Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity.

Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.

Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients.

Magnesium and vitamin D each have the possibility of affecting the immune system and consequently the cytokine storm and coagulation cascade in COVID-19 infections. Vitamin D is important for reducing the risk of upper respiratory tract infections and plays a role in pulmonary epithelial health. While the importance of vitamin D for a healthy immune system has been known for decades, the benefits of magnesium has only recently been elucidated. Indeed, magnesium is important for activating vitamin D and has a protective role against oxidative stress. Magnesium deficiency increases endothelial cell susceptibility to oxidative stress, promotes endothelial dysfunction, reduces fibrinolysis and increases coagulation. Furthermore, magnesium deficient animals and humans have depressed immune responses, which, when supplemented with magnesium, a partial or near full reversal of the immunodeficiency occurs. Moreover, intracellular free magnesium levels in natural killer cells and CD8 killer T cells regulates their cytotoxicity. Considering that magnesium and vitamin D are important for immune function and cellular resilience, a deficiency in either may contribute to cytokine storm in the novel coronavirus 2019 (COVID-19) infection.

Immune dysfunction and increased oxidative stress state in diet-induced obese mice are reverted by nutritional supplementation with monounsaturated and n-3 polyunsaturated fatty acids.

PURPOSE: Obesity is associated with impaired immune defences and chronic low levels of inflammation and oxidation. In addition, this condition may lead to premature aging. The aim of the study was to evaluate the effects of a nutritional supplementation with monounsaturated and n-3 polyunsaturated fatty acids on several functions and oxidative stress parameters in peritoneal immune cells of obese mice, as well as on the life span of these animals. METHODS: Obesity was induced in adult female ICR/CD1 by the administration of a high-fat diet (HFD) for 14 weeks. During the last 6 weeks of HFD feeding, one group of obese mice received the same HFD, supplemented with 1500 mg of 2-hydroxyoleic acid (2-OHOA) and another with 3000 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Several functions and oxidative stress parameters of peritoneal leukocytes were evaluated. RESULTS: The groups of obese mice treated with 2-OHOA or with EPA and DHA showed a significant improvement in several functions such as chemotaxis, phagocytosis, digestion capacity, Natural killer activity and lymphoproliferation in response to mitogens. All of these functions, which were decreased in obese mice, increased reaching similar levels to those found in non-obese controls. Both treatments also improved oxidative stress parameters such as xanthine oxidase activity, which decreased, catalase activity and glutathione levels, which increased. CONCLUSION: These data suggest that dietary supplementation with monounsaturated and n-3 polyunsaturated fatty acids could be an effective nutritional intervention to restore the immune response and oxidative stress state, which are impaired in obese mice.

Vitamin D in rheumatoid arthritis-towards clinical application.

In addition to its well-documented involvement in mineral homeostasis, vitamin D seems to have broad effects on human health that go beyond the skeletal system. Prominent among these so-called nonclassical effects of vitamin D are its immunomodulatory properties. In vitro studies have shown anti-inflammatory effects of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D. In addition, epidemiological analysis of patients with established inflammatory disease identified associations between vitamin D deficiency (low serum concentrations of inactive 25-hydroxyvitamin D, abbreviated to 25(OH)D) and inflammatory conditions, including rheumatoid arthritis (RA). The association of vitamin D deficiency with RA severity supports the hypothesis of a role for vitamin D in the initiation or progression of the disease, or possibly both. However, whether 25(OH)D status is a cause or consequence of RA is still incompletely understood and requires further analysis in prospective vitamin D supplementation trials. The characterization of factors that promote the transition from preclinical to clinical phases of RA has become a major focus of research, with the aim to facilitate earlier diagnosis and treatment, and improve therapeutic outcomes. In this Review, we aim to describe the current knowledge of vitamin D and the immune system specifically in RA, and discuss the potential benefits that vitamin D might have on slowing RA progression.

[Psychoneuroimmunology of the life span: impact of childhood stress on immune dysregulation and inflammatory disease in later life]. / Psychoneuroimmunologie des Lebenslaufs: Einfluss von Stress in der Kindheit auf Immunfunktionsstörung und entzündliche Erkrankung im weiteren Leben.

Studies have shown clearly that childhood mistreatment, abuse and neglect are associated with severe inflammatory disease in adulthood (e. g. cancer, heart disease, autoimmune disorder) and shortened life span. This review deals with the psychoneuroimmunological pathways of this connection. It shows that chronic stressors interfere very early in life with those protective mechanisms of the biological stress system that normally down-regulate potentially harmful inflammation. In the long term, serious inflammatory diseases, such as allergic asthma, can result. In this review, the pathogenetic connections between allergic asthma and early stress and stress system dysfunction are discussed. As our understanding of the dysfunctional psychophysiological mechanisms of inflammatory disease increases, psychodiagnostic and psychotherapeutic intervention in the treatment of physical disease will become more specific.

[Immune dysfunction and cognitive deficit in stress and physiological aging. Part II: New approaches to cognitive disorder prevention and treatment ].

Long-term stress as well as physiological aging result in similar immunological and hormonal disturbances including hypothalamic-pituitary-adrenal) axis depletion, aberrant immune response (regulatory T-cells, Tregs, and T(h17)-lymphocyte accumulation) and decreased dehydroepian-drosterone synthesis both in the brain and in the adrenal glands. Since the main mechanisms of inflammation control, "prompt" (stress hormones) and "delayed" (Tregs), are broken, serum cytokine levels increase and become sufficient for blood-brain-barrier disruption. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Structural and functional alterations of blood-brain-barrier as well as stress- (or age-) induced neuroinflammation promote influx of bone marrow derived dendritic cells and lymphocyte effectors into the brain parenchyma. Thereafter, mass intrusion ofpro-inflammatory mediators and immune cells having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets: 1) reduction of excessive Treg accumulation; 2) supporting hypothalamic-pituitary-adrenal axis and inflammatory reaction attenuation; 3) recovery of dehydroepiandrosterone level; 4) improvement of blood-brain-barrier function.

Membrane composition and cellular responses to fatty acid intakes and factors explaining the variation in response.

The lipid membrane bilayer undergoes continuous changes, and its lipid composition is both adaptive and highly varied, with substantial molecular variety. The balance of dietary fats, namely saturated versus unsaturated, and polyunsaturated fatty acids (PUFA) of the n-6 series versus those of the n-3 series, may change membrane composition thus affecting membrane order, intracellular signaling processes, and gene expression. As a consequence, changes in the production of both lipid and peptide mediators influencing the individual adaptive responses take place. More than that of all the other fatty acids, the n-3 PUFA composition of cell membranes depends on their dietary intake. n-3 PUFA levels in cell membranes are related to both inflammatory and immune diseases, possibly by downregulating the expression of genes involved in their synthesis and maybe the pathogenesis of processes associated with the disease itself. The interindividual variability of DNA sequences involved in the synthesis of long-chain PUFA may explain differences in responses to their dietary contribution in regulating the risk of disease. Lifestyle factors (such as smoking and alcohol consumption) may in turn negatively impact PUFA metabolism. Accordingly, different amounts of dietary PUFA may be necessary to meet the requirements for these nutrients in development and disease prevention on an individual basis.

Use of vitamin D in various disorders.

Approximately 1 billion people worldwide have been identified as vitamin D deficient in the 21st century, and the number is on the rise; non-classical actions of vitamin D were initially recognized around 30 y ago when receptors for vitamin D were detected in neoplastic cells lines. The aim of this review is to provide a brief overview of the non-classical actions of vitamin D. Reports describing the associations of non skeletal actions of vitamin D, especially pertaining to the immune system, inflammatory disorders, cancers and cardiovascular disease have been summarized in this paper. Reports support a role for the active form of vitamin D in mediating normal function of both the innate and adaptive immune systems. Studies also suggest a link between vitamin D deficiency and autoimmune diseases, such as rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus and type 1 diabetes. There is believed to be an inverse association between serum 25-hydroxyvitamin D concentrations and the incidence of colorectal cancer, sporadic colorectal adenoma and breast cancer. Vitamin D deficiency has been linked with various cardiovascular diseases such as hypertension, myocardial infarction, and stroke. Several epidemiological and genetic studies suggest a strong association between vitamin D and non skeletal acute and chronic disorders. However, currently, robust clinical data are still lacking to support raising intake requirements and target vitamin D plasma levels. Nonetheless, the high prevalence of vitamin D deficiency is alarming and requires implementation of clear supplementation guidelines.

Earthing: health implications of reconnecting the human body to the Earth's surface electrons.

Environmental medicine generally addresses environmental factors with a negative impact on human health. However, emerging scientific research has revealed a surprisingly positive and overlooked environmental factor on health: direct physical contact with the vast supply of electrons on the surface of the Earth. Modern lifestyle separates humans from such contact. The research suggests that this disconnect may be a major contributor to physiological dysfunction and unwellness. Reconnection with the Earth's electrons has been found to promote intriguing physiological changes and subjective reports of well-being. Earthing (or grounding) refers to the discovery of benefits-including better sleep and reduced pain-from walking barefoot outside or sitting, working, or sleeping indoors connected to conductive systems that transfer the Earth's electrons from the ground into the body. This paper reviews the earthing research and the potential of earthing as a simple and easily accessed global modality of significant clinical importance.

Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases.

Certain autoimmune diseases as well as asthma have increased in recent decades, particularly in developed countries. The hygiene hypothesis has been the prevailing model to account for this increase; however, epidemiology studies also support the contribution of diet and obesity to inflammatory diseases. Diet affects the composition of the gut microbiota, and recent studies have identified various molecules and mechanisms that connect diet, the gut microbiota, and immune responses. Herein, we discuss the effects of microbial metabolites, such as short chain fatty acids, on epithelial integrity as well as immune cell function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through lipid G-protein coupled receptors such as GPR43.

The side effects of phototherapy for neonatal jaundice: what do we know? What should we do?

Neonatal phototherapy (NNPT), a noninvasive, easily available therapy, has been widely used for the treatment of neonatal jaundice for more than half a century. Its efficiency in decreasing plasma bilirubin concentration is well documented, and NNPT leads to greatly reduced exchange transfusion rates for neonates with hyperbilirubinemia. It is generally accepted that the side effects of NNPT are not serious and seem to be well controlled. This review will focus on these possible side effects as well as the approaches to minimize them.

Vitamin E and immunity.

Vitamin E is the most important chain-breaking, lipid-soluble antioxidant present in body tissues of all cells and is considered the first line of defense against lipid peroxidation and it is important for normal function of the immune cells. However, vitamin E deficiency is rare in well-nourished healthy subjects and is not a problem, even among people living on relatively poor diets, both T- and B-cell functions are impaired by vitamin E deficiency. While immune cells are particularly enriched in vitamin E because of their high polyunsaturated fatty acid content, this point puts them at especially high risk for oxidative damage. Besides its immunomodulatory effects, vitamin E also plays an important role in carcinogenesis with its antioxidant properties against cancer, and ischemic heart disease with limiting the progression of atherosclerosis. Supplementation of vitamin E significantly enhances both cell mediated and humoral immune functions in humans, especially in the elderly and animals.

A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities.

Posttraumatic stress disorder (PTSD) is a serious and debilitating condition with a prevalence rate of approximately 8% in the United States. Given the number of veterans returning from conflicts around the globe with PTSD, and the substantial number of civilians experiencing traumas, new perspectives on the biology of PTSD are needed. Based on the concept that PTSD is a disorder of stress response systems, numerous studies have suggested changes in hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-adrenal-medullary (SAM) system function in patients with PTSD. Given that both glucocorticoids and catecholamines exert powerful effects on the immune system, it is surprising that relatively few studies have examined immune changes in patients with PTSD. Moreover, patients with PTSD are known to have increased rates of comorbidity with somatic disorders that involve immune and inflammatory processes. Patients with PTSD have been found to exhibit a number of immune changes including increased circulating inflammatory markers, increased reactivity to antigen skin tests, lower natural killer cell activity, and lower total T lymphocyte counts. Studies with humans and rodents suggest that certain proinflammatory cytokines are able to induce neurochemical and behavioral changes that resemble some key features of PTSD. This short article reviews immune alterations in PTSD, and considers possible mechanisms by which such changes may be related to neuroendocrine alterations and medical comorbidities of PTSD.

Is there a role for fatty acids in early life programming of the immune system?

There may be a causal relationship between n-6 PUFA intake and allergic disease and there are biologically plausible mechanisms, involving eicosanoid mediators of the n-6 PUFA arachidonic acid, that could explain this. There is some evidence that high linoleic acid intake is linked with increased risk of atopic sensitisation and allergic manifestations. Fish and fish oils are sources of long-chain n-3 PUFA and these fatty acids act to oppose the actions of n-6 PUFA. It is considered that n-3 PUFA will protect against atopic sensitisation and against the clinical manifestations of atopy. All five epidemiological studies investigating the effect of maternal fish intake during pregnancy on atopic or allergic outcomes in infants/children of those pregnancies concluded protective associations. Epidemiological studies investigating the effects of fish intake during infancy and childhood on atopic outcomes in those infants or children are inconsistent, although the majority of the studies (9/14) showed a protective effect of fish. Fish oil provision to pregnant women is associated with immunologic changes in cord blood. Provision of fish oil during pregnancy may reduce sensitisation to common food allergens and reduce the prevalence and severity of atopic dermatitis in the first year of life. This effect may persist until adolescence with a reduction in prevalence and/or severity of eczema, hayfever and asthma. Fish oil supplementation in infancy may decrease the risk of developing some manifestations of allergic disease, but whether this benefit persists as other factors come into play remains to be determined.

An onco-informatics database for anticancer drug interactions with complementary and alternative medicines used in cancer treatment and supportive care: an overview of the OncoRx project.

PURPOSE: Cancer patients are at high risk of manifesting interactions from use of anticancer drugs (ACDs) and complementary and alternative medicines (CAMs). These interactions can result in sub-therapeutic effects or increased toxicities which may compromise the outcome of chemotherapy. It is important for practitioners to gain convenient access to ACD-CAM interaction information so as to make better-informed decisions in daily practice. This paper describes the creation of an oncology database (OncoRx) that documents ACD-CAM interactions, including traditional Chinese medicines (TCMs) that are commonly used for cancer treatment, prevention, and supportive care therapy. METHODS: Information regarding ACDs, CAMs, and drug interactions were collated from 14 sources, inclusive of hardcopy and online resources, and input into a modified web server with a database engine and a programming interface using a combination of software and programming scripts. RESULTS: OncoRx currently contains a total of 117 ACDs and 166 CAMs. Users are able to search for interactions based on various CAM uses: cancer treatment or prevention, immune-system-related, alopecia, nausea, and vomiting, peripheral neuropathy and pain, inflammation, fatigue, and non-cancer related. Pharmacokinetic data on ACDs and CAMs, characteristics of CAMs based on TCM principles, and drug interaction parameters such as effects, mechanisms, evidences, and proposed management plans, are shown in the search results. CONCLUSION: OncoRx is an oncology database which detects ACD interactions. It is currently able to detect interactions with CAMs. It is hoped that OncoRx will serve as a useful resource to clinicians, educators, trainers, and students working in the oncology setting.

Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: implications for the etiopathology of schizophrenia.

It has been hypothesized that the maternal immune response to infection may influence fetal brain development and lead to schizophrenia. Animal experimentation has supported this notion by demonstrating altered sensorimotor gating (prepulse inhibition, PPI) in adult rats prenatally exposed to an immune challenge. In the present study, pregnant rats were exposed to the bacterial endotoxin lipopolysaccharide (LPS) throughout gestation and the offspring were examined by evaluating the PPI, dopaminergic function, brain protein expression and cytokine serum levels from weaning to late adulthood. Prenatal LPS exposure induced a deficit in PPI that emerged at 'puberty' and that persisted throughout adult life. This prenatal insult caused age-specific changes in accumbal dopamine levels and in synaptophysin expression in the frontal cortex. Moreover, serum cytokine levels were altered in an age- and cytokine-dependent manner. Here we show that prenatal LPS administration throughout pregnancy causes maturation-dependent PPI deficits and age-dependent alterations in dopamine activity, as well as in synaptophysin expression and cytokine levels.

Stress and health.

The impact of stress on physical functioning (endocrine, gastrointestinal, immune, and cardiovascular systems) is reviewed. The effect of stress on psychiatric functioning and health behaviors also is discussed. The importance of stress screening in primary care is emphasized, and several methods of stress reduction (including exercise, cognitive-behavioral therapy, and mindfulness-based stress reduction) appropriate to primary care settings are described.

Toll-like receptors, transduction-effector pathways, and disease diversity: evidence of an immunobiological paradigm explaining all human illness?

Membrane-bound Toll-like receptors (TLRs) are frontline guardians in the mammalian innate immune system. They primarily function to recognize pathogen-associated molecular patterns (PAMPs) of invading microorganisms and on activation mount rapid, nonspecific innate responses and trigger sequential delayed specific adaptive cellular responses, which are mediated by complex signal transduction pathways involving adaptor molecules, costimulatory ligands and receptors, kinases, transcription factors, and modulated gene expression. Increasing evidence of multiple functionality and diversity suggests TLRs play critical roles in noninfective medical conditions such as cardiovascular, gastrointestinal, neurologic, musculoskeletal, obstetric, renal, liver, and dermatologic diseases, allergy, autoimmunity, and tissue regeneration. The significance of TLR heterogeneity underscores the possibility for establishing a universal immunobiological model to explain all human disease. Novel immunomodulatory therapies targeting specific or multiple TLRs may in the future offer new tools to combat or eradicate pathogenesis potentially transforming the landscape of current medical treatments.

Zearalenone induces immunotoxicity in mice: possible protective effects of radish extract (Raphanus sativus).

Radish (Raphanus sativus) has been extensively studied for its preventive effects against different degenerative diseases. Zearalenone (ZEN) is a mycotoxin produced by Fusarium spp and is frequently implicated in immunological disorders and occasionally in hyperoestrogenic syndromes contributing to the increased risk of cancer and other diseases. The aims of this study were, firstly, to quantitatively evaluate the Tunisian radish extract (TRE) for its total flavonoids, isothiocyanates and antioxidant activity and, secondly, to investigate the protective role of TRE against immune system disorders in Balb/c mice treated with ZEN for two weeks. The results indicated that mice treated with ZEN (40 mg kg(-1)) alone showed a significant decrease in lymphocytes of the total white blood cells, immunoglobulin profile (IgG and IgM), B cells, T-cell sub-types (CD3+, CD4+ and CD8+) and natural killer and pro-inflammatory cytokines. Mice treated with TRE (5, 10 or 15 mg kg(-1)) for 7 days before, during or after ZEN treatment, however, showed a significant improvement in lymphocyte, immunoglobulin profile, T-cell sub-types, B cells and pro-inflammatory cytokines. Moreover, treatment with the highest dose of TRE (15 mgkg(-1)) enhanced the release of tumour necrosis factor-alpha and interleukin-1beta but the other parameters were comparable with those of the control. It could be concluded that TRE was effective in protecting against ZEN-induced immunological disorders. These results supported our hypothesis that TRE contains several compounds that are able to prevent or inhibit ZEN toxicity.

Vitamin D status in gastrointestinal and liver disease.

PURPOSE OF REVIEW: The purpose of this review is to report on the vitamin D status and its relationship with bone health in individuals with gastrointestinal and liver disorders. In addition, recommendations regarding replacement and maintenance of optimal vitamin D stores, as well as the state of knowledge regarding its effect on the disease through its actions on the immune system, will be reviewed. RECENT FINDINGS: The scientific community has revised upward the serum levels of vitamin D considered optimal, and doses of vitamin D much larger than those currently recommended may be needed to maintain these levels, especially in individuals with gastrointestinal and liver disorders. The relationship between vitamin D and bone health in this population is controversial. The role of vitamin D in the regulation of the immune system continues to be elucidated. SUMMARY: Hypovitaminosis D is prevalent among individuals with gastrointestinal and liver disease. Although replacement and supplementation guidelines have not been well defined, practitioners should aim for a serum 25-hydroxyvitamin D level of at least 32 ng/ml. The contribution of vitamin D to the bone health of these individuals and its role in altering disease course through its actions on the immune system remain to be elucidated.