Regulation Of Immune System Function Research Articles

Zα domain proteins mediate the immune response.

The Zα domain has a compact α/β architecture containing a three-helix bundle flanked on one side by a twisted antiparallel β sheet. This domain displays a specific affinity for double-stranded nucleic acids that adopt a left-handed helical conformation. Currently, only three Zα-domain proteins have been identified in eukaryotes, specifically ADAR1, ZBP1, and PKZ. ADAR1 is a double-stranded RNA (dsRNA) binding protein that catalyzes the conversion of adenosine residues to inosine, resulting in changes in RNA structure, function, and expression. In addition to its editing function, ADAR1 has been shown to play a role in antiviral defense, gene regulation, and cellular differentiation. Dysregulation of ADAR1 expression and activity has been associated with various disease states, including cancer, autoimmune disorders, and neurological disorders. As a sensing molecule, ZBP1 exhibits the ability to recognize nucleic acids with a left-handed conformation. ZBP1 harbors a RIP homotypic interaction motif (RHIM), composed of a highly charged surface region and a leucine-rich hydrophobic core, enabling the formation of homotypic interactions between proteins with similar structure. Upon activation, ZBP1 initiates a downstream signaling cascade leading to programmed cell death, a process mediated by RIPK3 via the RHIM motif. PKZ was identified in fish, and contains two Zα domains at the N-terminus. PKZ is essential for normal growth and development and may contribute to the regulation of immune system function in fish. Interestingly, some pathogenic microorganisms also encode Zα domain proteins, such as, Vaccinia virus and Cyprinid Herpesvirus. Zα domain proteins derived from pathogenic microorganisms have been demonstrated to be pivotal contributors in impeding the host immune response and promoting virus replication and spread. This review focuses on the mammalian Zα domain proteins: ADAR1 and ZBP1, and thoroughly elucidates their functions in the immune response.

Glutathione: pharmacological aspects and implications for clinical use

Glutathione is a tripeptide found in many tissues which plays a pivotal role in critical physiological processes such as maintenance of redox balance, reduction of oxidative stress by enhancement of metabolic detoxification of both xenobiotic and endogenous compounds, and regulation of immune system function. Glutathione depletion is associated with many chronic degenerative diseases and loss of function with aging and altered glutathione metabolism has been implicated in central nervous system diseases, frailty and sarcopenia, infected state, chronic liver diseases, metabolic diseases, pulmonary and cardiovascular diseases. Therefore, the glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Here we describe the main pharmacological aspects of glutathione, focusing on its synthesis and role in several vital functions including antioxidant defense, detoxification of xenobiotics and modulation of immune function and fibrogenesis and the clinical implications of its depletion and we discuss the different strategies for increasing glutathione cellular levels either by providing specific precursors and cofactors or directly administering the tripeptide.

Sarcopenia as potential biological substrate of long COVID-19 syndrome: prevalence, clinical features, and risk factors.

BackgroundSevere clinical pictures and sequelae of COVID‐19 disease are immune mediated and characterized by a ‘cytokine storm’. Skeletal muscle has emerged as a potent regulator of immune system function. The aim of the present study is to define the prevalence of sarcopenia among COVID‐19 survivors and the negative impact of sarcopenia on the post‐acute COVID‐19 syndrome and its related risk factors.MethodsA total of 541 subjects recovered from COVID‐19 disease were enrolled in the Gemelli Against COVID‐19 Post‐Acute Care between April 2020 and February 2021. They underwent a multidisciplinary clinical evaluation and muscle strength and physical performance assessment.ResultsMean age was 53.1 years (SD 15.2, range from 18 to 86 years), and 274 (51%) were women. The prevalence of sarcopenia was 19.5%, and it was higher in patients with a longer hospital stay and lower in patients who were more physically active and had higher levels of serum albumin. Patients with sarcopenia had a higher number of persistent symptoms than non‐sarcopenic patients (3.8 ± 2.9 vs. 3.2 ± 2.8, respectively; P = 0.06), in particular fatigue, dyspnoea, and joint pain.ConclusionsSarcopenia identified according to the EWGSOP2 criteria is high in patients recovered from COVID‐19 acute illness, particularly in those who had experienced the worst clinical picture reporting the persistence of fatigue and dyspnoea. Our data suggest that sarcopenia, through the persistence of inflammation, could be the biological substrate of long COVID‐19 syndrome. Physical activity, especially if associated with adequate nutrition, seems to be an important protective factor.

IDO activation, inflammation and musculoskeletal disease.

The IDO/kynurenine pathway is now established as a major regulator of immune system function. The initial enzyme, indoleamine 2,3-dioxygenase (IDO1) is induced by IFNγ, while tryptophan-2,3-dioxygenase (TDO) is induced by corticosteroids. The pathway is therefore positioned to mediate the effects of systemic inflammation or stress-induced steroids on tissue function and its expression increases with age. Disorders of the musculoskeletal system are a common feature of ageing and many of these conditions are characterized by an inflammatory state. In inflammatory arthritis and related disorders, kynurenine protects against the development of disease, while inhibition or deletion of IDO1 increases its severity. The long-term regulation of autoimmune disorders may be influenced by the epigenetic modulation of kynurenine pathway genes, with recent data suggesting that methylation of IDO may be involved. Osteoporosis is also associated with abnormalities of the kynurenine pathway, reflected in an inversion of the ratio between blood levels of the metabolites anthranilic acid and 3-hydroxy-anthranilic acid. This review discusses evidence to date on the role of the IDO/kynurenine pathway and the highly prevalent age-related disorders of osteoporosis and rheumatoid arthritis and identifies key areas that require further research.

Skeletal muscle as potential central link between sarcopenia and immune senescence.

As our population grows older, age-related pathologies are becoming more prevalent. Deterioration of skeletal muscle and the immune system manifests as sarcopenia and immune senescence respectively. The disease burden of these pathologies emphasizes the need for a better understanding of the underlying mechanisms. Skeletal muscle has emerged as a potent regulator of immune system function. As such, skeletal muscle might be the central integrator between sarcopenia and immune senescence in an aging biological system. Therapeutic approaches targeting skeletal muscle might be able to restore both muscle and immune system function. In this review, we therefore outline the current - however still fragmentary - knowledge about the potential communication pathways of muscle and immune system, how they are affected by aging of skeletal muscle and discuss possible treatment strategies. The review intends to be hypothesis-generating and should thereby stimulate further research in this important scientific field.

NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function.

Over the last decade, significant progress has been achieved in defining mechanisms underlying NLR regulation of immune system function. However, several NLR family members continue to defy our best attempts at characterization and routinely exhibit confounding data. This is particularly true for NLR family members that regulate signaling associated with the activation of other pattern recognition receptors. NLRX1 is a member of this NLR sub-group and acts as an enigmatic regulator of immune system function. NLRX1 has been shown to negatively regulate type-I interferon, attenuate pro-inflammatory NF-κB signaling, promote reactive oxygen species production, and modulate autophagy, cell death, and proliferation. However, the mechanism/s associated with NLRX1 modulation of these pathways is not fully understood and there are inconsistencies within the field. Likewise, it is highly likely that the full repertoire of biological functions impacted by NLRX1 are yet to be defined. Recent mouse studies have shown that NLRX1 significantly impacts a multitude of diseases, including cancer, virus infection, osteoarthritis, traumatic brain injury, and inflammatory bowel disease. Thus, it is essential that the underlying mechanism associated with NLRX1 function in each of these diseases be robustly defined. Here, we summarize the current progress in understanding mechanisms associated with NLRX1 function. We also offer insight into both unique and overlapping mechanisms regulated by NLRX1 that likely contribute to disease pathobiology. Ultimately, we believe that an improved understanding of NLRX1 will result in better defined mechanisms associated with immune system attenuation and the resolution of inflammation in a myriad of diseases.

A Review of Dietary (Phyto)Nutrients for Glutathione Support.

Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status.

Clinical Efficacy of Acupuncture on Rheumatoid Arthritis and Associated Mechanisms: A Systemic Review.

Objective The objective of this review is to investigate the detailed existing scientific information about the clinical efficacy of acupuncture on rheumatoid arthritis (RA) conditions and to reveal the proposed mechanisms. Methods We searched the PubMed, EMBASE, Cochrane, AMED (Allied and Complementary Medicine), NCCAM (The National Center for Complementary and Alternative Medicine), and CNKI (China National Knowledge Infrastructure) databases to identify relevant monographs and related references from 1974 to 2018. Chinese journals and theses/dissertations were hand searched. Results 43 studies were recruited. Each research was analyzed for study design, subject characteristics, intervention, selected acupoints, assessment parameters, proposed mechanisms, and results/conclusions. Conclusions In our review, we concluded that acupuncture alone or combined with other treatment modalities is beneficial to the clinical conditions of RA without adverse effects reported and can improve function and quality of life and is worth trying. Several important possible mechanisms were summarized including anti-inflammatory effect, antioxidative effect, and regulation of immune system function. However, there is still inconsistency regarding the clinical efficacy and lack of well-designed human/animal double-blinded RCTs. Future discussion for further agreement on taking traditional Chinese medicine (TCM) theory into consideration as much as possible is a top priority.

Melanocortins, Melanocortin Receptors and Multiple Sclerosis.

The melanocortins and their receptors have been extensively investigated for their roles in the hypothalamo-pituitary-adrenal axis, but to a lesser extent in immune cells and in the nervous system outside the hypothalamic axis. This review discusses corticosteroid dependent and independent effects of melanocortins on the peripheral immune system, central nervous system (CNS) effects mediated through neuronal regulation of immune system function, and direct effects on endogenous cells in the CNS. We have focused on the expression and function of melanocortin receptors in oligodendroglia (OL), the myelin producing cells of the CNS, with the goal of identifying new therapeutic approaches to decrease CNS damage in multiple sclerosis as well as to promote repair. It is clear that melanocortin signaling through their receptors in the CNS has potential for neuroprotection and repair in diseases like MS. Effects of melanocortins on the immune system by direct effects on the circulating cells (lymphocytes and monocytes) and by signaling through CNS cells in regions lacking a mature blood brain barrier are clear. However, additional studies are needed to develop highly effective MCR targeted therapies that directly affect endogenous cells of the CNS, particularly OL, their progenitors and neurons.

The Active Metabolite of Vitamin D3 as a Potential Immunomodulator.

In the past, vitamin D was known for its classical, skeletal action as a regulator of calcium and bone homoeostasis. Currently, vitamin D was found to have a role in numerous physiological processes in the human body; thus, vitamin D has pleiotropic activity. The studies carried out in the past two decades showed the role of vitamin D in the regulation of immune system functions. Basically, these effects may be mediated not only via endocrine mechanism of circulating calcitriol but also via paracrine one (based on cell-cell communication that leads to production of signal inducing the changes in nearby/adjacent cells and modulating their differentiation or behaviour) and intracrine mechanism (the action of vitamin D inside a cell) of 1,25-dihydroxycholecalciferol (1,25(OH)2 D3 ) synthetized from its precursor 25-hydroxyvitamin D3 (25(OH)D3 ). Both vitamin D receptor (VDR) and 25-hydroxyvitamin D3 1-α-hydroxylase (CYP27B1) are expressed in several types of immune cells (i.e. antigen presenting cells, T and B cells), and thus, they are able to synthetize the bioactive form of vitamin D that modulates both the innate and adaptive immune system. This review discusses the role of vitamin D as regulator of immune system, and our understanding of how vitamin D regulates both adaptive and innate immunity as well as inflammatory cascade on the cellular level.

Delayed viral clearance after respiratory tract infection results in prolonged inflammation in vitamin A deficient animals despite the presence of regulatory T cells (MUC1P.902)

Abstract Vitamin A deficiency (VAD) is a global health problem that persists in over half the countries in the world, affecting an estimated 250 million preschool children. VAD individuals suffer increased morbidity and mortality during enteric and respiratory infection, as vitamin A is an important regulator of immune system function. Previously, our lab has demonstrated that VAD mice have an impaired response to respiratory virus infection, exhibiting decreased IgA and CD8+ T cell responses to infection. Here we show that VAD mice fail to clear viral infection from the respiratory tract with the same efficiency as control vitamin A sufficient animals. We observed that prolonged viral presence can associate with an increased potential for T cell activation. As a result VAD animals experience a cytokine storm comprised of a mixed Th1/Th2 response including IFN-gamma, IL-4, IL-6 and IL-10 cytokines. Increased cytokine expression can be detected both on the transcriptional and protein level. Despite previous reports attributing VAD-related inflammation to a reduced frequency of regulatory T cells in the intestine, we observe no reduction in the number of FoxP3+ T cells in the respiratory tract of VAD animals compared to controls. Our results suggest that the increased inflammation observed during respiratory infection of VAD animals is due, at least in part, to poor IgA and CD8+ T cell responses and delayed viral clearance, and not exclusively to an absence of regulatory T cells.

1,25-dihydroxyvitamin D3 regulates the development of chronic colitis by modulating both T helper (Th)1 and Th17 activation.

T helper (Th)1 and Th17 cells play a critical role in inflammatory bowel disease (IBD). 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) has emerged as a direct regulator of immune system function. Mice were grouped as follows: Control group (received PBS, n = 10), DSS group (received 2% DSS and PBS, n = 10), and DSS+VD group (received 2% DSS and 1,25(OH)2 D3 , n = 10). The disease activity index (DAI), colon length, and damage store of the mice were observed; the spleen length, weight, spleen index, and mononuclear cells of spleen were measured; mononuclear cells from mesenteric lymph nodes (MLN) were measured, and the levels of Th 1 and Th17 cytokines in the colon mucosa and spleen were measured. Mice in the DSS group developed severe diarrhea, rectal bleeding, and marked BW loss. Histological examination revealed extensive ulceration and inflammatory cell infiltration in the colon, and the structure of the spleen was disordered, infiltrated with inflammatory cytokines in red pulp. In the DSS group, mononuclear cell numbers from MLN and spleen were increased, and enhanced proteins and mRNA levels of Th 1 and Th17 cytokines were detected. In the DSS+VD group, 1,25(OH)2 D3 ameliorated the inflammation of the colon and spleen. In addition, 1,25(OH)2 D3 down-regulated the levels of Th 1 and Th17 cytokines. 1,25(OH)2 D3 represents a novel therapeutic drug for UC, which may correlate to inhibit the activation of Th1 and Th17 cells.

Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10−7) and 15 (chr15:53338796A>G, p = 1.5×10−7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10–11 and p = 2.5×10−7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

Dynorphins in regulation of immune system functions.

Dynorphins constitute a family of opioid peptides manifesting the highest affinity for κ-opiate receptors. Immune system cells are known to express a κ-receptor similar to that in the central nervous system, and as a consequence dynorphins are involved in the interaction between cells of the nervous and immune systems. In this review, data on dynorphin structure are analyzed and generalized, the κ-opiate receptor is characterized, and data on the regulation by dynorphins of functioning of the innate and adaptive immunity cells are summarized.

Mechanisms underlying effects of 1,25-dihydroxyvitamin D3on the Th17 cells

Th17 cells, a class of CD4(+) T cells, have been identified as novel effector cells, which play a pivotal role in several inflammatory and autoimmune diseases. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has emerged as a direct regulator of immune system function in humans. Accumulating reports demonstrated that 1,25(OH)2D3 possessed anti-inflammatory activity on Th17 cells to maintain immunologic homeostasis. This report will review the novel immune regulatory role of 1,25(OH)2D3 in its potential use for Th17 cell-related inflammatory and autoimmune conditions.

HLA-F and MHC-I Open Conformers Cooperate in a MHC-I Antigen Cross-Presentation Pathway

Peptides that are presented by MHC class I (MHC-I) are processed from two potential sources, as follows: newly synthesized endogenous proteins for direct presentation on the surface of most nucleated cells and exogenous proteins for cross-presentation typically by professional APCs. In this study, we present data that implicate the nonclassical HLA-F and open conformers of MHC-I expressed on activated cells in a pathway for the presentation of exogenous proteins by MHC-I. This pathway is distinguished from the conventional endogenous pathway by its independence from TAP and tapasin and its sensitivity to inhibitors of lysosomal enzymes, and further distinguished by its dependence on MHC-I allotype-specific epitope recognition for Ag uptake. Thus, our data from in vitro experiments collectively support a previously unrecognized model of Ag cross-presentation mediated by HLA-F and MHC-I open conformers on activated lymphocytes and monocytes, which may significantly contribute to the regulation of immune system functions and the immune defense.

Vitamin D and HIV Infection: A Review of the Clinical Evidence

The positive effects of vitamin D in different acute and chronic diseases (e.g., bone and renal disorders, acute and chronic respiratory tract infections, and diabetes mellitus), and regulation of immune system function have been shown. In this review vitamin D status and the effects of its supplementation alone or in combination with other bone-modifying substances like calcium and bisphosphonates on the different aspects of human health have been investigated in HIV+individuals. Three scientific electronic databases have been investigated for extracting related articles. Searching only PubMed yielded 59 results with ‘HIV OR AIDS’ and ‘Vitamin D’ keywords. Because many of the studies in this field are observational or cross-sectional, designing comprehensive and eligible randomized clinical trials has been recommended by several authors in order to develop evidence-based clinical practice guidelines to determine the best regimen of vitamin D supplementation in HIV-infected patients.

HLA-F and MHC-I open conformers cooperate in an MHC-I antigen cross presentation pathway. (P5015)

Abstract Peptides that are presented by MHC class I (MHC-I) are processed from two potential sources - newly synthesized endogenous proteins for direct presentation on the surface of most nucleated cells and exogenous proteins for cross-presentation typically by professional antigen presenting cells. Here we present data that implicates the non-classical HLA-F and open conformers of MHC-I expressed on activated cells in a pathway for the presentation of exogenous proteins by MHC-I. This pathway is distinguished from the conventional endogenous pathway by its independence from TAP and Tapasin and its sensitivity to inhibitors of lysosomal enzymes, and further distinguished by its dependence on MHC-I allotype-specific epitope recognition for antigen uptake. Thus, our data from in vitro experiments collectively support a previously unrecognized model of antigen cross-presentation mediated by HLA-F and MHC-I open conformers on activated lymphocytes and monocytes, which may significantly contribute to the regulation of immune system functions and the immune defense.

Notch signalling in the regulation of peripheral T-cell function.

The Notch signalling pathway plays a highly-conserved role in regulating the cellular differentiation and proliferation events that characterise pattern formation in the embryo. As cells in the embryo respond to environmental signals, similarly T-cells in the peripheral immune system must monitor their environment for antigens and respond accordingly by entering one of several potential differentiation pathways. Recent studies have identified a role for the Notch pathway in regulating the responses of T-cells in the periphery. In this review, we discuss these findings in the context of the Notch signalling pathway's role as an orchestrator of cellular differentiation, and propose a central role for Notch as a regulator of immune system function.

Molecular analysis of the inhibition of monocyte chemoattractant protein-1 gene expression by estrogens and xenoestrogens in MCF-7 cells.

Xenoestrogens (XEs) are a diverse group of chemicals that mimic estrogenic actions and may have adverse effects on human health. The influence of these compounds on cytokine production or immune system function remains unclear. In this study we have examined the effects of 17beta-estradiol (E2) and XEs on chemoattractant cytokine (chemokine) production and analyzed the molecular mechanism. Monocyte chemoattractant protein-1 (MCP-1), also termed monocyte chemotactic and activating factor, is a member of the chemokine family and attracts mainly blood monocytes. Human mammary tumor cell line MCF-7 cells produce a large quantity of MCP-1 in response to interleukin-1alpha (IL-1alpha). Addition of E2 to MCF-7 cells inhibited MCP-1 production in a dose-dependent manner. XEs, bisphenol A, and NP also inhibited MCP-1 production, although the potency was 3-4 orders of magnitude lower than that of E2. E2, bisphenol A, and NP inhibited MCP-1 messenger RNA expression in MCF-7 cells. Two closely located nuclear factor-kappaB sites, A1 and A2, have been identified in the promoter of the human MCP-1 gene. A luciferase construct containing this enhancer region (pGLM-ENH) was activated by IL-1alpha, and a mutation at either the A1 or A2 site resulted in a loss of IL-1alpha responsiveness. Treatment with E2 or XEs decreased the IL-1alpha-inducible pGLM-ENH luciferase activity significantly. In an electrophoretic mobility shift assay and supershift analysis, we found that treatment with E2 or XEs diminished the IL-1alpha-induced complex formation with both A1 and A2 probes, which was identified immunochemically to consist of nuclear factor-kappaB, p50, and p65. The IL-1alpha-induced p50/c-Rel complex to the A2 probe was also, to a lesser extent, decreased by E2 or XE treatment. The effects of E2 and XEs on the expression of MCP-1 seem to be much more dramatic than the effects of these agents on the promoters used in the luciferase assay, suggesting the involvement of an additional site(s) of the promoter region of the MCP-1 gene or posttranscriptional regulation of MCP-1 gene expression by E2 and XEs. This work represents the first report describing possible regulation of immune system function by XEs through inhibiting chemokine production.