Immunization of mice with human 60-kd Ro peptides results in epitope spreading if the peptides are highly homologous between human and mouse

Scofield, R. Hal; Kaufman, Kenneth M.; Baber, Ursela; James, Judith A.; Harley, John B.; Kurien, Biji T.

doi:10.1002/1529-0131(199905)42:5<1017::aid-anr22>3.0.co;2-7

Cited by 58 publications

(36 citation statements)

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“…In another study, the detection of anti-La/SSB antibodies predated clinical evidence of Sjögren's syndrome by months and in some cases by years [13]. Furthermore, in an animal model of SLE, mice immunized with human Ro/SSA developed autoimmunity not only towards this molecule but also towards other immunologically similar molecules in a process equivalent to epitope spreading [14]. …”

Section: Introductionmentioning

confidence: 99%

Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden

et al. 2011

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IntroductionAutoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and in those with rheumatoid arthritis, suggesting a gradual development of these diseases. Therefore, we sought to identify autoantibodies in a northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.MethodsThe register of patients fulfilling the American College of Rheumatology criteria for SLE and with a given date of the onset of symptoms was coanalysed with the register of the Medical Biobank, Umeå, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Medical Biobank register (Umeå, Sweden). Antibodies against anti-Sjögren's syndrome antigen A (Ro/SSA; 52 and 60 kDa), anti-Sjögren's syndrome antigen B, anti-Smith antibody, ribonucleoprotein, scleroderma, anti-histidyl-tRNA synthetase antibody, double-stranded DNA (dsDNA), centromere protein B and histones were analysed using the AtheNA Multi-Lyte ANA II Plus Test System on a Bio-Plex Array Reader (Luminex200). Antinuclear antibodies test II (ANA II) results were analysed using indirect immunofluorescence on human epidermal 2 cells at a sample dilution of 1:100.ResultsAutoantibodies against nuclear antigens were detected a mean (±SD) of 5.6 ± 4.7 years before the onset of symptoms and 8.7 ± 5.6 years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA II, with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies, both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratios (ORs) for predicting disease were 18.13 for anti-dsDNA (95% confidence interval (95% CI), 3.58 to 91.84) and 11.5 (95% CI, 4.54 to 28.87) for ANA. Anti-Ro/SSA antibodies appeared first at a mean of 6.6 ± 2.5 years prior to symptom onset. The mean number of autoantibodies in prediseased individuals was 1.4, and after disease onset it was 3.1 (P < 0.0005). The time predating disease was shorter and the number of autoantibodies was greater in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations as the presenting symptoms.ConclusionsAutoantibodies against nuclear antigens were detected in individuals who developed SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR being for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.

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Section: Introductionmentioning

confidence: 99%

Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden

et al. 2011

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“…Thus, when metabolic stressors are produced in the lung in response to environmental stressors, they may diffuse through the blood-brain barrier and produce neurotoxicity [31,46] or generate neoantigens [45], which can be involved in generating autoimmunity through a process known as epitope spreading [45,47]. …”

Section: The Lung As a Target Of Inhaled Environmental Stressorsmentioning

confidence: 99%

“…In atopic patients, while allergen alone produces a two- to three-fold increase in allergen-specific IgE, a challenge of allergen combined with DEP enhances local allergen-specific IgE production 20- to 50-fold [62]. The study suggests that ROS and oxidatively modified bio-molecules might act as limiting factors in elucidating autoimmune responses by molecular mimicry and epitope spreading [47,87]. On the basis of this premise, it is argued that the amounts of metabolic stressors produced in the stressed lung and the adducts they form with proteins might play a pivotal role in inducing/accelerating autoimmune processes [88].…”

Section: Inhalation Of Environmental Stressors and Autoimmunitymentioning

confidence: 99%

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Inhalation of environmental stressors & chronic inflammation: Autoimmunity and neurodegeneration

Gomez-Mejiba

Zhai

Akram

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Human life expectancy and welfare has decreased because of the increase in environmental stressors in the air. An environmental stressor is a natural or human-made component present in our environment that upon reaching an organic system produces a coordinated response. This response usually involves a modification of the metabolism and physiology of the system. Inhaled environmental stressors damage the airways and lung parenchyma, producing irritation, recruitment of inflammatory cells, and oxidative modification of biomolecules. Oxidatively modified biomolecules, their degradation products, and adducts with other biomolecules can reach the systemic circulation, and when found in higher concentrations than normal they are considered to be biomarkers of systemic oxidative stress and inflammation. We classify them as metabolic stressors because they are not inert compounds; indeed, they amplify the inflammatory response by inducing inflammation in the lung and other organs. Thus the lung is not only the target for environmental stressors, but it is also the source of a number of metabolic stressors that can induce and worsen preexisting chronic inflammation. Metabolic stressors produced in the lung have a number of effects in tissues other than the lung, such as the brain, and they can also abrogate the mechanisms of immunotolerance. In this review, we discuss recent published evidence that suggests that inflammation in the lung is an important connection between air pollution and chronic inflammatory diseases such as autoimmunity and neurodegeneration, and we highlight the critical role of metabolic stressors produced in the lung. The understanding of this relationship between inhaled environmental pollutants and systemic inflammation will help us to: 1) understand the molecular mechanism of environment-associated diseases, and 2) find new biomarkers that will help us prevent the exposure of susceptible individuals and/or design novel therapies.

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“…Shifts in GAD 65 epitopes were detected in a subgroup of newly diagnosed children within the first 12 months after disease onset [9]. Moreover, epitope spreading has gained credence as a major driver underlying autoimmunity [10]. …”

Section: Introductionmentioning

confidence: 99%

Detection of autoantibodies against reactive oxygen species modified glutamic acid decarboxylase-65 in type 1 diabetes associated complications

et al. 2011

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BackgroundAutoantibodies against glutamate decarboxylase-65 (GAD65Abs) are thought to be a major immunological tool involved in pathogenic autoimmunity development in various diseases. GAD65Abs are a sensitive and specific marker for type 1 diabetes (T1D). These autoantibodies can also be found in 6-10% of patients classified with type 2 diabetes (T2D), as well as in 1-2% of the healthy population. The latter individuals are at low risk of developing T1D because the prevalence rate of GAD65Abs is only about 0.3%. It has, therefore, been suggested that the antibody binding to GAD65 in these three different GAD65Ab-positive phenotypes differ with respect to epitope specificity. The specificity of reactive oxygen species modified GAD65 (ROS-GAD65) is already well established in the T1D. However, its association in secondary complications of T1D has not yet been ascertained. Hence this study focuses on identification of autoantibodies against ROS-GAD65 (ROS-GAD65Abs) and quantitative assays in T1D associated complications.ResultsFrom the cohort of samples, serum autoantibodies from T1D retinopathic and nephropathic patients showed high recognition of ROS-GAD65 as compared to native GAD65 (N-GAD65). Uncomplicated T1D subjects also exhibited reactivity towards ROS-GAD65. However, this was found to be less as compared to the binding recorded from complicated subjects. These results were further proven by competitive ELISA estimations. The apparent association constants (AAC) indicate greater affinity of IgG from retinopathic T1D patients (1.90 × 10-6 M) followed by nephropathic (1.81 × 10-6 M) and uncomplicated (3.11 × 10-7 M) T1D patients for ROS-GAD65 compared to N-GAD65.ConclusionIncreased oxidative stress and blood glucose levels with extended duration of disease in complicated T1D could be responsible for the gradual formation and/or exposing cryptic epitopes on GAD65 that induce increased production of ROS-GAD65Abs. Hence regulation of ROS-GAD65Abs could offer novel tools for analysing and possibly treating T1D complications.

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Immunization of mice with human 60-kd Ro peptides results in epitope spreading if the peptides are highly homologous between human and mouse

Cited by 58 publications

References 35 publications

Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden

Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden

Inhalation of environmental stressors & chronic inflammation: Autoimmunity and neurodegeneration

Detection of autoantibodies against reactive oxygen species modified glutamic acid decarboxylase-65 in type 1 diabetes associated complications

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