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Care Med. Two mechanisms for toxic effects of hydroxylamines in human erythrocytes: involvement of free radicals and risk of potentiation. Blood Cells Mol. Microdetermination of oxyhemoglobin, methemoglobin and sulfhemoglobin in a single sample of blood. Human liver microsomal N-hydroxylation of dapsone by cytochrome PA4. Cytochrome Pdependent toxicity of dapsone in human erythrocytes. GILL, H. N-hydroxylation of dapsone by multiple enzymes of cytochrome P implications for inhibition of haematoxicity.

Methaemoglobinemia risk factors with inhaled nitric oxide therapy in newborn infants. Acta Paediatr. Role of aniline metabolites in aniline-induced hemolytic anemia. JO, Y. The effect of ethyl pyruvate on dapsone-induced methemoglobinemia in rats.

Hepatic and haematological adverse reactions associated with the use of multidrug therapy in leprosy a five year retrospective study. Indian J. Advances in the diagnosis and treatment of leprosy. Expert Rev. Nitric oxide is a mediator of the decrease in cytochrome Pdependent metabolism caused by immunostimulants.

USA , v. Effects of H 2 -receptor antagonists on dapsone-induced methaemoglobinaemia in rats. R, Sodium thiosulfate fails to reduce nitrite-induced methemoglobinemia in vitro. Dapsone treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.

Agents Chemother. Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo. Pharmacologic advances in the global control and treatment of malaria: combination therapy and resistance.

Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature , v. The antimalarial and hemolytic properties of 4,4-diaminodiphenyl sulfone DDS. Other Mycobact. The protective effect of vitamin E on the hemolysis associated with dapsone treatment in patients with dermatitis herpetiformis. Failure of intravenous N-acetylcysteine to reduce methemoglobin produced by sodium nitrite in human volunteers: a randomized controlled trial.

The chemical biology of nitric oxide: implications in cellular signaling. Free Radic. An investigation of the role of metabolism in dapsone-induced methaemoglobinemia using a two compartment in vitro test system.

Comparison of the metabolism and toxicity of dapsone in rat, mouse and man. Dapsone-induced hypersensitivity pneumonitis mimicking Pneumocystis carinii pneumonia in a patient with AIDS.

Methemoglobin-it's not just blue: a concise review. VAGE, C. Dapsone-induced hematologic toxicity: comparison of the methemoglobin-forming ability of hydroxylamine metabolites of dapsone in rat and human blood. Drug Metab. Hepatic disposition and effects of nitric oxide donors: rapid and concentration-dependent reduction in the cytochrome Pmediated drug metabolism in isolated perfused rat livers.

Short-term inhibitory effects of nitric oxide on cytochrome Pmediated drug metabolism: time dependency and reversibility profiles in isolated perfused rat livers. WARD, K. However, treatment with excessive amounts of either of these two peptides did not strengthen the T cell activation when compared to DDS stimulation alone Additional file 2 : Fig.

The peptide which predicted by the NetMHC 4. We further showed that DDS potentially binds to the F pocket of binding groove termed site 1 , which appeared to be stable due to a constant root-mean-square deviation RMSDs value Fig. For in-depth analysis of binding of DDS to the site 1, we conducted molecular modeling using Accelrys Discovery Studio.

The 2Fo-Fc map of the peptide contoured at 1. Besides, the van der Waals interactions that T B forms with adjacent amino acids, including W B , are stronger than those formed by I B While there is no significant difference between conformations of R B and T B , these two residues differently affect the electrostatic properties of the DDS-binding pocket, indicating that R B may also play an important role in DDS binding Fig.

The red points and gene names represent the SCAR-related genes as reported previously. P value of volcano plot was derived by Wilcoxon rank-sum test. The larger size of the circle represents the higher frequency of TCR.

In contrast, only up to 0. This would make the interaction between SFD and TCR energetically unfavorable because the related CDR3 region consists of multiple hydrophilic residues, such as serines. The alpha and beta chain of TCR were shown in purple. Drugs can potentially be recognized as foreign antigens and trigger cell-mediated adaptive immune responses such as SCARs [ 3 , 12 ]. Although HLA is known as an important immune receptor involved in drug presentation, few studies have investigated the structural basis for interactions between HLA and SCAR-associated drugs.

It suggested that TCR also plays an important role and can directly participate in HLA-drug interaction without any peptide involvement. In addition, our in vitro co-culture assays with TCR transfectants further validated the pathogenic role of immunodominant TCR clonotype i. The datasets supporting the conclusions of this article are included in this published article and its Additional files. Severe cutaneous adverse reactions to drugs.

Am J Med. Pathogenesis of drug-induced exanthems. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir.

Clin Ther. Medical genetics: a marker for Stevens-Johnson syndrome. J Allergy Clin Immunol. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Biomol Struct Dyn. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol. Article PubMed Google Scholar.

Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Severe cutaneous adverse drug reactions.

J Dermatol. Identification of drug-specific public TCR driving severe cutaneous adverse reactions. Nat Commun. The structural basis of HLA-associated drug hypersensitivity syndromes. Immunol Rev. Tangamornsuksan W, Lohitnavy M. JAMA Dermatol. J Invest Dermatol. N Engl J Med. Expert Opin Drug Saf. Front Immunol. Dapsone hypersensitivity syndrome DHS : a detrimental effect of dapsone? A case report. Curr Drug Saf.

Mortality due to dapsone hypersensitivity syndrome complicating multi-drug therapy for leprosy in Nepal. Trop Doct. Causes of death among active leprosy patients in China. Int J Dermatol. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. Wozel G. The story of sulfones in tropical medicine and dermatology.

Dapsone for chronic idiopathic thrombocytopenic purpura in children and adults—a report on 90 patients. Eur J Haematol. Eosinophilic fasciitis: a rare skin sclerosis. Patholog Res Int. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. Drug reaction with eosinophilia and systemic symptoms DRESS : an original multisystem adverse drug reaction.

Br J Dermatol. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. Within the form, select the 'Exact weight order' as the nature of enquiry and include your order number within the detail box. To view all certificates of analysis immediately, please login to your account or.

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Dapsone use is frequently associated to hematological side effects such as methemoglobinemia and hemolytic anemia, which are related to N-hydroxylation mediated by the P enzyme system.

The aim of the present study was to evaluate the influence of L-arginine supplementation, a precursor for the synthesis of nitric oxide, as single or multiple dose regimens on dapsone-induced methemoglobinemia. Blood samples were collected 2 hours after dapsone administration. Erythrocytic methemoglobin levels were assayed by spectrophotometry. This effect is mediated by nitric oxide formation, since the reduction in methemoglobin levels by L-arginine is blocked by simultaneous administration with L-NAME, a nitric oxide synthase inhibitor.

E-mail: rqueiroz fcfrp. Dapsone 4,4'-diaminodiphenylsulfone, DDS is a potent antibacterial and anti-inflammatory compound and has been clinically used in the treatment of leprosy as a component of a multidrug therapy that includes a combination of DDS, clofazimine and rifampicin Katoch ; Walker, Lockwood The drug is also used for the treatment of malaria and Pneumocystic carinii pneumonia in patients with acquired immunodeficiency syndrome Powell et al.

The co-oxidation of DDS-NOH and hemoglobin produces nitroso derivatives and methemoglobin, thus causing methemoglobinemia and hemolysis Tingle et al. The reduction of xenobiotic-induced metHb formation and the mechanisms underlying this effect have been widely investigated in the last few years.

The various attempts to reduce methemoglobinemia have included: preventing CYP-mediated oxidative metabolism of xenobiotics to hydroxylamines Coleman et al. NO is sufficiently nonpolar to cross membranes without a carrier and is known to modulate vasorelaxation and exhibit antioxidant properties due to superoxide scavenger and heme oxygenase inductor activities Wood et al. In spite of all the evidence pointing to the importance of ARG in vital pathways, the role of ARG supplementation in DDS-induced methemoglobinemia has yet to be described in the literature.

The aim of the present study was to evaluate the role of ARG in single and multiple dose regimens in DDS-induced methemoglobinemia. The animals had free access to chow and water throughout the experiment. ARG was administered orally p. The control group received the vehicle of ARG sterile physiological saline p. The control group received saline for five days p. On the fifth day, the animals received DMSO i. The DDS group received saline for five days p.

Methemoglobin levels were determined immediately. Methemoglobin levels relative to hemoglobin levels were determined according to the method described by Evelyn and Malloy modified by Harrison and Jollow, The hemolysate was then fractionated into four tubes. Tube 1 A 1 remained with hemolyzed blood.

The absorbance of each tube was measured at nm. Methemoglobin levels relative to hemoglobin levels were then calculated by the following equation:. The initial blood measurement A 1 is referent to MetHb and possible interferences. As there is no reference value for methemoglobin levels in rats, some preliminary studies were conducted in order to evaluate whether ARG or the vehicles could produce methemoglobinemia.

A single dose regimen control group was evaluated by administrating sterile physiological saline p. The administration of these vehicles resulted in 3. Methemoglobin levels were assayed in these groups, resulting in 1. These results showed that ARG alone did not produce methemoglobin. Methemoglobin levels of groups treated with ARG only, in a multiple drug regimen, did not produce significant levels of methemoglobin 1. The concentration of methemoglobin in erythrocytes is regulated by three systems: nicotinamide adenine dinucleotide NADHnicotinamide adenine dinucleotide phosphate NADPH and glutathione systems.

Finally, the conversion of reduced glutathione to glutathione influences methemoglobin levels by reducing oxidizing agents Evelo et al. The standard treatment for methemoglobinemia includes infusion with methylene blue, whose action depends on the availability of NADPH within the erythrocytes. In G6PD-deficient subjects, methylene blue therapy has been associated with hemolysis and methemoglobinemia Rehman, Several other substances have been investigated as alternatives to methylene blue therapy.

N -acetylcysteine, a precursor of glutathione, used in combination with DDS in rats, has shown increased methemoglobin levels in these animals compared to rats treated with DDS alone. Some authors have suggested that glutathione can regenerate DDS-NOH from dapsone nitroso derivatives thus resulting in higher methemoglobin levels De Moraes et al. In many cells and pathological conditions the supply of extracellular ARG is rate-limiting for NO production Brunini et al.

NO is considered a potent antioxidant agent in vitro and in vivo. Its antioxidant activity has been proven by suppressing iron-induced generation of hydroxyl radicals OH via the Fenton reaction, interrupting lipid peroxidation chain reaction, increasing the glutathione antioxidant potency and inhibiting cysteine proteases Chiueh, On the other hand, increased methemoglobin levels are a known toxic effect of inhaled NO therapy, commonly used for hypoxic neonates.

NO can combine with hemoglobin to produce nitrosylhemoglobin and thus form methemoglobin by oxidation Weinberger et al. Based on our observations, we can hypothesize that lower doses of ARG were beneficial to decrease methemoglobin levels because of the antioxidant properties of NO. However, higher doses of ARG do not decrease metHb levels because the antioxidant properties of NO are combined to its methemoglobinizant effect.

This metabolite can convert NO to a superoxide generator Thomas et al. NO also produces inhibitory effects in cytochrome P mediated drug metabolism. It is known that NO forms complexes with the catalytic center of P enzymes which results in a decrease in enzymatic activities of rat microsomes Khatsenko et al.

Thus, we can conclude that ARG supplementation can be an effective reducing agent for chronic treatment of DDS-induced methemoglobinemia and that its effect is mediated by NO. Open menu Brazil. Brazilian Journal of Pharmaceutical Sciences. Open menu. Abstract Resumo English Resumo Portuguese.

Text EN Text English. Uniterms: Dapsone. Nitric oxide. Unitermos: Dapsona. Single dose regimen The control group received the vehicle of ARG sterile physiological saline p. Multiple dose regimen The control group received saline for five days p. Methemoglobin assay Methemoglobin levels relative to hemoglobin levels were determined according to the method described by Evelyn and Malloy modified by Harrison and Jollow, Correspondence: R. Curcumin could prevent methemoglobinemia induced by dapsone in rats.

Food Chem. Nitric oxide, malnutrition and chronic renal failure. Agents Med. Treatment and prophylaxis of Pneumocystis carinii pneumonia. Neuroprotective properties of nitric oxide. The methaemoglobin forming and GSH depleting effects of dapsone and monoacetyl dapsone hydroxylamines in human diabetic and non-diabetic erythrocytes in vitro.

The effect of acetylation and deacetylation on the disposition of dapsone and monoacetyl dapsone hydroxylamines in human erythrocytes in-vitro. The use of cimetidine as a selective inhibitor of dapsone N-hydroxylation in man. Dapsone toxicity: some current perspectives. Potentiation of dapsone induced methemoglobinemia by N-acetylcysteine in rats. Reduction of NO-induced methemoglobinemia requires extremely high doses of ascorbic acid in vitro.

Intensive Care Med. Comparison of methylene blue, riboflavin and N-acetylcysteine for the reduction of nitric oxide-induced methemoglobinemia. Care Med.

Two mechanisms for toxic effects of hydroxylamines in human erythrocytes: involvement of free radicals and risk of potentiation. Blood Cells Mol. Microdetermination of oxyhemoglobin, methemoglobin and sulfhemoglobin in a single sample of blood.

Human liver microsomal N-hydroxylation of dapsone by cytochrome PA4. Cytochrome Pdependent toxicity of dapsone in human erythrocytes. GILL, H. N-hydroxylation of dapsone by multiple enzymes of cytochrome P implications for inhibition of haematoxicity.

Methaemoglobinemia risk factors with inhaled nitric oxide therapy in newborn infants. Acta Paediatr. Role of aniline metabolites in aniline-induced hemolytic anemia.

JO, Y. The effect of ethyl pyruvate on dapsone-induced methemoglobinemia in rats. Hepatic and haematological adverse reactions associated with the use of multidrug therapy in leprosy a five year retrospective study. Indian J. Advances in the diagnosis and treatment of leprosy. Expert Rev. Nitric oxide is a mediator of the decrease in cytochrome Pdependent metabolism caused by immunostimulants. USAv. Effects of H 2 -receptor antagonists on dapsone-induced methaemoglobinaemia in rats.

R, Sodium thiosulfate fails to reduce nitrite-induced methemoglobinemia in vitro.

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    Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Sodium thiosulfate fails to reduce nitrite-induced methemoglobinemia in vitro. Open menu. A positive result was defined as a 1. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Shiohara T, Mizukawa Y.

The hemolysate was then fractionated into four tubes. Tube 1 A 1 remained with hemolyzed blood. The absorbance of each tube was measured at nm. Methemoglobin levels relative to hemoglobin levels were then calculated by the following equation:. The initial blood measurement A 1 is referent to MetHb and possible interferences. As there is no reference value for methemoglobin levels in rats, some preliminary studies were conducted in order to evaluate whether ARG or the vehicles could produce methemoglobinemia.

A single dose regimen control group was evaluated by administrating sterile physiological saline p. The administration of these vehicles resulted in 3. Methemoglobin levels were assayed in these groups, resulting in 1. These results showed that ARG alone did not produce methemoglobin. Methemoglobin levels of groups treated with ARG only, in a multiple drug regimen, did not produce significant levels of methemoglobin 1. The concentration of methemoglobin in erythrocytes is regulated by three systems: nicotinamide adenine dinucleotide NADH , nicotinamide adenine dinucleotide phosphate NADPH and glutathione systems.

Finally, the conversion of reduced glutathione to glutathione influences methemoglobin levels by reducing oxidizing agents Evelo et al. The standard treatment for methemoglobinemia includes infusion with methylene blue, whose action depends on the availability of NADPH within the erythrocytes.

In G6PD-deficient subjects, methylene blue therapy has been associated with hemolysis and methemoglobinemia Rehman, Several other substances have been investigated as alternatives to methylene blue therapy. N -acetylcysteine, a precursor of glutathione, used in combination with DDS in rats, has shown increased methemoglobin levels in these animals compared to rats treated with DDS alone.

Some authors have suggested that glutathione can regenerate DDS-NOH from dapsone nitroso derivatives thus resulting in higher methemoglobin levels De Moraes et al. In many cells and pathological conditions the supply of extracellular ARG is rate-limiting for NO production Brunini et al. NO is considered a potent antioxidant agent in vitro and in vivo.

Its antioxidant activity has been proven by suppressing iron-induced generation of hydroxyl radicals OH via the Fenton reaction, interrupting lipid peroxidation chain reaction, increasing the glutathione antioxidant potency and inhibiting cysteine proteases Chiueh, On the other hand, increased methemoglobin levels are a known toxic effect of inhaled NO therapy, commonly used for hypoxic neonates.

NO can combine with hemoglobin to produce nitrosylhemoglobin and thus form methemoglobin by oxidation Weinberger et al. Based on our observations, we can hypothesize that lower doses of ARG were beneficial to decrease methemoglobin levels because of the antioxidant properties of NO.

However, higher doses of ARG do not decrease metHb levels because the antioxidant properties of NO are combined to its methemoglobinizant effect. This metabolite can convert NO to a superoxide generator Thomas et al. NO also produces inhibitory effects in cytochrome P mediated drug metabolism. It is known that NO forms complexes with the catalytic center of P enzymes which results in a decrease in enzymatic activities of rat microsomes Khatsenko et al. Thus, we can conclude that ARG supplementation can be an effective reducing agent for chronic treatment of DDS-induced methemoglobinemia and that its effect is mediated by NO.

Open menu Brazil. Brazilian Journal of Pharmaceutical Sciences. Open menu. Abstract Resumo English Resumo Portuguese. Text EN Text English. Uniterms: Dapsone. Nitric oxide. Unitermos: Dapsona. Single dose regimen The control group received the vehicle of ARG sterile physiological saline p.

Multiple dose regimen The control group received saline for five days p. Methemoglobin assay Methemoglobin levels relative to hemoglobin levels were determined according to the method described by Evelyn and Malloy modified by Harrison and Jollow, Correspondence: R.

Curcumin could prevent methemoglobinemia induced by dapsone in rats. Food Chem. Nitric oxide, malnutrition and chronic renal failure. Post-processing and quality control were performed by Novogene using the 10X Cell Ranger package v2.

Reads were aligned to mm10 or GRCh38, etc. At 48 h after transfection, the virus was collected, filtered through a 0. On day 3 post-infection, TCR expressing cells were sorted by flow cytometry to establish derivative cell lines as indicated. The transduced primary T cells were cultured for 48 h and then used for cytotoxicity assays.

To verify primer specificities, melting curve analyses and PCR product sequencing were performed. And next the complex structure was assembled by referring the existing crystal structure PDB code: 4EUP using structure alignment program TMalign [ 44 ].

Heatmaps were created using the built-in R heatmap function in stats package, and the Circos plots were generated using the VDJtools software MiLaboratory. The entire experiment was repeated thrice.

P-values for ratio estimates were calculated using a two-sided test. Differences were considered statistically significant at P-values of less than 0. All other data are available from the authors upon reasonable request.

The underlying conditions caused by treatment with DDS were mostly diagnosed as chronic inflammatory dermatoses, including exfoliative dermatitis, erythroderma and eosinophilia Table 1.

The average daily DDS dose was All study participants were of Chinese descent. S3A and B. This result was consistent with the clinal and genetic finding.

However, treatment with excessive amounts of either of these two peptides did not strengthen the T cell activation when compared to DDS stimulation alone Additional file 2 : Fig. The peptide which predicted by the NetMHC 4. We further showed that DDS potentially binds to the F pocket of binding groove termed site 1 , which appeared to be stable due to a constant root-mean-square deviation RMSDs value Fig. For in-depth analysis of binding of DDS to the site 1, we conducted molecular modeling using Accelrys Discovery Studio.

The 2Fo-Fc map of the peptide contoured at 1. Besides, the van der Waals interactions that T B forms with adjacent amino acids, including W B , are stronger than those formed by I B While there is no significant difference between conformations of R B and T B , these two residues differently affect the electrostatic properties of the DDS-binding pocket, indicating that R B may also play an important role in DDS binding Fig.

The red points and gene names represent the SCAR-related genes as reported previously. P value of volcano plot was derived by Wilcoxon rank-sum test. The larger size of the circle represents the higher frequency of TCR. In contrast, only up to 0. This would make the interaction between SFD and TCR energetically unfavorable because the related CDR3 region consists of multiple hydrophilic residues, such as serines. The alpha and beta chain of TCR were shown in purple. Drugs can potentially be recognized as foreign antigens and trigger cell-mediated adaptive immune responses such as SCARs [ 3 , 12 ].

Although HLA is known as an important immune receptor involved in drug presentation, few studies have investigated the structural basis for interactions between HLA and SCAR-associated drugs. It suggested that TCR also plays an important role and can directly participate in HLA-drug interaction without any peptide involvement.

In addition, our in vitro co-culture assays with TCR transfectants further validated the pathogenic role of immunodominant TCR clonotype i. The datasets supporting the conclusions of this article are included in this published article and its Additional files.

Severe cutaneous adverse reactions to drugs. Am J Med. Pathogenesis of drug-induced exanthems. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther. Medical genetics: a marker for Stevens-Johnson syndrome. J Allergy Clin Immunol. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Biomol Struct Dyn. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.

Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol. Article PubMed Google Scholar. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Severe cutaneous adverse drug reactions. J Dermatol. Identification of drug-specific public TCR driving severe cutaneous adverse reactions.

Nat Commun. The structural basis of HLA-associated drug hypersensitivity syndromes. Immunol Rev. Tangamornsuksan W, Lohitnavy M. JAMA Dermatol. J Invest Dermatol. N Engl J Med. Expert Opin Drug Saf. Front Immunol. Dapsone hypersensitivity syndrome DHS : a detrimental effect of dapsone? A case report. Curr Drug Saf.

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Journal of Biomedical Science volume 29Article number: 58 Cite this article. Metrics details. Severe cutaneous adverse drug reactions SCARs are a group of serious clinical conditions caused by immune reaction to certain drugs. Severe cutaneous adverse drug reactions SCARsincluding drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms DRESSStevens-Johnson syndrome SJS and toxic epidermal necrolysis TENare a group of potentially life-threatening adverse drug reactions with different clinical presentations and pathogenesis [ 12 ].

SCARs are delayed-type hypersensitivity reactions i. Naive T cells are primed upon initial treatment with the causative drug, following which a pool of memory T cells is gradually formed by re-stimulation during continued exposure.

Accordingly, SCARs resolve when treatment with the causative drug is discontinued and develop more rapidly upon renewal of its administration [ 34 ]. Individuals with predisposition to develop SCARs appear to possess specific human leukocyte antigen HLA alleles, which have been found to trigger the condition by mediating drug-induced T cell activation [ 56789 ].

Several theories, such as hapten and pro-haptenp-i pharmacological interaction with immune receptors [ 1213 ], peptide repertoire alteration [ 14 ] and altered TCR repertoire model, have been proposed to explain the HLA-associated drug hypersensitivity [ 1516 ].

More recently, a unique population of T cells, termed skin-resident memory T cells, have been identified as possible SCAR mediators [ 1016 ]. Besides, the structural bioinformatics approach, which has seen remarkable advance in recent years, is a promising way to computationally elucidate the structural basis, dynamics and energetic properties of HLA-drug association as well as its pathological role in SCARs. DDS has also been used to treat various dermatologic and non-dermatologic diseases, including Pneumocystis jirovecii pneumonia [ 28 ], dermatitis herpetiformis [ 29 ], immune thrombocytopaenia [ 30 ] and eosinophilic fasciitis [ 31 ].

DRESS was diagnosed according to the RegiSCAR criteria [ 3435 ] and was characterized by extensive erythematous maculopapular rash with periorbital edema and desquamation. The clinical course, dosage and duration of dapsone, systemic involvement, and mortality were analyzed. We also recruited ten DDS-tolerant control subjects who had been administered DDS for at least 3 months without any cutaneous adverse reactions.

In addition, twelve healthy control individuals were enrolled. Approvals were obtained from the institutional review board IRB No. G to Hmy2. The column was successively washed with 50 mL binding buffer containing 20 mM imidazole and mM imidazole, and target protein was eluted using binding buffer containing mM imidazole.

Crystallization drops contained 0. Diffraction quality crystals were grown in 0. All data were indexed and scaled using HKL software.

After several rounds of positional and B-factor refinement using Phenix. The quality of the final model was validated with MolProbity [ 41 ]. Detailed information on data collection and refinement statistics is listed in the Table 2. Responses of the interaction were reference subtracted and corrected with a standard curve for the DMSO effects.

BIA Evaluation software Version 1. The Kd value were determined by three independent experiments. Only high confident identified peptides were chosen for downstream protein identification analysis.

The T-cell clones were obtained by means of serial dilution. In addition, dimethyl sulfoxide DMSO was added to the medium as the solvent control, and phytohemagglutinin i. Approximately Numberetc. Library quality and concentration were assessed using Agilent Bioanalyzer Post-processing and quality control were performed by Novogene using the 10X Cell Ranger package v2. Reads were aligned to mm10 or GRCh38, etc. At 48 h after transfection, the virus was collected, filtered through a 0.

On day 3 post-infection, TCR expressing cells were sorted by flow cytometry to establish derivative cell lines as indicated. The transduced primary T cells were cultured for 48 h and then used for cytotoxicity assays. To verify primer specificities, melting curve analyses and PCR product sequencing were performed.

And next the complex structure was assembled by referring the existing crystal structure PDB code: 4EUP using structure alignment program TMalign [ 44 ]. Heatmaps were created using the built-in R heatmap function in stats package, and the Circos plots were generated using the VDJtools software MiLaboratory.

The entire experiment was repeated thrice. P-values for ratio estimates were calculated using a two-sided test. Differences were considered statistically significant at P-values of less than 0. All other data are available from the authors upon reasonable request. The underlying conditions caused by treatment with DDS were mostly diagnosed as chronic inflammatory dermatoses, including exfoliative dermatitis, erythroderma and eosinophilia Table 1.

The average daily DDS dose was All study participants were of Chinese descent. S3A and B. This result was consistent with the clinal and genetic finding. However, treatment with excessive amounts of either of these two peptides did not strengthen the T cell activation when compared to DDS stimulation alone Additional file 2 : Fig.

The peptide which predicted by the NetMHC 4. We further showed that DDS potentially binds to the F pocket of binding groove termed site 1which appeared to be stable due to a constant root-mean-square deviation RMSDs value Fig. For in-depth analysis of binding of DDS to the site 1, we conducted molecular modeling using Accelrys Discovery Studio.

The 2Fo-Fc map of the peptide contoured at 1. Besides, the van der Waals interactions that T B forms with adjacent amino acids, including W Bare stronger than those formed by I B While there is no significant difference between conformations of R B and T Bthese two residues differently affect the electrostatic properties of the DDS-binding pocket, indicating that R B may also play an important role in DDS binding Fig.

The red points and gene names represent the SCAR-related genes as reported previously. P value of volcano plot was derived by Wilcoxon rank-sum test. The larger size of the circle represents the higher frequency of TCR. In contrast, only up to 0. This would make the interaction between SFD and TCR energetically unfavorable because the related CDR3 region consists of multiple hydrophilic residues, such as serines. The alpha and beta chain of TCR were shown in purple.

Drugs can potentially be recognized as foreign antigens and trigger cell-mediated adaptive immune responses such as SCARs [ 312 ]. Although HLA is known as an important immune receptor involved in drug presentation, few studies have investigated the structural basis for interactions between HLA and SCAR-associated drugs. It suggested that TCR also plays an important role and can directly participate in HLA-drug interaction without any peptide involvement.

In addition, our in vitro co-culture assays with TCR transfectants further validated the pathogenic role of immunodominant TCR clonotype i.

The datasets supporting the conclusions of this article are included in this published article and its Additional files. Severe cutaneous adverse reactions to drugs. Am J Med. Pathogenesis of drug-induced exanthems. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther. Medical genetics: a marker for Stevens-Johnson syndrome.

J Allergy Clin Immunol. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Biomol Struct Dyn. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol. Article PubMed Google Scholar. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.

Severe cutaneous adverse drug reactions. J Dermatol. Identification of drug-specific public TCR driving severe cutaneous adverse reactions. Nat Commun. The structural basis of HLA-associated drug hypersensitivity syndromes.

Immunol Rev. Tangamornsuksan W, Lohitnavy M. JAMA Dermatol. J Invest Dermatol. N Engl J Med. Expert Opin Drug Saf. Front Immunol. Dapsone hypersensitivity syndrome DHS : a detrimental effect of dapsone? A case report. Curr Drug Saf. Mortality due to dapsone hypersensitivity syndrome complicating multi-drug therapy for leprosy in Nepal.

Dapsone, Sigma-Aldrich® ; Molar Mass, g/mol ; Bulk Density, - kg/m3 ; pH, - (H2O, 20 °C) (saturated aqueous solution) ; Synonyms, DDS, 4,4'-. Keywords: Memory, Dapsone, Nitric oxide, Scopolamine, Mice and scopolamine hydrobromide were obtained from Sigma Corporation and were. Dapsone; Methemoglobinemia; L-arginine; Nitric oxide; L-NAME L-NAME was purchased from Sigma-Aldrich (St. Louis, MO, USA). KCN was supplied by Merck. The anti-Pneumocystis carinii activity of atovaquone, dapsone and sulphamethoxazole alone Dapsone (Sigma–Aldrich) was initially. Purpose: To prepare dapsone tosylate salt (TD) and its two polymorphs (TD-I and TD-II), and study were purchased from Sigma-Aldrich®, and were. Published : 13 August All data were indexed and scaled using HKL software. The control group received the vehicle of ARG sterile physiological saline p.

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