scholarly journals Molecular Mechanisms of Premature Aging in Hemodialysis: The Complex Interplay between Innate and Adaptive Immune Dysfunction

2020 ◽  
Vol 21 (10) ◽  
pp. 3422
Author(s):  
Vincenzo Losappio ◽  
Rossana Franzin ◽  
Barbara Infante ◽  
Giulia Godeas ◽  
Loreto Gesualdo ◽  
...  
Keyword(s):  
Immune System ◽  
Adaptive Response ◽  
Molecular Mechanisms ◽  
B Lymphocyte ◽  
Treatment Guidelines ◽  
Immune Dysfunction ◽  
Premature Aging ◽  
Immune System Dysfunction ◽  
Wide Range ◽  
End Stage

Hemodialysis (HD) patient are known to be susceptible to a wide range of early and long-term complication such as chronic inflammation, infections, malnutrition, and cardiovascular disease that significantly affect the incidence of mortality. A large gap between the number of people with end-stage kidney disease (ESKD) and patients who received kidney transplantation has been identified. Therefore, there is a huge need to explore the underlying pathophysiology of HD complications in order to provide treatment guidelines. The immunological dysregulation, involving both the innate and adaptive response, plays a crucial role during the HD sessions and in chronic, maintenance treatments. Innate immune system mediators include the dysfunction of neutrophils, monocytes, and natural killer (NK) cells with signaling mediated by NOD-like receptor P3 (NLRP3) and Toll-like receptor 4 (TLR4); in addition, there is a significant activation of the complement system that is mediated by dialysis membrane-surfaces. These effectors induce a persistent, systemic, pro-inflammatory, and pro-coagulant milieu that has been described as inflammaging. The adaptive response, the imbalance in the CD4+/CD8+ T cell ratio, and the reduction of Th2 and regulatory T cells, together with an altered interaction with B lymphocyte by CD40/CD40L, have been mainly implicated in immune system dysfunction. Altogether, these observations suggest that intervention targeting the immune system in HD patients could improve morbidity and mortality. The purpose of this review is to expand our understanding on the role of immune dysfunction in both innate and adaptive response in patients undergoing hemodialysis treatment.

scholarly journals Clinical and morphological manifestations of immune system dysfunction in new coronavirus infection (COVID-19)

2021 ◽  
Vol 10 (1) ◽  
pp. 11-20
Author(s):  
L.M. Somova ◽  
◽  
E.A. Kotsyurbiy ◽  
E.I. Drobot ◽  
I.N. Lyapun ◽  
...  
Keyword(s):  
Immune System ◽  
Lymph Nodes ◽  
Immune Cell ◽  
Rapid Development ◽  
Immune Dysfunction ◽  
Cytokine Activation ◽  
Immune System Dysfunction ◽  
Wide Range ◽  
Circulating Lymphocytes ◽  
Coronavirus Infection

Rapid development in 2020 of the COVID-19 pandemic caused by SARS-CoV-2 initially indicated signifi-cant involvement of the immune system. However, information on specific changes in organs of the immune system is still limited. A wide range of alterations was revealed in our study: from pronounced devastation of B-dependent and T-dependent zones of lymphoid tissue, reminiscent of changes in HIV infection at the AIDS stage, to hyperplasia of the tissue of lymph nodes and spleen of varying degrees. Analyzing the literature data, we focused on the fact that pathomorphological changes revealed in the autopsy studies of patients with a severe COVID-19 were accompanied by premortal lymphopenia in most cases. However, the cause of lymphopenia in COVID-19 has not yet been disclosed, authors of the review hypothesized that unregulated apoptosis of circulating lymphocytes is one of the potential lymphopenia inductors. Cytokine activation (“cytokine storm”) may be associated with lymphoid organs’ atrophy, which also contributes to a decrease in the circulating lymphocyte count. There is no doubt about the relevance of further identification of the immune cell apoptosis as one of the causes of lymphopenia and immune dysfunction in COVID-19 patients, which has prospects for pharmacological developments to manage lymphocytic apoptosis. Keywords: coronavirus infection, COVID-19, pathomorphology, lymphopenia, lymph nodes, spleen, lym-phocytic apoptosis

MO902SERUM FREE LIGHT CHAINS IN HEMODIALYSIS PATIENTS: A BRIDGE BETWEEN INFLAMMATION, IMMUNE SYSTEM DYSFUNCTION AND MORTALITY RISK

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Antonio Lacquaniti ◽  
Susanna Campo ◽  
Teresa Casuscelli Di Tocco ◽  
Paolo Monardo
Keyword(s):  
Immune System ◽  
Mortality Risk ◽  
Innate Immune System ◽  
Roc Analysis ◽  
Immune Dysfunction ◽  
Innate Immune ◽  
Uremic Toxins ◽  
Immune System Dysfunction ◽  
Kaplan Meier

Abstract Background and Aims Uremic toxins, poor removed by conventional hemodialysis (HD), represent independent risk factors for mortality in end-stage renal disease (ESRD). Middle uremic toxin molecules were associated to pathological features of uremia, such as immune dysfunction and inflammation. These two entities are not mutually exclusive, but they could represent two sides of the same coin. ESRD-associated inflammation is closely related to the activation of innate immune system. Free light chain (FLC) may be a specific assessment of inflammation, representing a direct function of adaptive immunity through B-cell lineage production rather than a general marker of inflammation. While several studies have assessed the relation between FLCs and mortality risk in chronic kidney disease (CKD), FLCs, as uremic toxins in non-multiple myeloma dialyzed patients, were marginally analyzed. The aim of this prospective study was to evaluate the clinical impact of FLCs levels in HD patients, during a 2-years follow-up analysing the relations with biomarkers of inflammation, such as C-reactive protein (CRP) and procalcitonin (PCT), main lymphocytes subsets, such as CD4+ and CD8+ T cell count and high mobility group box (HMGB) -1 levels, as expression of the innate immune system. The potential link between FLCs levels and mortality risk was assessed. Method 190 patients on chronic hemodialysis at the Nephrology and Dialysis Unit of Papardo Hospital in Messina, Italy, were enrolled and followed for 2 years. Inclusion criteria were: age >18 years, absence or <200 ml/die residual diuresis, κ/λ ratio within the renal reference range (0.37–3.1). Receiver operating characteristics (ROC) analysis was performed to estimate the cut-off points of HMGB-1 and cFLC. Kaplan-Meier survival analysis and Cox proportional multivariate hazards model were used for clinical outcome. Results HD patients were characterized by high FLC levels. κFLC values were 182.3 (IQR: 140.2 – 216.1) mg/L, whereas λFLC levels were 108.2 (IQR: 72.7 – 143.2) mg/L. The median combined (c) FLC concentration was 182.9 mg/L (IQR = 207.8 – 330.2), which was extremely greater than the median reported in the general population (normal range = 9.3 – 43.3 mg/L) and in CKD patients [68.9 mg/L (IQR = 49.4 – 100.9)]. No differences in cFLC levels were revealed according to dialysis techniques. HD patients showed significant reduction of CD4+ and CD4+/CD8+ ratio. High HMGB1 levels were detected in HD patients (161.3 ± 39.7 ng/ml) and positively related to PCT and cFLC (r = - 0.38; p < 0.001), with an inverse relation to CD4+/CD8+ ratio. cFLC positively correlated with β2 microglobulin, hemoglobin, and HMGB1. Conversely, an inverse correlation was revealed with surrogate markers of inflammation, such as CRP, procalcitonin, neutrophil counts. There were 49 deaths during the follow-up. The majority (23/49) of deaths were attributed to cardiovascular disease, the remainder to infection and malignancy. cFLCs and sHMGB-1 levels in this group were significantly elevated. By ROC analysis, HMGB-1 levels > 100.9 ng/mL and cFLC > 223.4 mg/l were associated with a significantly lower survival rate (p < 0.02 by log-rank test) than for patients with lower levels when using Kaplan-Meier analysis. After adjusting for confounding factors, by Cox proportional hazards method, the difference remained statistically significant (p = 0.02) Conclusion Our study demonstrated an independent relation between high cFLC levels and mortality in HD patients. cFLCs represent a potential biomarker of “inflammunity”, a physiopathological process playing a pivotal role in ESRD, based on a vicious circle between inflammation and immune dysfunction. Further in-depth examinations should be verify our findings, determining whether therapeutic measures targeting cFLC balance, such as hemodiafiltration and expanded dialysis, would be helpful to reduce the “inflammunity” process, characterizing dialyzed patients.

scholarly journals Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections

2020 ◽  
Vol 2020 ◽  
pp. 1-27 ◽  
Author(s):  
Patricio L. Acosta ◽  
Alana B. Byrne ◽  
Diego R. Hijano ◽  
Laura B. Talarico
Keyword(s):  
Immune System ◽  
Host Defense ◽  
Immune Modulation ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Current Knowledge ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Effects ◽  
Wide Range

Type I interferons (IFN-I) are a group of related proteins that help regulate the activity of the immune system and play a key role in host defense against viral infections. Upon infection, the IFN-I are rapidly secreted and induce a wide range of effects that not only act upon innate immune cells but also modulate the adaptive immune system. While IFN-I and many IFN stimulated genes are well-known for their protective antiviral role, recent studies have associated them with potential pathogenic functions. In this review, we summarize the current knowledge regarding the complex effects of human IFN-I responses in respiratory as well as reemerging flavivirus infections of public health significance and the molecular mechanisms by which viral proteins antagonize the establishment of an antiviral host defense. Antiviral effects and immune modulation of IFN-stimulated genes is discussed in resisting and controlling pathogens. Understanding the mechanisms of these processes will be crucial in determining how viral replication can be effectively controlled and in developing safe and effective vaccines and novel therapeutic strategies.

Molecular mechanisms for B lymphocyte selection: induction and regulation of antigen-receptor-mediated apoptosis of mature B cells in normal mice and their defect in autoimmunity-prone mice

1994 ◽  
Vol 345 (1313) ◽  
pp. 297-301 ◽  
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Molecular Mechanisms ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Normal Function ◽  
T Helper ◽  
Helper Cells

Apoptosis (programmed cell death) has been suggested to be involved in clonal elimination of selfreactive lymphocytes for the normal function of the immune system. By crosslinking the antigen receptor (surface immunoglobulin; slg) on the peritoneal B cells of normal mice, we found that strong crosslinking of slg induces apoptosis of mature B cells, suggesting that interaction with membranebound self-antigens may eliminate self-reactive mature B cells by apoptosis. Antigen-receptor-mediated B cell apoptosis is blocked when a signal is transduced via the CD40 molecule on the B cell surface. Because the ligand of CD40 (CD40L) is expressed on activated T helper cells, B cells may escape from apoptosis and are activated when the immune system interacts with foreign antigens, which are normally able to activate T helper cells. Moreover, slg crosslinking fails to induce apoptosis of both bcl-2-transgenic mice and autoimmune-disease-prone New Zealand mice. In these mice, the defect in slg-mediated apoptosis of mature B cells may allow generation of self-reactive B cells, resulting in pathogenic consequences.

scholarly journals Immunology 101: fundamental immunology for the practicing hematologist

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 281-286
Author(s):  
Shannon A. Carty
Keyword(s):  
Immune System ◽  
Antitumor Immunity ◽  
Critical Role ◽  
Immune Dysfunction ◽  
Microbial Pathogens ◽  
Hematologic Disorders ◽  
Selective Pressures ◽  
Wide Range ◽  
The Impact ◽  
Host Tissues

Abstract From an evolutionary perspective, the immune system developed primarily to protect the host from pathogens. In the continuous balance between killing pathogens and protecting host tissues, selective pressures have shaped the discriminatory functions of the immune system. In addition to protection against microbial pathogens, the immune system also plays a critical role in antitumor immunity. Immune dysfunction, either under- or overactivity, is found in a wide range of hematologic disorders. Here we review the fundamental features of the immune system and the key concepts critical to understanding the impact of immune dysfunction on hematologic disorders.

scholarly journals Differential regulation of the immune system in a brain-liver-fats organ network during short term fasting

2020 ◽  
Author(s):  
Susie S.Y. Huang ◽  
Melanie Makhlouf ◽  
Eman H. AbouMoussa ◽  
Mayra L. Ruiz Tejada Segura ◽  
Lisa S. Mathew ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Fine Tuning ◽  
Short Term ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose ◽  
Wide Range ◽  
The Brain

ABSTRACTDifferent fasting regimens are known to promote health, mitigate chronic immunological disorders, and improve age-related pathophysiological parameters in animals and humans. Indeed, several clinical trials are currently ongoing using fasting as a potential therapy for a wide range of conditions. Fasting alters metabolism by acting as a reset for energy homeostasis. However, the molecular mechanisms underlying the beneficial effects of short-term fasting (STF) are still not well understood, particularly at the systems or multi-organ level. Here, we investigated the dynamic gene expression patterns associated with six periods of STF in nine different mouse organs. We cataloged the transcriptional dynamics within and between organs during STF and discovered differential temporal effects of STF among organs. Using gene ontology enrichment analysis, we identified an organ network sharing 37 common biological pathways perturbed by STF. This network incorporates the brain, liver, interscapular brown adipose tissue, and posterior-subcutaneous white adipose tissue, hence we named it the brain-liver-fats organ network. Using Reactome pathways analysis, we identified the immune system, dominated by T cell regulation processes, as a central and prominent target of systemic modulations during STF in this organ network. The changes we identified in specific immune components point to the priming of adaptive immunity and parallel the fine-tuning of innate immune signaling. Our study provides a comprehensive multi-organ transcriptomic profiling of mice subjected to multiple periods of STF, and adds new insights into the molecular modulators involved in the systemic immuno-transcriptomic changes that occur during short-term energy loss.

scholarly journals The Kynurenine Pathway—New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies

2021 ◽  
Vol 22 (18) ◽  
pp. 9879
Author(s):  
Anna Krupa ◽  
Irina Kowalska
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Kynurenine Pathway ◽  
Wide Range ◽  
Organ Specific ◽  
Autoimmune And Inflammatory Diseases

The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells’ differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies—type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.

scholarly journals Immunosenescence in Testicular Cancer Survivors: Potential Implications of Cancer Therapies and Psychological Distress

2021 ◽  
Vol 10 ◽  
Author(s):  
Silvia De Padova ◽  
Milena Urbini ◽  
Giuseppe Schepisi ◽  
Alessandra Virga ◽  
Elena Meggiolaro ◽  
...  
Keyword(s):  
Immune System ◽  
Testicular Cancer ◽  
Psychological Stress ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
T Cell Response ◽  
Premature Aging ◽  
High Dose ◽  
Hematopoietic Stem

Testicular cancer (TC) is the most frequent solid tumor diagnosed in young adult males. Although it is a curable tumor, it is frequently associated with considerable short-term and long-term morbidity. Both biological and psychological stress experienced during cancer therapy may be responsible for stimulating molecular processes that induce premature aging and deterioration of immune system (immunosenescence) in TC survivors, leading to an increased susceptibility to infections, cancer, and autoimmune diseases. Immunosenescence is a remodeling of immune cell populations with inversion of the CD4:CD8 ratio, accumulation of highly differentiated memory cells, shrinkage of telomeres, shift of T-cell response to Th2 type, and release of pro-inflammatory signals. TC survivors exposed to chemotherapy show features of immunological aging, including an increase in memory T-cells (CD4+ and CD8+) and high expression of the senescence biomarker p16INK4a in CD3+ lymphocytes. However, the plethora of factors involved in the premature aging of TC survivors make the situation more complex if we also take into account the psychological stress and hormonal changes experienced by patients, as well as the high-dose chemotherapy and hematopoietic stem cell transplantation that some individuals may be required to undergo. The relatively young age and the long life expectancy of TC patients bear witness to the importance of improving quality of life and of alleviating long-term side-effects of cancer treatments. Within this context, the present review takes an in-depth look at the molecular mechanisms of immunosenescence, describing experimental evidence of cancer survivor aging and highlighting the interconnected relationship between the many factors modulating the aging of the immune system of TC survivors.

scholarly journals Mouse models of immune dysfunction: Their neuroanatomical differences reflect their anxiety-behavioural phenotype

2021 ◽  
Author(s):  
Darren J Fernandes ◽  
Shoshana Spring ◽  
Christina Corre ◽  
Andrew Tu ◽  
Lily Qiu ◽  
...  
Keyword(s):  
Immune System ◽  
Mouse Models ◽  
Immune Dysfunction ◽  
Lateral Septum ◽  
Bayesian Hierarchical ◽  
Immune System Dysfunction ◽  
Immune Mediated ◽  
Magnetic Resonance Imaging Mri ◽  
Heterogeneous Effect

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging (MRI), we studied the neuroanatomical differences among 11 distinct genetically-modified mouse lines (n=371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures -- such as the corpus callosum, midbrain, and thalamus -- were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.

scholarly journals Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

2021 ◽  
Vol 9 ◽  
Author(s):  
Khairunnisa’ Md Yusof ◽  
Kira Groen ◽  
Rozita Rosli ◽  
Kelly A. Avery-Kiejda
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Lymphatic Vessels ◽  
Pathological Features ◽  
Secondary Lymphedema ◽  
Immune System Dysfunction ◽  
Lymphatic Fluid

Secondary lymphedema is characterized by lymphatic fluid retention and subsequent tissue swelling in one or both limbs that can lead to decreased quality of life. It often arises after loss, obstruction, or blockage of lymphatic vessels due to multifactorial modalities, such as lymphatic insults after surgery, immune system dysfunction, deposition of fat that compresses the lymphatic capillaries, fibrosis, and inflammation. Although secondary lymphedema is often associated with breast cancer, the condition can occur in patients with any type of cancer that requires lymphadenectomy such as gynecological, genitourinary, or head and neck cancers. MicroRNAs demonstrate pivotal roles in regulating gene expression in biological processes such as lymphangiogenesis, angiogenesis, modulation of the immune system, and oxidative stress. MicroRNA profiling has led to the discovery of the molecular mechanisms involved in the pathophysiology of auto-immune, inflammation-related, and metabolic diseases. Although the role of microRNAs in regulating secondary lymphedema is yet to be elucidated, the crosstalk between microRNAs and molecular factors involved in the pathological features of lymphedema, such as skin fibrosis, inflammation, immune dysregulation, and aberrant lipid metabolism have been demonstrated in several studies. MicroRNAs have the potential to serve as biomarkers for diseases and elucidation of their roles in lymphedema can provide a better understanding or new insights of the mechanisms underlying this debilitating condition.

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