Immunogenicity of DNA Damaged by Reactive Oxygen Species—Implications for Anti-DNA Antibodies in Lupus

Cooke, Marcus S.; Mistry, Nalini; Wood, C N; Herbert, Karl E.; Lunec, Joseph

doi:10.1016/s0891-5849(96)00283-3

Cited by 99 publications

(66 citation statements)

References 52 publications

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“…DNA extraction and 5-HTTLPR genotyping was performed at the Center for Addiction and Mental Health, in Toronto (Canada). For the SLC6A4 LPR variant, 4 mL total genomic DNA was combined with 13MBI Fermentas polymerase chain reaction (PCR) buffer containing (NH4)2SO4, 1.5 mM MgCl2 (MBI Fermentas, Burlington, Canada), 0.0325 mg each primer 41 ; forward primer labeled with 59 HEX fluorescent tag), 0.16 mM each dNTP (MBI Fermentas) and 1 U Taq polymerase (MBI Fermentas) to a total volume of 25 mL. The PCR reactions were subjected to an initial denaturation for 3 min at 95°C, followed by 40 cycles of amplification in an AB 2720 (Thermofisher Scientific, Burlington, Canada) thermal cycler: denaturing for 30 seconds at 95°C, annealing for 30 seconds at 61°C and extension for 1 minute at 71°C, and a final extension at 72°C for 10 minutes.…”

Section: Infant Genotypementioning

confidence: 99%

Effects of Genotype and Sleep on Temperament

et al. 2015

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, on behalf of the MAVAN research team abstract BACKGROUND AND OBJECTIVES: Sleep problems are frequent in young children; however, children vary in the degree to which they are affected by poor sleep quality. We investigated whether a polymorphism in the serotonin transporter gene, which is linked to emotional function, is a potential moderator of the influences of sleep duration on infant temperament using longitudinal data. METHODS:We examined the interactive effects of average sleep duration between 6 and 36 months of age and the 5-HTTLPR genotype on negative emotionality/behavioral dysregulation at 36 months in 209 children recruited into a longitudinal birth cohort study. Triallelic genotyping of 5-HTTLPR was performed by looking at SLC6A4 genotype, focusing on the serotonin transporter-linked polymorphic region (5-HTTLPR) including the SNP polymorphism (rs23351). Child sleep habits were assessed with a maternal self-report questionnaire.RESULTS: After controlling for demographics and both previous and concurrent maternal depression, multiple linear regression analyses revealed a significant interaction effect of average sleep duration for the first 3 years of life and 5-HTTLPR genotype on child negative emotionality/behavioral dysregulation such that the effects were exclusive to those with low-expressing 5-HTTLPR genotypes. CONCLUSIONS:The results suggest differential susceptibility to the effect of sleep duration early in life, which reiterates that the short allele of the 5-HTTLPR represents a marker of increased environmental sensitivity regarding emotional development. Differential susceptibility theory posits that certain factors may increase an individual's susceptibility to the environment, in either a positive or negative fashion. WHAT'S KNOWN ON THIS SUBJECT:Sleep disturbances in infants associate with individual differences in temperament. However, little is known about interindividual differences and potential moderating factors, such as genotype. WHAT THIS STUDY ADDS:The results suggest that the cumulative effect of total sleep duration during the first 3 years of life on temperament is moderated by child 5-HTTLPR genotype following a differential susceptibility model.

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Section: Infant Genotypementioning

confidence: 99%

Effects of Genotype and Sleep on Temperament

et al. 2015

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“…There is some evidence that T cell help in lupus is directed to ubiquitous self-Ag, such as chromatin or ribonuclear protein (18 -21). More subtle self-Ag, generated by posttranslational modifications are also potential targets (22)(23)(24). Finally, peptides from the BCR V region may provide an avenue of T cell help to autoreactive B cells.…”

Section: T Cell Tolerance To Germline-encoded Antibody Sequences In Amentioning

confidence: 99%

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

Guo

Smith

Guth

et al. 2005

The Journal of Immunology

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The BCR V region has been implicated as a potential avenue of T cell help for autoreactive B cells in systemic lupus erythematosus. In principle, either germline-encoded or somatically generated sequences could function as targets of such help. Preceding studies have indicated that class II MHC-restricted T cells in normal mice attain a state tolerance to germline-encoded Ab diversity. In this study, we tested whether this tolerance is intact in systemic lupus erythematosus-prone (New Zealand Black × SWR)F1 mice (SNF1). Using a hybridoma sampling approach, we found that SNF1 T cells were tolerant to germline-encoded Ab sequences. Specifically, they were tolerant to germline-encoded sequences derived from a lupus anti-chromatin Ab that arose spontaneously in this strain. This was true both for diseased and prediseased mice. Thus, there does not appear to be a global defect in T cell tolerance to Ab V regions in this autoimmune-prone strain either before or during autoimmune disease.

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“…With respect to oxidative stress, evidence of increased levels of phospholipid oxidation products, particularly in patients with antiphospholipid antibodies (8) has been reported, as well as elevated plasma DNA oxidation products, such as 8-hydroxydeoxyguanosine (8-oxodG), a product that also appears to be processed abnormally (9). Many of the autoantibodies produced in SLE exhibit a preference for oxidized substrates, including oxidized doublestranded DNA (dsDNA) (10) and phospholipids (11). Oxidative stress and antiphospholipid antibodies have also been implicated in the increased atherosclerosis seen in patients with SLE (8).…”

mentioning

confidence: 99%

Increased levels of serum protein oxidation and correlation with disease activity in systemic lupus erythematosus

Morgan¹,

Sturgess²,

Davies³

2005

Arthritis & Rheumatism

121

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Objective. To examine protein oxidation in systemic lupus erythematosus (SLE) and to correlate levels of protein oxidation products with disease activity.Methods. Serum was collected from SLE patients and healthy control subjects. Protein-bound carbonyls and the pro-oxidant enzyme myeloperoxidase (MPO) were quantified by enzyme-linked immunosorbent assay. Protein thiols were quantified using 5,5-dithionitrobenzoic acid. Protein-bound amino acids and methionine, tyrosine, and phenylalanine oxidation products were quantified by acid hydrolysis and highperformance liquid chromatography. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Levels of antidouble-stranded DNA (anti-dsDNA) antibodies were measured by radioimmunoassay.Results. Compared with control subjects, SLE patients exhibited elevated levels of protein carbonyls (0.108 ؎ 0.078 versus 0.064 ؎ 0.028 nmoles/mg of protein; P ‫؍‬ 0.046), decreased levels of protein thiols (3.9 ؎ 1.1 versus 4.9 ؎ 0.7 nmoles/mg of protein; P ‫؍‬ 0.003), decreased levels of protein-bound methionine (P ‫؍‬ 0.0007), and increased levels of protein-bound methionine sulfoxide (P ‫؍‬ 0.0043) and 3-nitrotyrosine (P ‫؍‬ 0.0477). SLE patients with high SLEDAI scores or elevated anti-dsDNA antibody levels exhibited increased oxidation compared with patients with low SLEDAI scores or low antibody levels. Serum MPO levels were decreased in SLE patients (P ‫؍‬ 0.03), suggesting that this enzyme is not responsible for the enhanced protein oxidation.Conclusion. We found elevated levels of multiple markers of protein oxidation in sera from SLE patients compared with controls, and these levels correlated with disease activity. The findings suggest that protein oxidation may play a role in the pathogenesis of chronic organ damage in SLE.

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Immunogenicity of DNA Damaged by Reactive Oxygen Species—Implications for Anti-DNA Antibodies in Lupus

Cited by 99 publications

References 52 publications

Effects of Genotype and Sleep on Temperament

Effects of Genotype and Sleep on Temperament

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

Increased levels of serum protein oxidation and correlation with disease activity in systemic lupus erythematosus

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