Nineteen matched pre-treatment and post-treatment glioblastoma tumors were subjected to gene expression profiling (Fluidigm, TaqMan assays), MGMT promoter methylation analysis (pyrosequencing) and protein expression analysis of the DNA repair pathways, known to be involved in temozolomide resistance (immunohistochemistry). Gene expression profiling to molecularly subtype tumors revealed that 26% of recurrent post-treatment specimens did not match their primary diagnostic specimen subtype. Post-treatment specimens had molecular changes which correlated with known resistance mechanisms including increased expression of APEX1 (p < 0.05) and altered MGMT methylation status. In addition, genes associated with immune suppression, invasion and aggression (GPNMB, CCL5, and KLRC1) and polarization toward an M2 phenotype (CD163 and MSR1) were up-regulated in post-treatment tumors, demonstrating an overall change in the tumor microenvironment favoring aggressive tumor growth and disease recurrence. This was confirmed by in vitro studies that determined that glioma cell migration was enhanced in the presence of M2 polarized macrophage conditioned media. Further, M2 macrophage-modulated migration was markedly enhanced in post-treatment (temozolomide resistant) glioma cells. These findings highlight the ability of glioblastomas to evade not only the toxic onslaught of therapy but also to evade the immune system suggesting that immune-altering therapies may be of value in treating this terrible disease.

Elucidating interactions between zebrafish innate immune system and cancer progression

In recent years, the innate immune system has been increasingly implicated in cancer prognosis. Neutrophils have been shown to migrate to the tumor microenvironment, release pro‐invasion factors, and even enhance angiogenesis. Here, we provide a glioblastoma tumor‐initiation model by transforming astrocytes with a constitutively activated form of kRasV12 in hopes of elucidating the contribution of neutrophil presence to tumorigenesis and progression. Constitutive expression of this oncogene has been demonstrated to induce malignant transformation in several models including the larval zebrafish. Additionally, the role of tumor suppressor protein p53 in relevance to this model remains largely unconfirmed. By expressing the oncogene in different p53 backgrounds, we demonstrate an increase in abnormal growth and mass formation in the absence of p53. Further experimental design perturbing neutrophil recruitment has the potential to identify novel interactions with the innate immune system and aggression of glioblastomas.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

К ВОПРОСУ О ДЕСИМПАТИЗАЦИИ ВЕРХНЕЙ КОНЕЧНОСТИ ПРИ ФЕНОМЕНЕ РЕЙНО

Objective: The review discussed the most important aspects of the implementation of various variants of upper sympathectomy under the Raynaud’s phenomenon. A short characteristic given, the indications, effectiveness and frequency of complications of open, video-thoracoscopic and periarterial digital sympathectomy, as well as the methods of chemical sympatholysis disclosed. The reasons for the relapse of the Raynaud’s phenomenon, in particular, include the preservation of additional sympathetic innervation of the upper limb, progressive immune aggression, rapid regeneration of the intersected nerve trunks, and the variability of the anatomy of the sympathetic nervous system discussed in details. In addition, the work reflects the issues of the volume of cervical and thoracic sympathectomy and their comparative effectiveness in the early and late periods of observation. The literature data show that the effectiveness of sympathectomy in the long-term follow-up period remains at 43.3-93.3% and depends, first, on the method of its conduct, the stage and genesis of the disease, and on the effect of trigger factors of vasospasm. Despite the contradictory results of the upper extremity sympathectomy in the Raynaud’s phenomenon, it continues to be the only hope in the arsenal of vascular surgeons, which in most cases can improve the circulation of the fingers and the hand. Keywords: Raynaud’s phenomenon, thoracic sympathectomy, chemical sympatholysis, videotoracoscopy, results.

The role of Kharkov orthopedic school in life and activity of professor Ilya Leont’evich Zaichenko (07.03.1896–06.15.1964)

The article reveals interesting details of the development of the system of health care and the development of the national orthopedics and traumatology in the period between the two world wars and the first post-war decades, and the importance of the developments of the Kharkov scientific school under the leadership of Professor Sitenko Mikhail Ivanovich. Under the influence of the Kharkov period, orthopedics became a vo­cation for Zaichenko Ilya Leontyevich, who, under the mot­to of the teacher (Sitenko M. I.), «to treat with his head, and not with his hands», remained loyal to the profession in the most difficult circumstances. A clear illustration of this was the medi­cal and underground activities of I. L. Zaichenko during the Second world war. In the postwar years, Professor Zaichen­ko I. L. trained 4 candidates and 1 doctor of medical sciences. Over the years of his scientific activity, he conducted more than 3 000 experiments, and in connection with this, he always re­called one of his teacher-teachers o Professor Yelenevsky K. F. It is worth noting the experiment of 1936 with the use of cold-preserved bone (Dr. Inklan applied a cold-frozen bone graft on a man in Cuba in 1942). Zaichenko I. L., MD, made three scientific discoveries: 1) created a scheme of regenerative pro­cess of bone tissue, consisting of six stages, which was formally adopted in the former USSR, which is reflected in the 14th volume of the Great Medical Encyclopaedia; 2) described in 1939 the process of resorption of the bone homotransplant by leu­cocytes «according to the type of ice melting» (now such cells are called immune competent, and clone them to create specific antisera that depress the host’s immune aggression against the graft); 3) manufactured an immunopreparation from rab­bit tissues treated before the preparation of oligopeptides. The achievements of Professor Zaichenko I. L. are still relevant today — his scientific works are cited, and the institutions and departments created by him continue to operate.

Experimental therapy of graft-versus-host disease by mesenchymal stromal cells grown on oxide nanocoatings

Immune aggression to transplanted allogeneic bone marrow, i.e. the graft-versus-host disease (GVHD), could be decreased by the suppression of effector and/or activation of T- regulatory cells (Treg). This task could be solved by co-transplantaiton of allogeneic bone marrow and mesenchymal stromal cells (MSCs). This study demonstrated the elevated immune modulating activity of MSCs by their culturing in vitro on Al₂0₃ oxide nanocoatings. Introduction of the cells to the animals with GVHD resulted in an increased content of Treg in the spleen of bone marrow recipients, reduced severity of the pathology, and higher survival of animals. Thefindings could be the basis for developing the new approaches to optimize the GVHD treatment methods involving the oxide nanocoating cultured MSCs.

Immuno-histochemical study of ovine cystic echinococcosis (Echinococcus granulosus) shows predominant T cell infiltration in established cysts

Ovine hydatidosis (OH; Echinococcus granulosus) is endemic in several European countries surrounding the Mediterranean basin. There have been a limited number of studies aimed at evaluating the local immune response to established tissue cysts in the ovine host. In the present study, immunohistochemical analysis of lymphocyte populations surrounding established cysts showed a predominance of CD3+ T cells compared to CD79+ B cells. A percentage of infiltrating lymphocytes were also FoxP3+, suggesting that established ovine cysts may be protected from immune aggression through the suppressive action of T regulatory cells. The present study contributes to the understanding of local immune responses to ovine echinococcosis.

Cytokines in Placental Physiology and Disease

Cytokines in Placental Physiology and Disease

Progenitor Cell Mobilizing Treatments Prevent Experimental Transplant Arteriosclerosis

Vascular rejection after organ transplantation is characterized by an arterial occlusive lesion, resulting from intimal proliferation occurring in response to arterial wall immune aggression. Our hypothesis is that an early endothelial repair may prevent vascular graft rejection. The aim of the current study was to compare different pharmacologic progenitor cell mobilizing treatments for their protective effects against vascular rejection. Aortic transplants were made from balb/c donor to C57Bl/6 recipient mice. Three different mobilizing pharmacologic agents were used: low molecular weight fucoidan (LMWF), simvastatin, and AMD3100. The circulating levels of progenitor cells were found to be increased by all three treatments, as determined by flow cytometry. For each treatment, the design was: treated allografts, nontreated allografts, treated isografts, and nontreated isografts. After 21 d, morphometric and immunohistochemical analyses were performed. We found that the three treatments significantly reduced intimal proliferation, compared with nontreated allografts. This was associated with intimal re-endothelialization of the grafts. Further, in chimeric mice that had previously received GFP-transgenic bone marrow transplantation, GFP-positive cells were found in the vascular allograft intima, indicating that re-endothelialization was, at least partly, due to the recruitment of bone marrow-derived, presumably endothelial progenitor circulating cells. In this aortic allograft model, three different mobilizing treatments were found to partially prevent vascular transplant rejection. Bone marrow-derived progenitor cells mobilized by the three treatments may play a direct role in the endothelial repair process and in the suppression of intimal proliferation.

Targeted nanotherapy for induction of therapeutic immune responses

Nanotechnology permits the design of therapeutic devices with defined structure and molecular composition. Modular designs employing surface-bound ligands provide specific homing devices for loaded cargo, and biocompatible and biodegradable constructs provide surrogate temporary microenvironments. We first present a case for developing 'smart' modular constructs as immunogenic vaccines to prime immune memory against specific pathogens where current vaccines fail. Second, we argue that nanotherapeutic intervention can harness pivotal molecular pathways recently discovered to regulate lineage development between pathogenic TH17 cells associated with autoimmune disease, versus tolerogenic regulatory T cells (Treg). Underpinned by molecular mechanisms that enable exquisitely specific responses in adaptive immunity, targeted nanodevices designed to stimulate either immune aggression or immune tolerance signify the birth of a new era in therapeutics.