Immune Disturbances Research Articles

The relation of Toxoplasma gondii with Tumor Necrotizing Factor-α in type II Diabetic patients

Toxoplasma gondii is an obligate intracellular parasite that can cause variable clinical symptoms or can even be asymptomatic in immuno-competent individuals , whereas more severe symptoms are observed in immuno-compromised patients. Type 2 diabetes mellitus (T2DM) continues to be a major challenge for public health community, many factors play important role in the pathogenesis of diabetes such as obesity, physical inactivity, and dietary patterns.Moreover many infectious agents may play role in the pathogenesis of diabetes. Both toxoplasmosis and diabetes are very common in Iraq. Recently, some reports have spotlighted the probable relevance of diabetes mellitus (DM) and infectious agent as T. gondii, and it has been proposed that as a likely cause of diabetes. Objective: To determine the possible relation between T2DM and Toxoplasm by detection and evaluating IgM and IgG Toxoplasma gondii antibody and investigating the level of TNF-a, HbA1C in diabetic patients whether infected or not infected with Toxoplasma gondii. Methods: This case control study was conducted on 180 patients with T2DM along with 40 healthy age and gender matched individuals who were included as healthy control.All patients were investigated for the presence of Toxoplasma gondii by Rapid chromatographic test and by ECLA(ElectrochemiluminescenceImmunoassay). All samples whether positive or negative for toxoplasma, will be subjected for measuring HbA1C by automated Fluorescence Immunoassay (AFIAS) and TNF-a by ELISA technique. Results: This study showed that 42.2% of diabetic patients were infected with Toxoplasma gondii and 25% of apparently healthy control subjects were infected with Toxoplasma gondii ; moreover 46.4 % of diabetic patients on insulin therapy were infected with T.gondii whereas 37 % of diabetic patients on oral hypoglycemic agents (OHA) were infected with T. gondii. Furthermore IgG level , HbA1c levels and TNF were significantly high in diabetic patients on insulin who were infected with Toxoplasma gondii. Conclusion: Since the incidence of T.gondii in Diabetic patients was higher than in control group thus we may predict that immune disturbance in diabetes had paved the way to Toxoplasma infection or may be due to the parasite itself had direct effect on Beta cell of the pancreas that may lead to diabetes.

Elevated Serum Level of CXCR4 in Breast Cancer Women

Breast cancer is a disease that can be described as malignant cells from the breast tissues. Immune deregulation has been postulated to be one of the mechanisms underlying the pathogenesis of breast cancer. The current study is planned to shed light on the following profiles and identify the relationships serum levels of CXCR4 among obesity postmenopausal, and Breast cancer. This study hypothesized that CXCR4 level would have a link with breast cancer patients. The serum CXCR4 level was measured by enzyme-linked immunosorbent assay (ELISA) in breast cancer patients (n=60) and healthy controls (n=61). The observations indicate a significant increase (P =0.05) in breast cancer patient’s serum levels of CXCR4 compared with healthy control. The study also presented a significant difference among age and Body Mass Index (BMI) between patients and control groups. The results supported that the immune disturbance is related tobreast cancer patients and might play an important role in the pathophysiology of breast cancer.

Порушення місцевого імунітету та цитокінового статусу у хворих на генералізований пародонтит

Порушення місцевого імунітету та цитокінового статусу у хворих на генералізований пародонтит

Cesarean Section Induces Microbiota-Regulated Immune Disturbances in C57BL/6 Mice.

Epidemiological studies have shown that children born by cesarean section (CS) are at higher risk of developing chronic inflammatory diseases, and it has been suggested that a skewed gut microbial colonization process early in life and altered priming of the immune system are causative. The aim of this study was to clarify whether impaired regulatory immunity in CS-delivered C57BL/6 mice is dependent on gut microbiota (GM) disturbances. The GM of conventionally bred mice born by CS differed clearly from mice born by vaginal delivery. The proportion of regulatory T cells was reduced in mice born by CS, whereas the invariant NKT (iNKT) cell subset was increased compared with vaginal delivery mice. In addition, regulatory markers (Foxp3, Il10, Ctla4) and macrophage markers (Cd11c, Egr2, Nos2) were downregulated, whereas iNKT markers (Il4, Il15) were upregulated in ileum of CS-delivered mice. The GM of CS-delivered mice was sufficient to transfer the shifts in immunity associated with delivery mode when inoculated into germ-free mice. Feeding a prebiotic diet reestablished gene expression of intestinal immune markers and iNKT cells in CS mice but was not sufficient to restore the level of regulatory T cells. The results support that CS delivery is associated with microbiota-mediated shifts in regulatory immunity and, therefore, provide a basis for future microbiota-directed therapeutics to infants born by CS.

Prevention of Hearing Loss by Alteration of the Systemic Immune System

Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4+ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.

Skim milk powder with high content of Maillard reaction products affect weight gain, organ development and intestinal inflammation in early life in rats

BackgroundThe intestinal tract is important for development of immune tolerance and disturbances are suggested to trigger autoimmune disorders. The aim of this study was to explore the effect of Maillard products in skim milk powder obtained after long storage, compared to fresh skim milk powder. MethodsYoung rats were weaned onto a diet based on skim milk powder with high concentration of Maillard products (HM-SM, n = 18) or low (C-SM, n = 18) for one week or four weeks. Weekly body weight and feed consumption were noted. At the end, organ weights, intestinal histology, permeability and inflammatory cytokines were evaluated. ResultsRats fed with HM-SM had after one week, 15% less weight gain than controls, despite equal feed intake. After one week thymus and spleen were smaller, intestinal mucosa thickness was increased and acute inflammatory cytokines (IL-17, IL-1β, MCP-1) were elevated. After four weeks, cytokines associated with chronic intestinal inflammation (fractalkine, IP-10, leptin, LIX, MIP-2, RANTES and VEGF) were increased in rats fed with HM-SM compared to C-SM. ConclusionHigh content of Maillard products in stored milk powder caused an intestinal inflammation. Whether this is relevant for tolerance development and future autoimmune diseases remains to be explored.

Post-Transplant Cyclophosphamide Ameliorates Lethal Thymic GVHD By Restoring Regulatory and Effector T Cell Homeostasis in Recipients with Prior PD-1 Blockade Therapy

Allogeneic HSCT has a curative potential for patients with hematological malignancies. However, graft-versus-host disease (GVHD) remains to be a significant cause of morbidity and mortality after HSCT. Regulatory T cells (Tregs) are critical mediator for immune tolerance after HSCT and we recently reported that PD-1 plays an essential role for Treg survival (Asano et al, Blood 2017). Clinical studies suggested that PD-1 blockade prior to HSCT could be a risk of increasing severe GVHD. However, the mechanisms about GVHD induced by PD-1 blockade have largely unclear and there remains a paucity of data on appropriate GVHD prophylaxis for patients who undergo HSCT after PD-1 blockade. To address these issues, we investigated the impact of PD-1 expression on donor T cells on immune reconstitution with murine BMT models. First, lethally irradiated B6D2F1 mice were transplanted with 10 million of C57BL/6-background PD-1+/+ or PD-1-/- spleen cells with 5 million of bone marrow cells from normal C57BL/6, and GVHD scores and overall survival was monitored. Recipients receiving PD-1-/- graft developed severe GVHD resulting in a significant shorter survival than recipients receiving PD-1-/- graft (P<0.0001). We analyzed lymphocytes in spleen and thymus on day3, 7, and 14. We found that CD8 T cells in PD-1-/- group showed markedly higher Ki67 expression and CFSE-dilution until day3. Interestingly, PD-1-/- Tregs increased aggressively at day3 but it could not maintain until day14, while PD-1-/- CD8 T cells and conventional CD4 T cells (CD4 Tcons) continued to increase until day+14, resulting in the significant higher CD8/Treg ratio in PD-1-/- group (P<0.05, vs PD-1+/+ group). PD-1-/- Tregs showed significantly higher expression of Annexin V on day+7 and thymus CD4- and CD8- double-positive (DP) cells were in the extremely low levels in PD-1-/- group on day+14 (P<0.05, vs PD-1+/+ group). Thymic analysis showed that donor PD-1-/- graft-derived CD8 T cells infiltrated thymus in PD-1-/- group, suggesting reconstruction of thymic function was critically disturbed by severe GVHD. These data suggest that loss of PD-1 signaling resulted in unbalanced reconstitution of donor-derived T cell subsets as a consequence of continuous CTL expansion and increased Treg apoptosis. Next, to evaluate the impact of post-transplant cyclophosphamide (PTCy) on the abnormal reconstitution after PD-1 blockade, we administered 50mg/kg of Cy or control vehicle on day3. PTCy efficiently ameliorated GVHD in PD-1-/- group and extended overall survival by safely regulating the proliferation and apoptosis of T cell subsets. Of note, after PTCy, Tregs regained the ability of continuous proliferation in the first 2 weeks, resulting in well-balanced reconstitution of donor-derived T cell subsets. Thymic DP cells on day 14 was markedly increased in PD-1-/- group with PTCy intervention as compared to without PTCy, suggesting PTCy could rescue thymus from PD-1 blockade-related severe GVHD. Finally, to evaluate GVL activity, we performed BMT with co-infusion of P815L tumor cells on day0 and we confirmed that PTCy treatment for PD-1-/- recipients reduced the severity of GVHD with maintaining sufficient GVL effect. In summary, our data suggested three insights about the impact of PD-1 signaling on immune reconstitution. First, PD-1 inhibition influenced graft-derived T cells very differently within T cell subsets. PD-1-/- Tregs increased transiently but it was counterbalanced by accelerated apoptosis, while PD-1-/- CD4+Tcons and CD8 T cells continued the drastic expansion. Second, we found that PD-1-/- donor T cells developed severe GVHD in thymus. Few reports have concentrated on the impact of donor graft PD-1 expression to thymus after BMT and acute GVHD in thymus could lead late central immune disturbance. Third, PTCy successfully ameliorated GVHD induced by PD-1-/- donor T cells preserving GVL effect. Cell proliferation study implied that PD-1-/- graft-derived CD8 T cells might be more susceptible for PTCy because of the high-rate proliferation. In conclusion, PD-1-/- graft cause lethal thymic GVHD and PTCy successfully ameliorated it. The influence of PD-1 inhibition was different within T cell subtypes. PTCy might be appropriate GVHD prophylaxis strategy for patients who had prior usage of PD-1 blockade. DisclosuresNo relevant conflicts of interest to declare.

Hepatic encephalopathy: Sometimes more portal than hepatic.

Hepatic encephalopathy is a severe complication of both chronic and acute liver diseases. The term hepatic encephalopathy stems from the belief that hepatic insufficiency is its fundamental etiopathogenic factor. However, most clinical cases show liver failure along with mesenteric venous portal hypertension. This portal hypertension would explain the abnormal mechanical forces suffered by the digestive tract in the early stages of the disorder. These forces could regulate some gut biochemical pathological pathways in a process known as mechanotransduction. Thus, portal hypertension would begin with the establishment of a mechanotransduced afferent or sensory inflammatory gut-brain pathway, resulting in functional and structural changes in the central nervous system. In this review, we will revisit the term "hepatic encephalopathy" in light of new results where portal hypertension occurs before liver failure and is accompanied by brain changes. Moreover, we will point out cellular links that can explain the microbiota, immune, gut, and brain axis disturbances found in this disorder.

T cell epigenetic remodeling and accelerated epigenetic aging are linked to long-term immune alterations in childhood cancer survivors

BackgroundCancer treatments have substantially improved childhood cancer survival but are accompanied by long-term complications, notably chronic inflammatory diseases. We hypothesize that cancer treatments could lead to long-term epigenetic changes in immune cells, resulting in increased prevalence of inflammatory diseases in cancer survivors.ResultsTo test this hypothesis, we established the epigenetic and transcriptomic profiles of immune cells from 44 childhood cancer survivors (CCS, > 16 years old) on full remission (> 5 years) who had received chemotherapy alone or in combination with total body irradiation (TBI) and hematopoietic stem cell transplant (HSCT). We found that more than 10 years post-treatment, CCS treated with TBI/HSCT showed an altered DNA methylation signature in T cell, particularly at genes controlling immune and inflammatory processes and oxidative stress. DNA methylation remodeling in T cell was partially associated with chronic expression changes of nearby genes, increased frequency of type 1 cytokine-producing T cell, elevated systemic levels of these cytokines, and over-activation of related signaling pathways. Survivors exposed to TBI/HSCT were further characterized by an Epigenetic-Aging-Signature of T cell consistent with accelerated epigenetic aging. To investigate the potential contribution of irradiation to these changes, we established two cell culture models. We identified that radiation partially recapitulated the immune changes observed in survivors through a bystander effect that could be mediated by circulating factors.ConclusionCancer treatments, in particular TBI/HSCT, are associated with long-term immune disturbances. We propose that epigenetic remodeling of immune cells following cancer therapy augments inflammatory- and age-related diseases, including metabolic complications, in childhood cancer survivors.

Oxidative stress and immune aberrancies in attention-deficit/hyperactivity disorder (ADHD): a case-control comparison.

The objective of this study is to compare oxidative stress and immune biomarkers between attention-deficit/hyperactivity disorder (ADHD) patients and controls without ADHD. A case-control comparison between 57 paediatric (6-12years) untreated ADHD patients from the Antwerp University Hospital and 69 controls without ADHD from random schools in Flanders, Belgium, was conducted. Erythrocyte glutathione (GSH) and plasma lipid-soluble antioxidants (retinol, α-tocopherol, γ-tocopherol, retinyl palmitate, β-carotene, and co-enzyme Q10) were determined by HPLC with electrochemical detection, plasma malondialdehyde (MDA) by HPLC with fluorescence detection, plasma cytokines (interleukin (IL)-1β, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF) and interferon (INF)-γ) and immunoglobulins (IgE, IgG and IgM) by flow cytometry and urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels by ELISA assay. Dietary habits were determined by a food frequency questionnaire. Plasma MDA levels were on average 0.031µM higher in patients than in controls (p < 0.05), and a trend for higher urinary 8-OHdG was observed. Erythrocyte GSH and plasma retinyl palmitate levels, as well as IgG and IgE levels, were higher in patients than in controls as well (on average 93.707µg/ml, 0.006µg/ml, 301.555µg/ml and 125.004µg/ml, resp., p < 0.05). Finally, a trend for lower plasma IL-5 levels was observed. After Bonferroni correction for multiple testing, the difference in GSH levels remained statistically significant (nominally significant for retinyl palmitate), while significance was lost for MDA, IgG and IgE levels. Dietary habits do not appear to cause the observed differences. These results point at the potential involvement of slight oxidative stress and immune disturbances in ADHD.

Nucleic Acid Induced Interferon and Inflammasome Responses in Regulating Host Defense to Gastrointestinal Viruses.

The gut bacterial and fungal communities residing in the gastrointestinal tract have undisputed far-reaching effects in regulating host health. In the meantime, however, metagenomic sequencing efforts are revealing enteric viruses as the most abundant dimension of the intestinal gut ecosystem, and the first gut virome-wide association studies showed that inflammatory bowel disease as well as type 1 diabetes could be linked to the presence or absence of particular viral inhabitants in the intestine. In line with the genetic component of these human diseases, mouse model studies demonstrated how beneficial functions of a resident virus can switch to detrimental inflammatory effects in a genetically predisposed host. Such viral-induced intestinal immune disturbances are also recapitulated by several gastrointestinal infectious viruses such as rotavirus and human norovirus. This wide range of viral effects on intestinal immunity emphasizes the need for understanding the innate immune responses to gastrointestinal viruses. Numerous nucleic acid sensors such as DexD/H helicases and AIM2 serve as cytosolic viral guardians to induce antiviral interferon and/or pro-inflammatory inflammasome responses. In both cases, pioneering examples are emerging in which RNA helicases cooperate with particular Nod-like receptors to trigger these cellular responses to enteric viruses. Here we summarize the reported beneficial versus detrimental effects of enteric viruses in the intestinal immune system, and we zoom in on the mechanisms through which sensing of nucleic acids from these enteric viruses trigger interferon and inflammasome responses.

Dermatological aspects of the S2k guidelines on Down syndrome in childhood and adolescence.

With an incidence of 1 in 700 births, Down syndrome (DS) is not an uncommon condition. It is associated with various disorders of different organ systems. Serious disorders include cardiac defects and leukemia. With an onset during the newborn period, the latter does not always progress to classic myeloid leukemia (transient myeloproliferative disorder). Skin manifestations in newborns include pustules/vesiculopustules. In individuals with DS, such lesions should not only prompt suspicion for typical neonatal rashes and infections but also for transient myeloproliferative disorder. However, most dermatoses are benign. They essentially comprise disorders of keratinization that present as xerosis, keratosis pilaris, lichenification, and ichthyosis vulgaris. Also typical but not specific is the four-finger palmar crease (simian crease). Patients frequently develop folliculitides, which - due to elastolysis - subsequently progress to anetoderma. The known immune disturbance in DS patients explains the occurrence of autoimmune diseases such as alopecia areata and vitiligo. Typical skin conditions associated with DS include elastosis perforans serpiginosa, syringomas, milia-like calcinosis cutis, and multiple eruptive dermatofibromas.

Cardiovascular disease in systemic lupus erythematosus: an update.

The mechanisms leading to the development of premature atherosclerosis and vascular injury in systemic lupus erythematosus (SLE) remain to be fully elucidated. This is a comprehensive review of recent research developments related to the understanding of cardiovascular disease (CVD) in lupus. SLE patients with lupus nephritis display significantly increased risk of myocardial infarction and CVD mortality than SLE patients without lupus nephritis. SLE disease-related parameters could be taken into consideration when calculating CVD risks. The type I interferon pathway is detrimental to the vasculature and may contribute to the development of insulin resistance. The level of low-density granulocytes, a distinct subset of proinflammatory neutrophils present in SLE, was independently associated with coronary plaque burden and endothelial dysfunction. Invariant natural killer T cells may promote an atheroprotective effect in SLE patients with asymptomatic atherosclerotic plaques. Oxidized lupus high-density lipoprotein promotes proinflammatory responses in macrophages. Recent discoveries have further strengthened the critical role of SLE-related immune dysregulation and metabolic disturbances in promoting accelerated CVD. Understanding how these pathogenic factors promote vascular injury may provide better molecular candidates for therapeutic targeting, and ultimately to improve CVD outcomes.

Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development.

Numerous studies have reported immune system disturbances in individuals with autism and their family members; however, there is considerable variability in findings with respect to the specific immune conditions involved, their timing, and the family members affected and little understanding of variation by autism subphenotype. Using data from the Study to Explore Early Development (SEED), a multi-site case-control study of children born 2003-2006 in the United States, we examined the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD). We investigated maternal immune conditions during the pregnancy period, as well as lifetime history of these conditions in several family members (mother, father, siblings, and study child). Logistic regression analyses included 663 children with ASD, 984 children with DD, and 915 controls ascertained from the general population (POP). Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD. Risk estimates varied by specific ASD subphenotypes in association with these exposures. In addition, children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls. No association was observed for paternal history or family history of these immune conditions for either ASD or DD. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes, and further suggest that associations may differ by ASD phenotype of the child. Autism Research 2019, 12: 123-135. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multi-site study in the US-the Study to Explore Early Development-we found that women with a history of eczema/psoriasis and asthma are more likely to have children with ASD or DD. In addition, children with ASD are more likely to have a history of psoriasis/eczema or allergies than typically developing children. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes.

Depressive disorders in women of climacteric age (review of foreign literature for 2012–2016)

Objective:to systematically review foreign literature and interpret results of the review. Tasks: to review foreign papers where factors are considered which provoke development of depression: hormonal, psychological, social as well as neuromediators, hormonal and immune disturbances in depressive disorders in women with physiological climacteric and climacteric syndrome; issues of differential diagnostics of depressions, psychopharmaco- and psychotherapy with subsequent evaluation of clinical efficiency; personality profile of pateints with affective psychopathology.Methods of search: by keywords in Web of Science Core Collection database across foreign journals (2012– 2016). Criteria of inclusion of papers in the review are determined by themes of studies: 1) women of climacteric age; 2) presence of depression or depressive symptoms; 3) presence of climacteric disturbances. In the abstract-bibliographic and scientometric database Web of Science Core Collection 70 bibliographic sources are selected across foreign journals between 2012 and 2016, including journals with high Impact Factor. Studies included in the review are performed at the university clinics, specialized centers. Clinical and sociodemographic characteristics of female patients meet the criterion of compatibility. Most discussed papers are devoted to study of clinical and social-psychological factors of development of climacteric depression. In a number of papers the efficiency of antidepressant therapy, alternative methods and supplementary therapy in women with depressive disorders, climacteric disturbances and co-occurring physical diseases is shown. Most works are performed with involvement of questionnaires (sociodemographic data, anamnesis) and international clinical scales. The main results of the discussed papers are outlined in thematic rubrics.Conclusion. The European and American papers are used in this review more frequently; studies from Asian countries are used more seldom. Reviewed foreign publications reflect worldwide trend to increase of climacteric depression (CD) in the female population with presence in the anamnesis of adolescent (psychoendocrine alteration) and postpartum depression, premenstrual syndrome. Low timely diagnostics of depressions, high incidence rate of somaticized CD are noted. In the structure of climacteric syndrome the psychoemotional disturbances predominate above neurovegetative and metabolic-endocrine or are combined with vegetative dysfunction. The participation in formation of CD (with predominance of mild/moderate severity) of neurohormonal, genetic, biochemical, social-environmental, psychological factors is shown. In the reviewed sources low mood, loss of previous priorities, decrease of productivity and concentration of attention, position of being unprotected, dependence, lack of confidence, self-humiliation, repentance, unbelief in future, insomnias, hypo-/hyperrexia with change of body mass are described in CD but there are no publications on suicidal ideation. It is indicated that CD can flow with hysteric- and nosophobic, somatohypochondriac and asthenohypochondriac component. The authors consider that somatization as an experience of climacteric stress leads to somaticized CD with accent on physical symptoms and repression of depression and anxiety although an association of specific somatic nosologies with symptoms of CD is not described. The association of CD with social-environmental factors (gender, education, profession, social position, financial wealth) is discussed, achievement of the woman is considered as a actor of reduction of CD risk. The authors are highly interested in search for genetic markers (heredity, suicides in relatives), impairment of neuromediator exchange (neurotransmitters serotonin, dopamine, adrenaline, and noradrenaline), neuromorphologic alterations in brain sensorimotor cortex (motor function, attention, perception, memory, and emotional-motivational response), hormonal disturbances (neuroendocrine and metabolic) and psychoneuroimmunological patterns of association with CD. Psychopharmacotherapy in CD is constructed with account for depressive symptoms (antidepressants of activating/sedative action in long-term maintenance regime), background and co-occurring diseases (adequate and pathogenetic and immunotherapy) with involvement in case of absence of contraindications of substitutive hormonotherapy (estrogen, progesterone). Beyond conventional schemes of the therapy the alternative therapy of CD (acupuncture, yoga, phytoestrogen collections, and food additives) is discussed. For heightening the efficiency and safety of the therapy of CD the training in detection of CD signs both for female patients and nurses, psychologists, social workers is proposed.

Mechanistic Clues to Overcome Spaceflight-Induced Immune Dysregulation

To recapitulate the latest findings from comprehensive studies of relatively long-duration spaceflight aboard the International Space Station, followed by exciting research published recently that illuminates the means by which we may be able to correct the immune system disturbances associated with spaceflight. While in space, most astronauts experience immune perturbations that may manifest as a form of immunodeficiency or, alternatively, a hypersensitivity reaction. When it occurs, the dysregulation persists stably for the duration of the mission. T lymphocytes – a population of the adaptive immune system that is essential for life – are particularly prone to spaceflight-induced malaise. Using cells from crewmembers during spaceflight, as well as cells in simulated microgravity model environments, researchers have begun to define specific alterations in antigen recognition, cell signaling, and gene expression patterns that may be responsible, in whole or in part, for the apparent depression in immune cell function. Given the next major objective of the global space exploration community is voyage to Mars -- which means the missions will be of an unprecedented duration – it is reasonable to hypothesize the crewmembers’ health will be at greater risk than ever before. Thus, our communal goal is to devise a set of countermeasures that will obviate this risk. A prerequisite to this end is an understanding of the mechanisms underlying the immune perturbations.

Is There a Role for Hematopoietic Growth Factors During Sepsis?

Sepsis is a complex syndrome characterized by simultaneous activation of pro- and anti-inflammatory processes. After an inflammatory phase, patients present signs of immunosuppression and possibly persistent inflammation. Hematopoietic growth factors (HGFs) are glycoproteins that cause immune cells to mature and/or proliferate. HGFs also have a profound effect on cell functions and behavior. HGFs play crucial role in sepsis pathophysiology and were tested in several clinical trials without success to date. This review summarizes the role played by HGFs during sepsis and their potential therapeutic role in the Management of sepsis-related immune disturbances.

The potential importance of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of Alzheimer's disease.

The exact cause of Alzheimer's disease (AD) is still unknown, but the deposition of amyloid-β (Aβ) plaques and chronic inflammation indicates that immune disturbances are involved in AD pathogenesis. Recent genetic studies have revealed that many candidate genes are expressed in both microglia and myeloid cells which infiltrate into the AD brains. Invading myeloid cells controls the functions of resident microglia in pathological conditions, such as AD pathology. AD is a neurologic disease with inflammatory component where the immune system is not able to eliminate the perpetrator, while, concurrently, it should prevent neuronal injuries induced by inflammation. Recent studies have indicated that AD brains are an immunosuppressive microenvironment, e.g., microglial cells are hyporesponsive to Aβ deposits and anti-inflammatory cytokines enhance Aβ deposition. Immunosuppression is a common element in pathological disorders involving chronic inflammation. Studies on cancer-associated inflammation have demonstrated that myeloid-derived suppressor cells (MDSCs) have a crucial role in the immune escape of tumor cells. Immunosuppression is not limited to tumors, since MDSCs can be recruited into chronically inflamed tissues where inflammatory mediators enhance the proliferation and activation of MDSCs. AD brains express a range of chemokines and cytokines which could recruit and expand MDSCs in inflamed AD brains and thus generate an immunosuppressive microenvironment. Several neuroinflammatory disorders, e.g., the early phase of AD pathology, have been associated with an increase in the level of circulating MDSCs. We will elucidate the immunosuppressive armament of MDSCs and present evidences in support of the crucial role of MDSCs in the pathogenesis of AD.

Maternal immune activation induced by lipopolysaccharide triggers response inflammatory, oxidative damage and damage to blood brain barrier integrity and placental barrier in Wistar rats pregnant and fetus

Abstract Evidence suggest that prenatal immune system disturbance contributes largely to the pathophysiology of neuropsychiatric disorders. A bacterial infection animal model widely accepted is administration of lipopolysaccharide (LPS). We investigated if maternal immune activation (MIA) could induce inflammatory alterations, oxidative damage and damage to blood brain barrier integrity (BBB) and placental barrier (PB) in fetal brain and pregnant Wistar rats. On gestational day 15, Wistar pregnant rats received LPS (0.25 mg/kg) to induce MIA. After 6, 12 and 24 h, fetus brain, placenta, and amniotic fluid were collected to evaluate early effects of LPS. Other group of rats from postnatal day (PND) 54 received injection of ketamine at the doses of 5, 15, and 25 mg/kg. On PND 60 rats were subjected to the spontaneous locomotor activity and pre-pulse inhibition test (PPI). MIA increased oxidative stress in the amniotic fluid and fetal brain. The BBB integrity in the hippocampus and cerebral cortex as well integrity of PB in the placenta and fetus brain were dysregulated after LPS induction. We also found elevated levels of cytokines such as interleukin (IL)-1β, IL-2, IL-4, IL-5, interferon (IFN)-γ, macrophage colony stimulating factor (M-CSF), IL-6, IL-10, IL-18, macrophage inflammatory protein (MIP)-3a, tumor necrosis factor (TNF)-α-, IL-7, MIP-1a and erythropoietin. Rats that receive MIA plus ketamine had locomotor activity impairment and a deficit in the PPI. In the present study, it was concluded that MIA increased the permeability of BBB and PB, the circulation of inflammatory mediators in fetal brains. This immune response in the prenatal period may be responsible for the behavioral changes in the adult life of offspring induced by MIA.

Prostaglandin E2 and IL-23 interconnects STAT3 and RoRγ pathways to initiate Th17 CD4+ T-cell development during rheumatoid arthritis.

The chronic inflammation associated with rheumatoid arthritis (RA) leads to focal and systemic bone erosion of the joints resulting in a crippling disability. Recent reports indicate an increase in the incidence of RA in the coming years, placing a significant burden on healthcare resources. The incidence of RA is observed to be increasing with age and a significant proportion of those new cases will be aggressively erosive. The altered physiology, due to immune disturbances, contributes towards RA pathogenesis. The imbalance of inflammatory cytokines and non-cytokine immune modulators such as prostaglandin E2 (PGE2) and IL-23-induced pathogenic IL-17, plays a crucial role in persistent inflammation and bone degradation during RA. However, the molecular mechanism of IL-23, a key cytokine, and PGE2 in the development and perpetuation of IL-17 producing effector Th17 cells is poorly understood. This review focuses on research findings that provide insight into the contribution of PGE2 and IL-23 during the development of pathogenic Th17 cells. We also highlight the key transcriptional factors required for Th17 development and therapeutic strategies to disrupt the interaction between IL-23 and IL-17 to prevent the end-organ damage in RA.