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Growing evidence indicates that arsenic can cause long-lasting and irreversible damage to the function of the human immune system. It is known that forkhead box protein 3(Foxp3), which is specifically expressed in regulatory T cells (Tregs), plays a decisive role in immunoregulation and is regulated by DNA methylation. While evidence suggests that epigenetic regulated Foxp3 is involved in the immune disorders caused by arsenic exposure, the specific mechanism remains unclear. In this study, after primary human lymphocytes were treated with different doses of NaAsO2, our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35), and increasing the ratio of CD4+/CD8+ T cells in lymphocytes. Treatment with DNA methyltransferase inhibitor 5-Aza-CdR can notably inhibit the expression of DNMT1, effectively restoring the hypermethylation of the Foxp3 promoter region in primary human lymphocytes and upregulating the expression levels of Foxp3, balancing the ratio of CD4+/CD8+ T cells in lymphocytes. It also activates the secretion of anti-inflammatory cytokines and restores the immune regulatory functions of Tregs. In conclusion, our study provides limited evidence that DNMT1-mediated Foxp3 gene promoter hypermethylation is involved in immune dysfunction caused by arsenic in primary human lymphocytes. The study can provide a scientific basis for further understanding the arsenic-induced immune dysfunction in primary human lymphocytes.

Significance: Lupus nephritis (LuN) is a chronic inflammatory kidney disease. The cellular mechanisms by which LuN progresses to kidney failure are poorly characterized. Automated instance segmentation of immune cells in immunofluorescence images of LuN can probe these cellular interactions. Aim: Our specific goal is to quantify how sample fixation and staining panel design impact automated instance segmentation and characterization of immune cells. Approach: Convolutional neural networks (CNNs) were trained to segment immune cells in fluorescence confocal images of LuN biopsies. Three datasets were used to probe the effects of fixation methods on cell features and the effects of one-marker versus two-marker per cell staining panels on CNN performance. Results: Networks trained for multi-class instance segmentation on fresh-frozen and formalin-fixed, paraffin-embedded (FFPE) samples stained with a two-marker panel had sensitivities of 0.87 and 0.91 and specificities of 0.82 and 0.88, respectively. Training on samples with a one-marker panel reduced sensitivity (0.72). Cell size and intercellular distances were significantly smaller in FFPE samples compared to fresh frozen (Kolmogorov–Smirnov, p≪0.0001). Conclusions: Fixation method significantly reduces cell size and intercellular distances in LuN biopsies. The use of two markers to identify cell subsets showed improved CNN sensitivity relative to using a single marker.

The SARS-CoV-2 virus is known as the causal agent for the current COVID-19 global pandemic. The majority of COVID-19 patients develop acute respiratory distress syndrome (ARDS), while some experience a cytokine storm effect, which is considered as one of the leading causes of patient mortality. Lipids are known to be involved in the various stages of the lifecycle of a virus functioning as receptors or co-receptors that controls viral propagation inside the host cell. Therefore, lipid-related metabolomics aims to provide insight into the immune response of the novel coronavirus. Our study has focused on determination of the potential metabolomic biomarkers utilizing a Teslin® Substrate in paper spray mass spectrometry (PS-MS) for the development of a rapid detection test within 60 seconds of analysis time. In this study, results were correlated with PCR tests to reflect that the systemic responses of the cells were affected by the COVID-19 virus.

Whole-body exposure to low-dose radiation due to diagnostic imaging procedures, occupational hazards and radiation accidents is a source of concern. In this study, we analyzed the effects of single and long-term low-dose irradiation on the immune system. Male Balb/c mice received a single whole-body dose of irradiation (0.01, 0.05, 0.2, 0.5 or 1 Gy). For long-term irradiation, mice were irradiated 10 times (total dose of 0.2, 0.5 or 1 Gy) over a period of 6 weeks. Two days after single or long-term irradiation, the numbers of splenic macrophages, natural killer cells and dendritic cells were reduced, and the spleen organ coefficient was decreased. At 2 Days after long-term low-dose irradiation, the number of white blood cells in the peripheral blood of the mice decreased. Between 7 and 14 Days after long-term low-dose irradiation, the number of immune cells in the thymus and spleen began to increase and then stabilized. Th1/Th2 cytokines and reactive oxygen species-related proteins first decreased and then increased to a plateau. Our results show a significant difference in the effects of single and long-term low-dose irradiation on the immune system.

The current study investigates anti-neoplastic and immunomodulatory activities of co-treatment based on bovine lactoferrin (bLF) and/or muramyl dipeptide (MDP) with or without cisplatin (Cis) in tumor-bearing mice. In the present study, bLF (100 mg/kg; orally) and MDP (0.5 mg/kg; subcutaneously) was administered alone or together. MDP or bLF was co-treated with Cis (1 mg/kg; intraperitoneally) in mice-bearing Ehrlich solid carcinoma. Tumor size, tumor mass proliferation, apoptosis using immunohistochemistry, the alteration in spleen cell proliferation, phenotype using flow cytometry and white blood cells total and differential counts were detected. Treatment with Cis or (bLF and MDP) significantly reduced tumor size, upregulated the pro-apoptotic p53 expression and downregulated the anti-apoptotic Bcl-2 and proliferative marker PCNA expression compared to non-treated tumor-bearing animals. Moreover, co-treatment of MDP and Cis significantly potentiated the reduction of the tumor size, downregulated the Bcl-2 and PCNA expression and upregulated the p53 expression compared to Cis-treated animals. While bLF and Cis co-treatment positively controlled PCNA and p53 expression compared to tumor-bearing animals, it significantly potentiated the reduction of the tumor size and downregulated the Bcl-2 expression compared to Cis-treated animals. Co-treatment of (bLF and MDP), (bLF and Cis) or (MDP and Cis) increased the spleen cell proliferation and altered the immunological profile of the CD3+CD4+, CD3+CD8+, CD3+CD4+CD69+, CD3+CD8+CD69+ and CD11b+Ly6G+ cells to achieve better immune response against tumor. In conclusion, co-treatments based on bLF and/or MDP are promising therapies against cancer, through their potency to control proliferation, enhance apoptosis and improve the immune status against tumor cells.

Objectives Recombinant feline interferon-ω therapy is an immunomodulator currently used in the treatment of different retroviral diseases including feline immune deficiency virus and feline leukaemia virus. Although its mechanism of action remains unclear, this drug appears to potentiate the innate response. Acute phase proteins are one of the key components of innate immunity and studies describing their use as a monitoring tool for the immune system in animals undergoing interferon-ω therapy are lacking. This study aimed to determine whether interferon-ω therapy influences acute phase protein concentrations namely serum amyloid-A, α-1-glycoprotein and C-reactive protein. Methods A single-arm study was performed using 16 cats, living in an animal shelter, naturally infected with retroviruses and subjected to the interferon-ω therapy licensed protocol. Samples were collected before (D0), during (D10 and D30) and after therapy (D65). Serum amyloid-A and C-reactive protein were measured by specific enzyme-linked immunosorbent assay kits and α-1-glycoprotein by single radial immunodiffusion. Results All the acute phase proteins significantly increased in cats undergoing interferon-ω therapy (D0/D65: P

Background: Induction of a humoral response against amyloid-β peptide may be beneficial for Alzheimer’s disease (AD) patients and may alleviate the onset and progression of AD. DNA-based vaccination provides a unique alternative method of immunization for treatment and prevention of AD. Currently, the two major delivery methods used for enhancing DNA uptake and immune responses to DNA vaccines in humans are electroporation (EP) and gene gun (GG). Objective: The goal of this translational study was to evaluate the efficacy of an AD DNA epitope vaccine (DepVac) delivered intramuscularly by EP or intradermally by GG. Methods: Humoral and cellular immune responses to immunization with DepVac were evaluated by ELISA and ELISPOT, respectively. Functional activity of the antibodies was also assessed. Results: EP- and GG-mediated immunizations with DepVac induced similar anti-amyloid-β (Aβ) antibody and T cell responses. Anti-Aβ antibodies bound to amyloid plaques in AD brain tissue and to toxic forms of Aβ42 peptide. Conclusion: Both delivery methods are effective at promoting potent antibodies specific for Aβ.

The two main arms of the stress system include the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. These two neural stress systems coordinate the response of many other physiological systems to a stressor, including the immune and cardiovascular systems, bringing the body back to homeostasis. The nervous and immune systems communicate with each other in a bidirectional manner. In this review, we will discuss the use of noninvasive methods to evaluate the immune system, ANS and HPA axis. Collection of sweat and saliva, and measurement of heart rate variability are noninvasive methods that can be applied to evaluate neuroimmune interactions. Recently, we validated a new methodology to simultaneously evaluate a large array of neural and immune biomarkers in sweat, collected through cutaneous sweat patches and measured by recycling immunoaffinity chromatography. Noninvasive and ambulatory methodologies of biomarker collection can overcome several limitations intrinsic to invasive methods, such as reducing the stress triggered by collection itself and allowing a wider application to field and community-based settings. Ultimately, simultaneous evaluation of neural and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems and their role in disease susceptibility and progression of stress-related disorders.

An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have support- ed epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation.

Psychological stress is an important factor in susceptibility to many diseases. Our laboratory has been investigating the impact of stress on the susceptibility to Theiler’s virus-induced demyelination (TVID), a mouse model of multiple sclerosis. Using immunodominant viral peptides specific for identification of either CD4+ or CD8+ T cells, stress reduced IFN-γ-producing virus-specific CD4+ and CD8+ T cells in the spleen and CD8+ T cells in the CNS. Expression of mRNA for the Th1 transcription factor T-bet and the Th2 transcription factor GATA-3 were decreased in spleen cells isolated from stressed mice. Cytokine production by cells isolated from the CNS or spleens following stimulation with virus indicated that stress decreased both type 1 and type 2 responses. The adverse effects of stress were partially reversed by concurrent RU486 administration but mimicked by dexamethasone, indicating a major role for glucocorticoids. Global stress-induced immunosuppression resulted in higher levels of virus replication and dissemination. The higher viral load subsequently led to an earlier disease onset and more severe clinical and histological signs of demyelinating disease. Our results have important implications for understanding the pathogenesis of MS, and suggest that stressful events during early infection with an agent capable of inducing demyelination may result in immunosuppression and failure to eliminate the pathogen, which in turn may lead to the development of MS.

Stress is known to suppress immune function and increase susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate asthma, and allergic, autoimmune and inflammatory diseases, although such diseases should be ameliorated by immunosuppression. Moreover, the short-term fight-or-flight stress response is one of nature’s fundamental defense mechanisms that enables the cardiovascular and musculoskeletal systems to promote survival, and it is unlikely that this response would suppress immune function at a time when it is most required for survival (e.g. in response to wounding and infection by a predator or aggressor). These observations suggest that stress may suppress immune function under some conditions while enhancing it under others. The effects of stress are likely to be beneficial or harmful depending on the type (immunoprotective, immunoregulatory/inhibitory, or immunopathological) of immune response that is affected. Studies have shown that several critical factors influence the direction (enhancing vs. suppressive) of the effects of stress or stress hormones on immune function: (1) Duration (acute vs. chronic) of stress: Acute or short-term stress experienced at the time of immune activation can enhance innate and adaptive immune responses. Chronic or long-term stress can suppress immunity by decreasing immune cell numbers and function and/or increasing active immunosuppressive mechanisms (e.g. regulatory T cells). Chronic stress can also dysregulate immune function by promoting proinflammatory and type-2 cytokine-driven responses. (2) Effects of stress on leukocyte distribution: Compartments that are enriched with immune cells during acute stress show immunoenhancement, while those that are depleted of leukocytes, show immunosuppression. (3) The differential effects of physiologic versus pharmacologic concentrations of glucocorticoids, and the differential effects of endogenous versus synthetic glucocorticoids: Endogenous hormones in physiological concentrations can have immunoenhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immunosuppressive. (4) The timing of stressor or stress hormone exposure relative to the time of activation and time course of the immune response: Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response. We propose that it is important to study and, if possible, to clinically harness the immunoenhancing effects of the acute stress response, that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve. In view of the ubiquitous nature of stress and its significant effects on immunoprotection as well as immunopathology, it is important to further elucidate the mechanisms mediating stress-immune interactions and to meaningfully translate findings from bench to bedside.

Background: Little is known about long term prognosis and course after immune treatments in chronic inflammatory demyelinating polyneuropathy (CIDP). Objective: To study long term outcomes and prognostic factors in patients with CIDP. Methods: Clinical and electrophysiological findings, responses to immune modulating treatments, and outcomes five years after the start of treatment were reviewed in 38 CIDP patients. Results: Patients were treated with corticosteroids (89%), immunoglobulin infusion (45%), or plasmapheresis (34%), and 58% received combined therapy. Five years after treatment was begun, 10 (26%) of the patients had complete remission (lasting >2 years with normal nerve conduction studies), and 23 (61%) had partial remission (able to walk) with (26%) or without (34%) immune treatments. The remaining five patients (13%) still had severe disability (unable to walk) or treatment dependent relapses. Patients with complete remission more often had subacute onset, symmetrical symptoms, good response to initial corticosteroid treatment, and nerve conduction abnormalities predominant in the distal nerve terminals. In contrast, insidious onset, asymmetrical symptoms, and electrophysiological evidence of demyelination in the intermediate nerve segments were associated with refractoriness to treatment or treatment dependent relapse. Conclusions: The long term prognosis of CIDP patients was generally favourable, but 39% of patients still required immune treatments and 13% had severe disabilities. Mode of onset, distribution of symptoms, and electrophysiological characteristics may be prognostic factors for predicting a favourable outcome.

Where malaria surveillance and health care is inadequate, iron supplements given without food can increase the severity of malarial infections. The likely explanation is that the rate of iron influx into the plasma from high-dose oral supplements exceeds the rate of iron binding to transferrin and a quantity of non-transferrin-bound iron (NTBI) is formed. It is proposed that NTBI increases the intensity of malarial infections by increasing the sequestration of malaria-infected red cells in the capillaries of the brain and intestine, causing more cerebral malaria and further increasing the permeability of the intestinal barrier to the passage of pathogens. Bacteremia is frequently reported in children with severe malaria. At the same time, high iron doses stimulate the growth of pathogenic bacteria in the stool, further increasing the potential for bacteremia. The normal immune response to malaria, as well as other infections and inflammatory disorders, is to prevent further microbial growth by stimulating hepcidin synthesis and preventing the passage of iron into the plasma. Iron absorption is decreased and the efficacy of the iron interventions would be expected to be lower in the presence of infections.

In normal conditions, human gut mucosa is infiltrated with a large number of mononuclear cells. This is a reflection of the fact that human intestine is continuously subjected to a massive stimulation by luminal antigens. This state of "physiological" inflammation is a tightly controlled phenomenon, as several mucosal cells interact to generate and maintain an appropriate local immune response. Changes in cell type number and/or function, including the release of soluble mediators, have been associated with the development of chronic inflammatory diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease. Evidence also indicates that the type of inflammatory response occurring in the intestine of patients with CD differs from that in UC, and this probably reflects distinct pathways of immune activation. In CD mucosa, a Th1 response with high IL-12 and IFNgamma production prevails, while in UC a humoral immunity appears to be predominant. Despite this, CD and UC share downstream inflammatory events, characterised by high levels of inflammatory cytokines, free radicals, matrix-degrading enzymes and growth factors.

The present study was designed to examine, whether, effluents from a modern pulp and paper mill using elemental chlorine-free/total chlorine-free (ECF/TCF) bleaching, exert effects on the immune system of fish and, in addition, to relate these findings to physiological parameters known to be affected by bleached kraft-mill effluents (BKME). Roach (Rutilus rutilus) were exposed in laboratory conditions to primary- or secondary-treated effluent from a pulp and paper mill. In order to study their capability to respond to foreign antigens they were immunised with bovine gamma-globulin (BGG) prior to exposure. The number of anti-BGG antibody-secreting cells (ASC) and the number of immunoglobulin-secreting cells (ISC) in the spleen and blood as well as the level of anti-BGG specific antibodies and concentration of plasma immunoglobulin (IgM) were studied. Phagocytosis and migration of granulocytes of the head kidney were also determined. In addition to the immunological parameters, the activity of hepatic biotransformation enzymes, the carbohydrate metabolism and osmoregulation were examined. Exposure of roach for 21 days to BKME affected several immunological parameters. Both effluents, primary- and secondary-treated, impaired the immunoreactivity of the fish. Sex-related differences in the immune responses were evident in many parameters e.g. in the number of blood ISC and splenic ASC. Sex also had effects on cortisol levels and in the induction of 7-ethoxyresorufin O-deethylase (EROD). These results demonstrate that both primary- and secondary-treated effluent from a pulp and paper mill using ECF/TCF bleaching have effects on fish immune functions. Further, these findings suggest that steroids may contribute to immunomodulation in fish.

The immunotoxic potential of bleached kraft pulp mill effluent (BKME) to cell-mediated immunity in mink (Mustela vison) was investigated October 1993 through May 1994. For 26 weeks, 20 mink were fed a diet based upon fish caught within 6 km downstream of a bleached kraft mill in Saskatchewan, Canada. Water for this group contained 25% softwood-run BKME. Twenty control mink were fed nutritionally matched diets based upon fish from lakes receiving no municipal or industrial effluent and tap water. Using in vitro and in vivo immunotoxicity assays, the proliferative response of mink peripheral blood mononuclear cells (PBMC) to mitogens was optimal, at 72 hr with 10 micrograms/ml Concanavalin A, 1/80 dilution pokeweed mitogen, and 1/80 dilution phytohemagglutinin. Bacterial cell wall Escherichia coli lipopolysaccharide did not stimulate mitosis of the mink PBMC. No difference (P0.05) in PBMC proliferation was seen between the control and BKME-exposed mink with any of the mitogens used. Delayed type hypersensitivity (DTH), a cell mediated response, was assessed in mink vaccinated with live bacille Calmette-Guérin (BCG) and then challenged by intradermal toe web injection with 200 micrograms of sonicated BCG approximately 6 weeks later. The DTH response in the BKME-exposed mink was impaired based upon assessment using skin thickness measurements, histopathological assessment and image analyzer technology. This decreased response is evidence for suboptimal immune function associated with BKME exposure, which could affect the competitive fitness of piscivorous mammals naturally exposed to BKME.

Antibodies to Pseudomonas aeruginosa from 10 cystic fibrosis patients with chronic P. aeruginosa lung infections were quantitatively and qualitatively analyzed. The development of specific antibodies in patient serum was evaluated in a longitudinal study (1972 to 1987). The concentrations and specificities of immunoglobulin G (IgG) and IgM antibodies to purified lipopolysaccharides (LPS) from clinical isolates of P. aeruginosa and to a variety of other gram-negative bacteria were studied by immunoblotting and enzyme-linked immunosorbent assay techniques. Results were compared with the number of immunoprecipitates to P. aeruginosa whole-cell extracts detected by crossed immunoelectrophoresis. IgG, but not IgM, anti-Pseudomonas LPS concentrations increased significantly at the onset of chronic infection and continued to increase during the course of the infection. There was a good positive correlation between the concentration of IgG anti-Pseudomonas LPS antibodies and the number of crossed-immunoelectrophoresis precipitins. The increases in IgG anti-LPS antibody concentrations were much higher to Pseudomonas LPS than to other LPSs. Binding studies demonstrated an increase in binding of IgG anti-Pseudomonas LPS during infection, whereas the binding of other anti-LPS antibodies decreased. Immunoblotting studies confirmed that antibodies reacted strongly with Pseudomonas LPS and weakly with Escherichia coli core-lipid A. The specificity of the reaction with Pseudomonas LPS increased with the duration of infection. It is concluded that anti-LPS response in cystic fibrosis patients during chronic P. aeruginosa infection demonstrates a marked increase in IgG anti-Pseudomonas LPS antibody concentration, specificity, and affinity. The anti-LPS enzyme-linked immunosorbent assay is proposed as a routine test to diagnose and to follow the course of chronic P. aeruginosa lung infection in patients with cystic fibrosis.