Oxidative stress and autoimmune diseases -
Reactive oxygen species, specifically the hydroxyl radical, respond with lipid layers and produces receptive aldehydes, including malondialdehyde and 4-hydroxynonenal HNE , in three phage responses.
It can "spread" oxidative damage through flow in SLE patients [ 25 ]. In the start stage an essential receptive radical concentrates a hydrogen iota from a methylene gathering to begin peroxidation.
These outcomes in the development of a conjugated diene, leaving an unpaired electron on the carbon. Carbon-focused unsaturated fat radicals consolidate with sub-atomic oxygen in the proliferation stage, yielding profoundly receptive peroxyl radicals that respond with an alternate lipid particle to structure hydroperoxides.
Peroxyl radicals are fit for creating new unsaturated fat radicals, bringing about a radical chain response. The course of lipid peroxidation bring about a mixed bag of unsafe final items including conjugated dienes, isoprostanes, 4-hydroxynonenal HNE , HNE-altered proteins, malondialdehyde MDA , MDA-adjusted proteins, protein-bound acrolein and oxHDL,which are associated with SLE disease activity [ 26 - 28 ].
In addition to the involvement of ROS in lipid peroxidation, it can modify both structure and function of proteins in SLE patients [ 21 , 29 ].
Metal-catalyzed protein oxidation brings about expansion of carbonyl gatherings, cross-connecting, or discontinuity of proteins. Lipid peroxidation aldehydes can respond with sulfhydryl cysteine or essential amino acids histidine, lysine.
Essentially, adjustment of individual nucleotide bases, single-strand breaks and cross-connecting are regular impacts of ROS on nucleic acids.
All these communications of ROS with protein, lipid and nucleic corrosive prompts the development of adducts items which are exceedingly immunogenic and are perceived as an outside molecule to our body, which may be included in arrangement of pathogenic auto-immune response in SLE [ 30 , 31 ].
The impact of ROS is restricted by the presence of various regulatory systems in aerobic organisms to maintain redox homeostasis. A comparatively large number of compounds possess some measurement of antioxidant activities.
They keep up a harmony between the generation and scavenger of ROS, and shield the cell from oxidative damage [ 32 , 33 ]. Antioxidant enzymes comprise SOD superoxide dismutase , CAT catalase and glutathione related enzymes; GPx glutathione peroxidase , GR glutathione reductase and GST Glutathione S-transferase , while non-enzymatic scavengers include vitamins E, C and A and thiol containing compounds such as glutathione [ 34 ].
Reduced glutathione L-γ-glutamyl-L-cysteinylglycine is the most prevalent cellular thiol and the most abundant low molecular weight peptide present in all cells [ 35 ]. GSH has an amazingly essential role as a reductant in the very oxidizing environment of the erythrocyte.
GSH levels in human tissues ordinarily run from 0. Reduced form of glutathione is required for many critical cellular processes and plays a cardinal role in cell maintenance and regulation of the thiol-redox [ 37 ].
Changes in this ratio relate with disease activity in SLE patients [ 15 , 29 ]. Cellular GSH levels affect T helper cell maturation [ 38 ], T cell proliferation [ 39 ], and susceptibility to ROS secreted by inflammatory cells.
Additionally, many correlations exist between immune system dysfunction and alterations in GSH levels in the cells of SLE patients.
We and others have reported that GSH depletion in antigen presenting cells inhibits Th1-related cytokine production like IFN-γ and IL, which supports Th2- mediated humoral immune response in SLE patients [ 39 ]. Protection against oxidative damage is normally afforded by replenishing intracellular reduced glutathione through an antioxidant supplement of glutathione precursors N-acetylcysteine NAC.
Evidence from SLE patients and lupus prone mice supports the role of glutathione as antioxidant therapy to diminish oxidative stress and severity of disease. In NZB × NZW F1 lupus-prone mice NAC treatment prevented the decline of glutathione, including GSSG ratios, reduced autoantibody production, development of nephritis, and prolonged survival [ 40 ].
Two pilot studies of NAC treatment in SLE patients, Tewthanom 40 SLE patients and Perl 36 SLE patients , showed that NAC treatment is effective in reversing glutathione depletion and improving disease activity and fatigue in SLE patients [ 16 , 41 ]. These studies demonstrated that intracellular depletion displays an increased in oxidative stress and replenishment of intracellular glutathione may diminish disease activity in SLE patients.
Superoxide dismutase is a metalloprotein, thought to be the first line of resistance against free radicals. It catalyzes the dismutation of superoxide radical into oxygen and hydrogen peroxide [ 42 ].
If not rummaged successfully, superoxide radicals might specifically inactivate a few proteins like CAT and GPx, which are expected to take out hydrogen peroxide from intracellular medium [ 43 ].
This enzyme is found in 3 forms in human are: SOD1 located in the cytoplasm, SOD2 in the mitochondria, and extracellular SOD3 [ 44 ]. While SOD1 is dimeric [ 42 ], SOD2 and SOD3 are tetrameric [ 45 , 46 ].
SOD1 and SOD3 contain copper and zinc, while SOD2 has manganese in its reactive center. Several groups reported decreased SOD activity and formation of auto-antibodies against SOD in SLE patients [ 47 - 49 ]. Antibodies against SOD are reported to have a role in the inactivation of SOD enzyme during increase oxidative state are responsible to deleterious effect in SLE patients.
It catalyzes hydrogen peroxide to water and oxygen without production of free radicals [ 50 , 51 ]. CAT is most elevated in the liver, kidney and erythrocytes and low in connective tissues [ 52 ].
In the most organs e. Under the physiological condition, H 2 O 2 is catalyzed by glutathione peroxidase high affinity for H 2 O 2 while at high concentration H 2 O 2 is removed by catalase enzyme [ 12 ].
The important of catalase enzyme in the SLE patients is well documented in SLE patients. The polymorphism catalase enzyme CC genotype showed remarkable association with several disease activities such as thrombocytopenia, renal manifestations, as well as production of anti-nRNP and anti-Scl antibodies in SLE patients [ 53 ].
An elegant study by Mansour et al. reported that elevated levels of auto-antibodies against catalase in excessive oxidative stress state in SLE patients are associated with disease activity [ 54 ].
In two different studies they demonstrated that SLE patients have increased levels of IgG antibodies Ab against CAT in SLE patients compared to control subjects [ 54 , 55 ]. Glutathione peroxidase belongs to the selenoprotein family and is one of the most important anti-oxidant enzymes in human.
It catalyses hydroperoxides and protects biomembranes and cell structures from oxidative damage. This enzyme accomplishes these protections through utilization of glutathione as a reducing substrate and converting hydroperoxides to free hydrogen peroxide to water [ 57 ].
In animals studies the important of this enzyme can be illustrated by following evidences. Glutathione peroxidase knockout mice have abnormal cardiac mitochondria and associated with increase mitochondrial ROS production and oxidative mtDNA damage.
In SLE patients, decrease activity of glutathione peroxidase enzyme has been associated with increase in oxidized redox environment in cell [ 47 ]. Since, glutathione peroxidase enzyme is also required for maintaining intracellular glutathione levels, which is key antioxidant and control oxidative stress and involved in regulating several immune functions such as apoptosis [ 58 ]and cytokine network [ 38 ] in SLE pathogenesis.
Excessive oxidative stress and altered redox signaling are most commonly known to be involved in cell death signaling cascades.
However, their role in regulation of autophagy is largely unknown in autoimmune diseases. Autophagy is a persistent homeostatic process in which certain cell components are engulfed by autophagosomes and, subsequently degraded in order to produce energy or preserve cellular viability and homeostasis [ 59 ].
Autophagy breaks down compromised cellular components, such as damaged organelles and aggregated proteins. Deposition of these components within cells can lead to toxicity, resulting in destruction of tissues, organisms, and biological systems [ 60 ].
Elevated ROS causing autophagy promotes either cell survival or cell death, the fate of which depends upon the severity of stress occurring with a particular disease. Several studies have shown that ROS accumulation in the cell activates the autophagy process. For example, a mutation in an antioxidative superoxide dismutase SOD1 gene modulates autophagy.
Reports from different laboratories have described autophagy activation in transgenic mice expressing mutant SOD1 [ 61 , 62 ]. In the first report, SOD1 G93A transgenic mice displayed inhibition of mTOR and accumulation of lipid-conjugated LC3, the mammalian homologue of Atg8 [ 62 ]. A recent report showed that mutant SOD1 interacts directly with p62 also called SQSTM1 , an LC3 binding partner known to target protein aggregates for autophagic degradation.
Indeed, this interaction is proposed to mediate autophagic degradation of mutant SOD1 [ 63 ]. Ruth Scherz-Shouval's group has suggested two major ROS H 2 O 2 and O 2 -. as the main regulators of autophagy [ 64 ]. H 2 O 2 is a striking contender for signaling because it is comparatively stable and long- lived as compared to other ROS species.
Its neutral ionic state enables it to exit the mitochondria with ease. It has been implicated as a signaling molecule in various signal transduction pathways, including autophagy [ 65 ].
Indeed, ATG4, an essential protease in the autophagic pathway, has been identified as a direct target for oxidation by H 2 O 2 during starvation [ 66 ]. Other studies report autophagy activation in response to exogenous H 2 O 2 treatment [ 67 ] In most cases, this treatment leads to oxidative stress and mitochondrial damage, which induce autophagy.
Taken together, this evidence supports the vital role of oxidative stress in the induction of autophagy. Redox signaling involves targeted modification by reactive species through a chemically reversible reaction.
Oxidative damage in response to oxidative stress leads to irreversible oxidation of proteins lipids and nucleic acids [ 68 ]. However, since amino-acid residues in proteins, fatty acids in lipids and nucleic acid bases have different susceptibility to oxidative stress. Oxidative damage can be repaired to a certain extent, as evident in the diverse array of DNA repair systems.
In addition, oxidized proteins can be effectively degraded and recycled by both proteasome and autophagy systems. Proteasomal degradation of oxidatively modified proteins requires protein unfolding; thus, only mildly oxidized proteins are suitable proteasome substrates.
NAC decreased both cellular ROS production and autophagy, implicating redox thiol signaling as an important regulator of autophagy. Redox signaling, generally occurs in the absence of an overall imbalance of pro-oxidants and antioxidants [ 71 ].
However, although oxidative damage to proteins, lipids, and nucleic acids is associated with activation of programmed cell death, both pro-apoptotic and pro-survival signaling proteins are modulated by specific reversible oxidative modifications [ 71 , 72 ].
Oxidative stress, redox signaling, and autophagy: cell death versus survival. In addition, 4 lysosomal membrane permeabilization induced by stress can also contribute to cell death. Oxidative damage can be repaired to a certain extent and oxidized biomolecules, such as proteins, can be degraded and recycled by distinct processes, including autophagy.
A clear distinction between both oxidative stress and redox signaling is hard to define. There is a lack of literature on the role of redox signaling by oxidative cysteine modification in autophagy. In response to ROS or RNS, redox-sensitive cysteines undergo reversible and irreversible thiol modifications.
Almost all physiological oxidants react with thiols [ 74 ]. O 2 - and peroxides H 2 O 2 , and ONOO - mediate one- and two-electron oxidation of protein cysteines respectively, leading to formation of reactive intermediates protein sulfenic acids PSOH and protein thiyl radicals PS , respectively.
PSOH can lead to formation of additional oxidative modifications that act as signaling events regulating protein function. The reaction of PSOH with either another protein cysteine or GSH will generate a disulfide bond or a glutathionylated residue PSSG. PSSG is considered as a protective modification against irreversible cysteine oxidation.
PSOH can undergo further reaction with H 2 O 2 and irreversibly generate protein sulfinic PSO 2 H and sulfonic PSO 3 H acids. The reversible covalent adduction of a nitroso group NO to a protein cysteine is referred to as protein nitros yl ation PSNO.
PSNO occurs by endogenous NO-mediated nitros yl ating agents such as dinitrogen trioxide N 2 O 3 or by transition metal-catalyzed addition of NO.
The transfer of NO groups between PSNO and GSNO transnitros[yl]ation is one of the major mechanisms mediating PSNO. GSNO is formed during oxidation of NO in the presence of GSH, or as a by-product from the oxidation of GSH by ONOO - [ 75 ].
Reversible conjugation of the Atg8 family of proteins to autophagosomal membrane is a hallmark event in the autophagic process. All Atg8 homologues including LC3 are substrates for the Atg4 family of cysteine proteases. Atg4s cleave Atg8 near the C-terminus downstream of a conserved glycine, enabling its conjugation to PE.
Atg4 further cleaves Atg8 LC3 -PE, releasing it from the membrane. Thus, after initial cleavage of Atg8 LC3 -like proteins, Atg4 must be inactivated to ensure the conjugation of Atg8 LC3 to the autophagosomal membrane.
After the autophagosome fuses with the lysosome, Atg4 is re-activated in order to dilapidate and recycle Atg8 LC3. Recently, it was revealed that upon starvation, increased generation of mitochondrial H 2 O 2 oxidizes and inactivates Atg4 after the initial cleavage of LC3, ensuring structural integrity of the mature form [ 66 ].
A number of signaling molecules regulating apoptosis are reported to be regulated by oxidative cysteine modifications. For example, glutathionylation PSSG of nuclear factor-kappa B NF-kB and caspases, have been reported to regulate apoptotic cell death [ 76 ].
Similarly, caspases and the anti-apoptotic Bcl-2 protein have been shown to be nitros yl ated PSNO under basal conditions in human lung epithelial cancer cells, and their denitros yl ation is necessitated for their activation during apoptosis [ 77 ].
Both apoptosis and autophagy are simultaneously activated by the distinct stressors. Thus, both glutathionylation and nitrosylation might exert regulatory roles in autophagy by indirect regulation of Bcl-2 and caspase activity [ 77 ].
Protein nitros yl ation exert inhibitory effects on autophagy. Nitros yl ation and inhibition of JNK1 and IKKb signaling pathways are also reported to inhibit autophagy by increased BclBeclin-1 interaction and decreased AMPK phosphorylation [ 79 ].
AMPK is a key regulator of metabolism, particularly glycolysis. By regulation of ULK1 and mTORC1 complexes, AMPK has been demonstrated to regulate autophagy [ 80 ].
In HEK cells, H 2 O 2 was recently demonstrated to oxidize cysteine residues of α- Cys and Cys and β-subunits of AMPK via glutathionylation, with a concomitant increase in its kinase activity.
Ataxia-telangiectasia mutated ATM protein kinase is activated by DNA double strand breaks DSBs to initiate DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. Oxidation of ATM directly induces its activation in the absence of DNA damage via a disulfide-cross-linking dimerization [ 82 ].
Activation of ATM by oxidative stress or genotoxic damage was recently reported to activate AMPK and the tuberous sclerosis complex 2 TSC2 , which in turn participates in energy sensing and growth factor signaling to repress the kinase mTOR in the mTORC1 complex [ 83 ].
Studies regarding mechanisms by which ROS, redox signaling, and autophagy regulate autoimmune disease progression is a new research field that could provide pivotal information toward understanding and development of therapeutic to manage the disease.
SLE is an autoimmune disorder characterized by the auto-antibodies directed against self-antigens, immune complex formation and immune deregulation, resulting in damage to any organ, including kidneys, skin, blood cells, and nervous system [ 84 ].
It is a multifactorial disease and its etiology comprises hormonal, environmental and genetic background.
While mechanisms underlying this systemic autoimmune response remain largely unknown, several vital studies show that uncontrolled reactive oxygen generation and defect in regulation of antioxidant system are, in part, crucial factors for the pathogenesis of SLE [ 85 ].
The uncontrolled oxidative species generations are speculated to be involved in the production, expansion of antibody flares [ 86 ] and various clinical features in SLE [ 87 ]. Oxidative damage mediated by ROS results in formation of deleterious byproducts, such as aldehydic products, and leads to development of adducts with proteins.
The consequence of this effect makes them highly immunogenic, thus inducing pathogenic antibodies in SLE [ 88 ]. In the last 2 decades, there has been substantial progress in understanding the mechanism of oxidative stress in SLE pathogenesis Figure 2 and the level of intracellular glutathione has been regarded as a checkpoint of oxidative stress [ 1 ].
Altered signal transduction pathways, mTOR is activated by relative depletion of glutathione and supplementation of N-acetyl cysteine NAC , a precursor of glutathione. mTOR replenishes intracellular glutathione, inhibits mTOR signaling and diminished oxidative stress mediated damage in SLE [ 89 ].
Glutathione is a key cellular component, a small tri-peptide constructed from three amino acids glycine, glutamic acid and cysteine , known to be a powerful antioxidant.
The main function of glutathione is to protect the cell and mitochondria from oxidative damage, indicating its role in energy utilization.
Management of disease through supplement of NAC and rapamycin has shown promise as a therapy for SLE patients. Administration of rapamycin decreased production of autoantibodies, glomerular deposits of immunoglobulins, development of proteinuria, and prolonged survival in murine SLE.
Interestingly, autophagy is regulated by mTOR pathway, and mTOR is activated by relative depletion of glutathione. Thus, redox signaling may provide a link between altered autophagy and depletion of glutathione and autophagy regulation by replenishment of intracellular glutathione may have a therapeutic intervention for disease management [ 90 ].
Oxidative stress involvement in the pathogenesis of SLE. MDA, malondialdehyde; 4-HNE, 4-hydroxynonenal; GSH, glutathione; MHP, mitochondrial hyperpolarization; NO, nitric oxide; O 2 -, superoxide; ONOO - , peroxynitrite. It has been shown that changes in the intracellular redox environment of in cells, through oxidative stress, have been reported to be critical for cellular immune dysfunction [ 48 ], activation of apoptotic enzymes, and apoptosis [ 15 ].
Similarly, Tewthanom et al. Lai et al. demonstrated that GSH regulates elevation of mitochondrial transmembrane potential Δψ m or mitochondrial hyperpolarization MHP , which in turn activates mTOR in lupus T cells [ 91 ].
These studies are important as they suggest the blockade of mTOR with rapamycin and NAC improves lupus disease activity [ 89 , 91 ]. In recent years, perturbation in autophagy has been implicated in a number of diseases, including SLE [ 8 ].
Towns et al. Several other groups have reported activated autophagy pathway in T and B lymphocytes as a mechanism for survival of autoreactive T and B lymphocytes.
Inhibition of autophagy by blocking mTOR signaling has been suggested as a novel target for treatment in this disease. Importantly, Lai et.
has shown that blockade of mTOR with supplementation of NAC reversing glutathione depletion and improving disease activity and fatigue in SLE patients [ 91 ]. Indeed, NAC reversed expansion of CD4 — CD8 — T cells, which exhibited the most prominent mTOR activation before treatment with NAC, and may be responsible for promoting anti-DNA autoantibody production by B cells.
Since, activation of autophagy has been considered to be principally regulated by the mTOR pathway, supplementation of NAC block mTOR signaling in SLE patients. The autophagic process is highly regulated and is stimulated by several factors including oxidative stress.
However, whether autophagy leads to a pro-survival response or cell death depends on the situation and severity of oxidative stress occurring in a particular pathologic setting. Evidence from genetics, cell biology and lupus animal model studies suggests a pivotal role of autophagy in mediating occurrence and development of SLE.
Importantly, autophagy is regulated by the mTOR pathway, and mTOR is activated by relative depletion of glutathione. This suggests that redox signaling may provide a link between altered redox signaling and autophagy in SLE. Therefore it will be interesting to study the effect of therapeutic supplements of NAC on autophagy in animal models of lupus and in SLE patients.
Such controlled clinical studies encourage exploration of the therapeutic potential of NAC, which might prove to provide an inexpensive and significant alternative therapy for SLE. The authors thank Xana Kim-Howard for excellent assistance in editing and reviewing this manuscript.
We also acknowledge the grant support from NIH AI, AR for this work. Some sections of this chapter were previously published in: Shah D and Nath SK. About us Contact. Copyright notice Privacy policy Advertising policy Contact us.
Journals Books eBooks Events. Developed by Bentus. Current issue Archive Manuscripts accepted About the journal Special Issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors Ethical standards and procedures Editorial System Submit your Manuscript Search.
Air pollution, oxidative stress, and exacerbation of autoimmune diseases. Central European Journal of Immunology. APA Gawda, A. Central European Journal of Immunology, 42 3 , Central European Journal of Immunology 42 3 : Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species.
Efimova O, Szankasi P, Kelley TW. Padgett LE, Tse HM. NADPH oxidase-derived superoxide provides a third signal for CD4 T cell effector responses. Tse HM, Thayer TC, Steele C, Cuda CM, Morel L, Piganelli JD, et al. NADPH oxidase deficiency regulates Th lineage commitment and modulates autoimmunity.
Gelderman KA, Hultqvist M, Pizzolla A, Zhao M, Nandakumar KS, Mattsson R, et al. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J Clin Invest. Yang Z, Shen Y, Oishi H, Matteson EL, Tian L, Goronzy JJ, et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis.
Thayer TC, Delano M, Liu C, Chen J, Padgett LE, Tse HM, et al. Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes. Padgett LE, Burg AR, Lei W, Tse HM. Loss of NADPH oxidase-derived superoxide skews macrophage phenotypes to delay type 1 diabetes.
Seleme MC, Lei W, Burg AR, Goh KY, Metz A, Steele C, et al. Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice. Padgett LE, Anderson B, Liu C, Ganini D, Mason RP, Piganelli JD, et al.
Loss of NOX-derived superoxide exacerbates diabetogenic CD4 T-cell effector responses in type 1 diabetes. Peterson JD, Herzenberg LA, Vasquez K, Waltenbaugh C. Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns.
Frossi B, De Carli M, Piemonte M, Pucillo C. Oxidative microenvironment exerts an opposite regulatory effect on cytokine production by Th1 and Th2 cells. Mol Immunol.
Kaminski MM, Sauer SW, Klemke CD, Süss D, Okun JG, Krammer PH, et al. Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression.
Yang L, Chen S, Zhao Q, Sun Y, Nie H. Mediat Inflamm. Yu X, Lao Y, Teng XL, Li S, Zhou Y, Wang F, et al. SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation. Lu D, Liu L, Ji X, Gao Y, Chen X, Liu Y, et al. The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation.
Dan L, Liu L, Sun Y, Song J, Yin Q, Zhang G, et al. The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity. Lee HJ, Park JS, Yoo HJ, Lee HM, Lee BC, Kim JH.
The selenoprotein MsrB1 instructs dendritic cells to induce T-helper 1 immune responses. Antioxidants Basel, Switzerland. Travis MA, Sheppard D. TGF-β activation and function in immunity. Worthington JJ, Kelly A, Smedley C, Bauché D, Campbell S, Marie JC, et al.
Integrin αvβ8-mediated TGF-β activation by effector regulatory T cells is essential for suppression of T-cell-mediated inflammation. Amarnath S, Dong L, Li J, Wu Y, Chen W. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, et al. Zhang D, Jin W, Wu R, Li J, Park SA, Tu E, et al.
High glucose intake exacerbates autoimmunity through reactive-oxygen-species-mediated TGF-β cytokine activation. Zhang D, Chia C, Jiao X, Jin W, Kasagi S, Wu R, et al. D-mannose induces regulatory T cells and suppresses immunopathology.
Nat Med. Fu G, Xu Q, Qiu Y, Jin X, Xu T, Dong S, et al. J Exp Med. Nicke B, Bastien J, Khanna SJ, Warne PH, Cowling V, Cook SJ, et al. Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells.
Mol Cell. Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, et al. Bile acid metabolites control T H 17 and T reg cell differentiation. Gelderman KA, Hultqvist M, Holmberg J, Olofsson P, Holmdahl R. T cell surface redox levels determine T cell reactivity and arthritis susceptibility.
Yang Z, Fujii H, Mohan SV, Goronzy JJ, Weyand CM. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. Zhao C, Gu Y, Zeng X, Wang J. NLRP3 inflammasome regulates Th17 differentiation in rheumatoid arthritis. Clin Immunol Orlando, Fla.
Abimannan T, Peroumal D, Parida JR, Barik PK, Padhan P, Devadas S. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells. van de Geer A, Cuadrado E, Slot MC, van Bruggen R, Amsen D, Kuijpers TW. Regulatory T cell features in chronic granulomatous disease.
Clin Exp Immunol. Perl A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol. Efimov I, Basran J, Thackray SJ, Handa S, Mowat CG, Raven EL. Structure and reaction mechanism in the heme dioxygenases.
Thomas SR, Terentis AC, Cai H, Takikawa O, Levina A, Lay PA, et al. Post-translational regulation of human indoleamine 2,3-dioxygenase activity by nitric oxide. Mándi Y, Vécsei L. The kynurenine system and immunoregulation. J Neural Transm Vienna, Austria: Maghzal GJ, Thomas SR, Hunt NH, Stocker R.
Cytochrome b5, not superoxide anion radical, is a major reductant of indoleamine 2,3-dioxygenase in human cells. Romani L, Fallarino F, De Luca A, Montagnoli C, D'Angelo C, Zelante T, et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Dang Y, Dale WE, Brown OR.
Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase of the kynurenine pathway. Kim HR, Lee A, Choi EJ, Hong MP, Kie JH, Lim W, et al. Reactive oxygen species prevent imiquimod-induced psoriatic dermatitis through enhancing regulatory T cell function.
Kim HR, Kim JH, Choi EJ, Lee YK, Kie JH, Jang MH, et al. Hyperoxygenation attenuated a murine model of atopic dermatitis through raising skin level of ROS. Popov A, Abdullah Z, Wickenhauser C, Saric T, Driesen J, Hanisch FG, et al. Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection.
J Clin Investig. De Ravin SS, Zarember KA, Long-Priel D, Chan KC, Fox SD, Gallin JI, et al. Jürgens B, Fuchs D, Reichenbach J, Heitger A. Intact indoleamine 2,3-dioxygenase activity in human chronic granulomatous disease.
Maghzal GJ, Winter S, Wurzer B, Chong BH, Holmdahl R, Stocker R. Tryptophan catabolism is unaffected in chronic granulomatous disease. Vottero E, Mitchell DA, Page MJ, MacGillivray RT, Sadowski IJ, Roberge M, et al. Cytochrome b 5 is a major reductant in vivo of human indoleamine 2,3-dioxygenase expressed in yeast.
FEBS Lett. Hill M, Tanguy-Royer S, Royer P, Chauveau C, Asghar K, Tesson L, et al. Song H, Park H, Kim YS, Kim KD, Lee HK, Cho DH, et al. L-kynurenine-induced apoptosis in human NK cells is mediated by reactive oxygen species.
Int Immunopharmacol. Cronin SJF, Seehus C, Weidinger A, Talbot S, Reissig S, Seifert M, et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Korge P, Calmettes G, Weiss JN. Increased reactive oxygen species production during reductive stress: the roles of mitochondrial glutathione and thioredoxin reductases.
Biochimica et biophysica acta. Poljsak B, Milisav I. Review: metabolic control of immune system activation in rheumatic diseases.
Arthritis Rheumatol Hoboken, N. Balogh E, Veale DJ, McGarry T, Orr C, Szekanecz Z, Ng CT, et al. Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis.
Arthritis Res Ther. Mateen S, Moin S, Zafar A, Khan AQ. Redox signaling in rheumatoid arthritis and the preventive role of polyphenols. Clinica Chimica Acta. Battersby AC, Braggins H, Pearce MS, Cale CM, Burns SO, Hackett S, et al.
Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom. Hultqvist M, Bäcklund J, Bauer K, Gelderman KA, Holmdahl R.
Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice. Shakya AK, Kumar A, Holmdahl R, Nandakumar KS.
Macrophage-derived reactive oxygen species protects against autoimmune priming with a defined polymeric adjuvant. George-Chandy A, Nordström I, Nygren E, Jonsson IM, Postigo J, Collins LV, et al. Th17 development and autoimmune arthritis in the absence of reactive oxygen species.
Guerard S, Holmdahl R, Wing K. Reactive oxygen species regulate innate but not adaptive inflammation in ZAPmutated SKG arthritic mice. Hultqvist M, Olofsson P, Gelderman KA, Holmberg J, Holmdahl R. A new arthritis therapy with oxidative burst inducers.
PLoS Med. Olofsson P, Nerstedt A, Hultqvist M, Nilsson EC, Andersson S, Bergelin A, et al. Arthritis suppression by NADPH activation operates through an interferon-beta pathway. BMC Biol. Zhong J, Yau ACY, Holmdahl R. Regulation of T cell function by reactive nitrogen and oxygen species in collagen-induced arthritis.
Antioxid Redox Signal. Basan M, Hui S, Okano H, Zhang Z, Shen Y, Williamson JR, et al. Overflow metabolism in Escherichia coli results from efficient proteome allocation.
Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation.
Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M, Ilkayeva O, et al. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al.
The CD28 signaling pathway regulates glucose metabolism. Maciver NJ, Jacobs SR, Wieman HL, Wofford JA, Coloff JL, Rathmell JC. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival.
Okar DA, Wu C, Lange AJ. Adv Enzyme Regul. Telang S, Clem BF, Klarer AC, Clem AL, Trent JO, Bucala R, et al. Small molecule inhibition of 6-phosphofructokinase suppresses t cell activation. J Transl Med. Rashida Gnanaprakasam JN, Wu R, Wang R.
Metabolic reprogramming in modulating T cell reactive oxygen species generation and antioxidant capacity. Metzler B, Gfeller P, Guinet E. Restricting glutamine or glutamine-dependent purine and pyrimidine syntheses promotes human T cells with high FOXP3 expression and regulatory properties.
Kono M, Yoshida N, Maeda K, Suárez-Fueyo A, Kyttaris VC, Tsokos GC. Arthritis Rheumatol Hoboken, NJ. Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A, Contreras DC, et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Takahashi S, Saegusa J, Sendo S, Okano T, Akashi K, Irino Y, et al.
Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. Mak TW, Grusdat M, Duncan GS, Dostert C, Nonnenmacher Y, Cox M, et al. Glutathione primes T cell metabolism for inflammation.
Shao L, Fujii H, Colmegna I, Oishi H, Goronzy JJ, Weyand CM. Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. Weyand CM, Fujii H, Shao L, Goronzy JJ. Rejuvenating the immune system in rheumatoid arthritis. Li Y, Goronzy JJ, Weyand CM. DNA damage, metabolism and aging in pro-inflammatory T cells: rheumatoid arthritis as a model system.
Exp Gerontol. Shen Y, Wen Z, Li Y, Matteson EL, Hong J, Goronzy JJ, et al. Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells.
Fearon U, Canavan M, Biniecka M, Veale DJ. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions.
PLoS Biol. Pucino V, Bombardieri M, Pitzalis C, Mauro C. Lactate at the crossroads of metabolism, inflammation, and autoimmunity. Ivashkiv LB The hypoxia-lactate axis tempers inflammation.
Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Devaraj S, Jialal I. Oxidized low-density lipoprotein and atherosclerosis.
Int J Clin Lab Res. Batooei M, Tahamoli-Roudsari A, Basiri Z, Yasrebifar F, Shahdoust M, Eshraghi A, et al. Evaluating the effect of oral N-acetylcysteine as an adjuvant treatment on clinical outcomes of patients with rheumatoid arthritis: a randomized, double blind clinical trial.
Rev Recent Clin Trials. León Fernández OS Viebahn-Haensler R Cabreja GL Espinosa IS Matos YH Roche LD. Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis. Eur J Pharmacol. Abdollahzad H, Aghdashi MA, Asghari Jafarabadi M, Alipour B.
Effects of coenzyme Q10 supplementation on inflammatory cytokines TNF-α, IL-6 and oxidative stress in rheumatoid arthritis patients: a randomized controlled trial. Arch Med Res. Niki E Oxidant-specific biomarkers of oxidative stress.
Association with atherosclerosis and implication for antioxidant effects. Sun T, Jiang D, Rosenkrans ZT, Ehlerding EB, Ni D, Qi C, et al. A melanin-based natural antioxidant defense nanosystem for theranostic application in acute kidney injury. Adv Funct Mater. Bao Q, Hu P, Xu Y, Cheng T, Wei C, Pan L, et al.
Simultaneous blood-brain barrier crossing and protection for stroke treatment based on edaravone-loaded ceria nanoparticles. ACS Nano. Aviello G, Knaus UG.
NADPH oxidases and ROS signaling in the gastrointestinal tract. Mucosal Immunol. Nóbrega-Pereira S, Fernandez-Marcos PJ, Brioche T, Gomez-Cabrera MC, Salvador-Pascual A, Flores JM, et al. G6PD protects from oxidative damage and improves healthspan in mice. Batinic-Haberle I, Tome ME.
Autoimmuune stress is a major Chromium for glucose metabolism in athletes of cellular damage in Oxidatie cells from Omega- fatty acids and blood pressure with systemic lupus erythematosus SLE diseaees amongst others syress the generation of Muscle mass secrets Th17 cells. Autoimune of NRF2 therefore Chromium for glucose metabolism in athletes to represent a putative therapeutic target in Xutoimmune, which oxidative stress and autoimmune diseases nevertheless challenged by several findings suggesting tissue and cell specific differences in the effect of NRF2 expression. This review focusses on the current understanding of oxidative stress in SLE T cells and its pathophysiologic and therapeutic implications. Oxidative stress might be a central factor in the immunopathogenesis of Systemic Lupus Erythematosus SLE 1. There are data supporting the hypothesis that excessive reactive oxygen species ROS production is, along with many other factors, one of the factors that induce SLE 2. Indeed, ROS production associates with enhanced apoptosis and might delay clearance of apoptotic cells, both of which are hallmarks of SLE 34. A common Trigger or cause ddiseases autoimmune disease, Thyroid disease, Diabetes, Chronic Pain, and Depression xutoimmune oxidative stress and autoimmune diseases notion Daily calorie intake Oxidative stress. Oxidxtive stress, defined as a disturbance in the balance between the production of oxidative stress and autoimmune diseases oxygen species free radicals and antioxidant defenses. One of the tests I routinely perform on patients is a test that helps me understand a patients Oxidative stress levels, injury due to free radicals, and that individuals anti-oxidant status. Assessment and amelioration of oxidative stress are invaluable components of preventive approaches to optimizing health and longevity. Reactive oxygen species ROS are produced as a result of normal oxygen metabolism or exposure to xenobiotics.
Wacker, die Phantastik))))
Ich denke, dass Sie nicht recht sind. Ich kann die Position verteidigen. Schreiben Sie mir in PM.