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Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting from the complex interplay of genetic and environmental factors, meriting exploration using temporally dynamic biomarkers. DNA methylation-based algorithms have been trained to accurately estimate biological age, and deviation of predicted age from true age (epigenetic age acceleration) has been implicated in several inflammatory diseases, including asthma. Objective: We sought to determine the role of epigenetic and biological aging, telomere length, and epigenetically inferred abundance of 7 inflammatory biomarkers in AD. Methods: We performed DNA methylation-based analyses in a pediatric AD cohort (n = 24, mean ± standard deviation [SD] age 2.56 ± 0.28 years) and age-matched healthy subjects (n = 24, age 2.09 [0.15] years) derived from blood using 5 validated algorithms that assess epigenetic age (Horvath, Skin&Blood) and biological age (PhenoAge, GrimAge), telomere length (TelomereLength), and inflammatory biomarker levels. Results: Epigenetic and biological age, but not telomere length, were accelerated in AD patients for 4 algorithms: Horvath (+0.88 years; 95% confidence interval [CI], 0.33 to 1.4; P = 2.3 × 10-3), Skin&Blood (+0.95 years; 95% CI, 0.67 to 1.2; P = 1.8 × 10-8), PhenoAge (+8.2 years; 95% CI, 3.4 to 13.0; P = 1.3 × 10-3), and GrimAge (+1.8 years 95% CI, 0.22 to 3.3; P = .026). Moreover, patients had increased levels of ß2 microglobulin (+47,584.4 ng/mL; P = .029), plasminogen activation inhibitor 1 (+3,432.9 ng/mL; P = 1.1 × 10-5), and cystatin C (+31,691 ng/mL; P = 4.0 × 10-5), while levels of tissue inhibitor metalloproteinase 1 (-370.7 ng/mL; P = 7.5 × 10-4) were decreased compared to healthy subjects. Conclusion: DNA methylation changes associated with epigenetic and biological aging, and inflammatory proteins appear early in life in pediatric AD and may be relevant clinical biomarkers of pathophysiology.
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Disparities in environmental and social determinants of health (DOH) are associated with morbidity in atopic dermatitis (AD). The socioecological model (SEM) is a framework that can be applied to better understand how such DOH impacts patients with AD. We include a case scenario of a remote Indigenous patient reflective of real-world situations of living with AD and examine relevant impact, gaps in knowledge, and further research needs. This review highlights a variety of social and environmental exposures as important DOH which must be addressed to achieve optimal management in AD. The "rainbow model" is a modified framework to help illustrate how complex environmental and social forces impact both AD presentation and therapeutic success. However, practical applications and outcome metrics for health promotion are limited. An inter- and transdisciplinary approach is paramount to address the complex challenges associated with AD care, as well as multistakeholder approach integrating culturally-competent equitable health frameworks. This review underscores the importance of expanding the focus of AD management beyond basic science and clinical trials to recognize and address health disparities and to promote optimal health and well-being in patients with AD, and contributes a working approach to mapping the complex interventions and patient-oriented research needed using a focus on remote North American Indigenous patients affected by AD.
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Dermatitis Atópica , Humanos , Dermatitis Atópica/epidemiología , Dermatitis Atópica/terapia , Promoción de la Salud , Grupos Raciales , Población Rural , América del NorteRESUMEN
Atopic dermatitis (AD) is associated with high levels of psychosocial burden, often resulting in poor mental health outcomes. Despite this association, few studies have evaluated the efficacy of mental health interventions within this population. Utilization of multidisciplinary and peer-led support, in addition to equipping patients with psychological tools, may be beneficial in improving mental health outcomes. Future research is needed to determine which interventions and formats are desired by, effective in and accessible to patients and caregivers with AD.
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Dermatitis Atópica , Humanos , Dermatitis Atópica/epidemiología , Salud Mental , Cuidadores/psicología , Calidad de VidaRESUMEN
BACKGROUND: The potential benefit of inducing delayed-type hypersensitivity (DTH) reaction in healthy volunteers (HVs) as experimental models to study skin inflammatory disorders was recently reported using bulk molecular technologies. Immunophenotype of skin T cells, including cellular source of Type 1, 2, and 3 cytokines, in a local DTH reaction and their modulation by oral drugs remain to be investigated. METHOD: Purified protein derivative (PPD), nickel, diphencyprone (DPCP), or house dust mite (HDM) was administered as sensitizer to 40 HVs. In addition, 20 HVs were randomized to receive oral prednisone or placebo before DPCP challenge. We characterized the immunophenotype and cytokine profile of CD3+ T cell infiltrate, and examined the modulation by oral prednisone at single-cell level using multiparameter flow cytometry and unsupervised analysis. RESULTS: PPD was biased toward a Th1 and Tc1 response, and HDM a Th2/Th17 and Tc2. Nickel and DPCP displayed a mixed Th1/Th2/Th17 and Tc1 response. CD4+ CD25+ FoxP3+ regulatory T cells (Tregs), the minor CD4+ CD25+ FoxP3- ICOS+ PD-1+ (activated PD-1+ Th), and CD103+ tissue resident memory (TRM) cells were detected in all groups. DPCP uniquely elicited rare CD8+ CD103+ CD25+ RoRγt+ PD-1+ ICOS+ IFNγ+ T cells (activated CD8+ IFNγ+ PD-1+ TRM). Oral prednisone decreased frequencies of activated PD-1+ Th and CD8+ IFNγ+ PD-1+ TRM subsets relative to placebo in DPCP reaction. The latter was positively correlated with improvement of clinical parameters with prednisone. CONCLUSION: DTH and skin CD3+ T cell profiles elicited by common sensitizers can be modulated by oral drugs. Corticosteroids reduce the frequencies of activated PD-1+ Th and CD8+ IFNγ+ PD-1+ TRM cells after DPCP exposure.
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Níquel , Receptor de Muerte Celular Programada 1 , Humanos , Prednisona/uso terapéutico , Factores de Transcripción Forkhead/metabolismoRESUMEN
Atopic dermatitis (AD) is known as a skin disease; however, T cell immunopathology found in blood is associated with its severity. Skin Staphylococcus aureus (S. aureus) and associated host-pathogen dynamics are important to chronic T helper 2 (Th2)-dominated inflammation in AD, yet they remain poorly understood. This study sought to investigate the effects of S. aureus-derived molecules and skin alarmins on human peripheral blood mononuclear cells, specifically testing Th2-type cells, cytokines, and chemokines known to be associated with AD. We first show that six significantly elevated Th2-related chemokine biomarkers distinguish blood from adult AD patients compared to healthy controls ex vivo; in addition, TARC/CCL17, LDH, and PDGF-AA/AB correlated significantly with disease severity. We then demonstrate that these robust AD-associated biomarkers, as well as associated type 2 T cell functions, are readily reproduced from healthy blood mononuclear cells exposed to the alarmin TSLP and the S. aureus superantigen SEB in a human in vitro model, including IL-13, IL-5, and TARC secretion as well as OX-40-expressing activated memory T cells. We further show that the agonism of nucleotide-binding oligomerization domain-containing protein (NOD)2 inhibits this IL-13 secretion and memory Th2 and Tc2 cell functional activation while inducing significantly increased pSTAT3 and IL-6, both critical for Th17 cell responses. These findings identify NOD2 as a potential regulator of type 2 immune responses in humans and highlight its role as an endogenous inhibitor of pathogenic IL-13 that may open avenues for its therapeutic targeting in AD.
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Dermatitis Atópica , Adulto , Humanos , Dermatitis Atópica/tratamiento farmacológico , Interleucina-13/metabolismo , Leucocitos Mononucleares/metabolismo , Staphylococcus aureus/metabolismo , Citocinas/metabolismo , Quimiocinas/metabolismo , Biomarcadores , Proteína Adaptadora de Señalización NOD2/metabolismoRESUMEN
BACKGROUND: Treatment of inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, is undergoing transformative changes, highlighting the need to develop experimental models of skin inflammation in humans to predict treatment responses. METHODS: We topically or intradermally administered four common sensitizers (dust mite (DM), diphencyprone (DPCP), nickel (Ni), and purified protein derivative (PPD)) to the backs of 40 healthy patients and the skin hypersensitivity response was biopsied and evaluated using immunohistochemistry, RNA-seq, and RT-PCR. RESULTS: All agents induced strong increases in cellular infiltrates (T-cells and dendritic cells) as compared to untreated skin (p < .05), with variable T helper polarization. Overall, DPCP induced the strongest immune responses across all pathways, including innate immunity (IL-1α, IL-8), Th1 (IFNγ, CXCL10), Th2 (IL-5, CCL11), and Th17 (CAMP/LL37) products, as well as the highest regulatory tone (FOXP3, IL-34, IL-37) (FDR <0.01). Nickel induced Th17 (IL-17A), Th1 (CXCL10) and Th2 (IL-4R) immune responses to a lesser extent than DPCP (p < .05). PPD induced predominantly Th1 (IFNγ, CXCL10, STAT1) and Th17 inflammation (IL-17A) (p < .05). DM induced modulation of Th2 (IL-13, CCL17, CCL18), Th22 (IL-22), and Th17/Th22 (S100A7/9/12) pathways (p < .05). Barrier defects that characterize both AD and psoriasis were best modeled by DPCP and Ni, followed by PPD, including downregulation of terminal differentiation (FLG, FLG2, LOR, LCEs), tight junction (CLDN1/CLDN8), and lipid metabolism (FA2H, FABP7)-related markers. CONCLUSION: Our data imply that DPCP induced the strongest immune response across all pathways, and barrier defects characteristic of AD and psoriasis.
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Dermatitis Atópica , Psoriasis , Humanos , Alérgenos , Interleucina-17 , Níquel/efectos adversos , Citocinas/metabolismo , Piel/patología , Inflamación/patología , Células Th17 , Células Th2RESUMEN
Introduction: Since its approval for adults with moderate-to-severe atopic dermatitis (AD) in 2017, dupilumab has been incorporated into clinical practice guidelines (CPGs). However, recommendations differ internationally, and the quality assessment of their development is unclear. Objective: We aimed to systematically review and appraise the quality of CPGs for adult AD reported since 2017 and map the recommendations for dupilumab initiation relative to conventional systemic therapy (CST). Materials and Methods: A literature search was conducted in June 2020 in MEDLINE, EMBASE, SCOPUS, and CINAHL. Twelve CPGs were retrieved. Methodological quality was assessed using the validated Appraisal of Guidelines for Research & Evaluation II tool (AGREE-II). Recommendations were extracted and compared. Results: AGREE-II median scores per domain of the CPGs were (%, r = range): scope/purpose, 78% (50-96); stakeholder involvement, 54% (28-85); rigor of development, 39% (21-63); clarity of presentation, 85% (69-100); applicability, 27% (6-51); and editorial independence, 76% (42-100). Neither met the threshold of 70% quality criteria for rigor of development nor the applicability domains. Three CPGs met the criteria for recommendation without modification. CPGs' approach to dupilumab initiation was as follows: second line, preferred over CST and nbUVB (n = 1/12 CPG); second line, equivalent to CST or nbUVB (n = 3/12 CPGs); third line, after nbUVB or CST (n = 5/12 CPGs); and fourth line after nbUVB and CST (n = 2/12). No consensus was reached for n = 1/12 CPG. Conclusion and Relevance: Dupilumab is now incorporated into CPGs for adult AD. These CPGs exhibited good quality in scope/purpose, clarity, and editorial independence domains. However, none met AGREE-II criteria for methodological rigor/applicability. Gaps were found in mechanisms for updates, facilitators/barriers, resource implications, and stakeholder involvement. Only n = 3/12 CPGs met quality criteria for recommendation without modifications. Of these, two favored a conservative sequential approach for the initiation of dupilumab relative to CST, while one did not reach consensus. Our findings highlight divergent recommendations AD treatment, underlining a need to incorporate quality criteria into future guideline development.
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Type 2 immunity, illustrated by T helper 2 lymphocytes (Th2) and downstream cytokines (IL-4, IL-13, IL-31) as well as group 2 innate lymphoid cells (ILC2), is important in host defense and wound healing.1 The hallmark of type 2 inflammation is eosinophilia and/or high IgE counts and is best recognized in atopic diathesis. Persistent eosinophilia, such as seen in hypereosinophilic syndromes, leads to fibrosis and hence therapeutic Type 2 inhibition in fibrotic diseases is of high interest. Furthermore, as demonstrated in cutaneous T cell lymphoma, advanced disease is characterized by Th1 to Th2 switch allowing cancer progression and immunosuppression. Development of targeted monoclonal antibodies against IL-4Rα (eg, dupilumab) led to a paradigm shift for the treatment of atopic dermatitis (AD) and stimulated research to better understand the role of Type 2 inflammation in other skin conditions. In this review, we summarize up to date knowledge on the role of Type 2 inflammation in skin diseases other than AD and highlight whether the use of Type 2 targeted therapies has been documented or is being investigated in clinical trials. This manuscript reviews the role of Type 2 inflammation in dermatitis, neurodermatitis, IgE-mediated dermatoses (eg, bullous pemphigoid, chronic spontaneous urticaria), sclerodermoid conditions and skin neoplasms.
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Inmunidad Innata , Inmunoterapia/métodos , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/terapia , Cicatrización de Heridas/inmunología , Citocinas/inmunología , Humanos , Células Th2/inmunologíaRESUMEN
INTRODUCTION: Dupilumab is approved to treat moderate-to-severe atopic dermatitis (AD) in several countries in patients as young as 6 years of age. Since its approval, practical issues related to the use of dupilumab for AD have arisen, with particular interest in transitioning from current therapies and managing medication overlap, considerations for special populations of patients with AD, and management of potential adverse events. METHODS: This article aims to review the literature addressing several practical management issues related to dupilumab use for AD and to provide a framework for clinical decision-making in these circumstances and sub-populations. Each statement was reviewed, revised and voted on by authors to provide their level of agreement and degree of uncertainty for each statement. RESULTS: An agreement level > 80% was achieved for all of the statements. CONCLUSION: The expert panel provides statements considering the practical management of patients with AD taking dupilumab to inform clinical decision-making in specific but frequently encountered clinical situations.
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BACKGROUND: In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk-related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients. METHODS: We used 18-FDG PET-CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD-related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk. RESULTS: We found significant correlations between vascular inflammation and Th2-related products in skin and blood of AD patients as well as atherosclerosis-related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET-CT. CONCLUSION: Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis-related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD.
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Dermatitis Atópica , Eccema , Dermatitis Atópica/epidemiología , Humanos , Inflamación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Índice de Severidad de la Enfermedad , PielRESUMEN
Severity of atopic dermatitis (AD) correlates with impact on health-related quality of life (HRQoL), work productivity, and burden on health systems. Tools to measure severity inform regulatory approval, drug access, and value- or measurement-based care. A core set of instruments for measuring AD has been established. Clinician-reported tools are divided broadly into multi-item global estimates or precise calculators that also weigh affected corporeal surfaces. Increasingly, subjective patient-reported outcomes are valued, with the potential to capture vast amounts of health-related data. Patient-reported outcomes can be disease-agnostic, skin-related, or AD-specific, and evaluate global disease, itch severity, long-term control, or overall HRQoL. Patient-reported outcomes are expansive in number; therefore, item banks and adaptive digital user interfaces will be increasingly needed, along with capacity to store and analyze data. Technologies for AD include tools for communication, severity assessment, or data exchange, as well as electronic health records (EHRs). For clinicians, a limited number of applications exist, with relatively poor interoperability with EHRs to date. For patients, a growing number of mobile health (mHealth) applications exhibit variable compliance with international guidelines for self-management. Data privacy and information security governance are key considerations in the development of information technologies for AD. Integrated and streamlined digital operational processes for disease measurements may build capacity for high value and efficient care of patients with AD across the globe.
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Dermatitis Atópica , Eccema , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/epidemiología , Dermatitis Atópica/terapia , Electrónica , Humanos , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. OBJECTIVE: Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. METHODS: A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. RESULTS: We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential TH2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of TH17-related (IL-17A/F and IL-36A/IL-36G), TH1-related (IFN-γ and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. CONCLUSION: RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers.
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Citocinas , Dermatitis Atópica , Psoriasis , RNA-Seq , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Citocinas/genética , Citocinas/inmunología , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Femenino , Proteínas Filagrina , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/genética , Psoriasis/inmunologíaRESUMEN
Dupilumab, a monoclonal antibody against the common receptor of interleukin (IL)-4 and IL-13, was the first biologic therapy approved in Canada for treatment of moderate-to-severe atopic dermatitis (AD). While it is considered safe and effective, dupilumab is not universally effective and 8%-38% of patients develop conjunctivitis, while some patients develop head and neck dermatitis. Thus, new therapeutic options are warranted. While both IL-4 and IL-13 play important roles in the pathogenesis of AD, it has been recently demonstrated that IL-13 is the primary upregulated cytokine in AD skin biopsy samples. A placebo-controlled phase 2b clinical trial evaluating the efficacy and safety of lebrikizumab, an IL-13 inhibitor, in AD demonstrated that, at 16 weeks, Eczema Area and Severity Index (EASI) 75 and Investigator's Global Assessment (IGA) 0/1 were achieved by 60.6% and 44.6% of patients taking lebrikizumab at its highest dose (vs 24.3% and 15.3% of patients taking placebo, respectively). Moreover, treatment with lebrikizumab was associated with rapid improvement of pruritus and low rates of conjunctivitis (1.4%-3.8%). Another IL-13 monoclonal antibody, tralokinumab, was evaluated for safety and efficacy in moderate-to-severe AD. By week 12, among adults receiving 300 mg tralokinumab, 42.5% achieved EASI-75 and 26.7% achieved IGA 0/1 score (vs 15.5% and 11.8% in the placebo group, respectively). Both lebrikizumab and tralokinumab demonstrated acceptable safety profiles in AD (and non-AD) trials with adverse events often being comparable between treatment and control groups. Thus, IL-13 inhibitors may provide a safe and effective treatment alternative for patients with moderate-to-severe AD.
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Anticuerpos Monoclonales/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Interleucina-13/antagonistas & inhibidores , HumanosAsunto(s)
Colitis Ulcerosa/complicaciones , Úlcera del Pie/diagnóstico , Paroniquia/diagnóstico , Piodermia/diagnóstico , Estomatitis/diagnóstico , Adulto , Diagnóstico Diferencial , Úlcera del Pie/etiología , Úlcera del Pie/patología , Humanos , Masculino , Paroniquia/etiología , Piodermia/etiología , Piodermia/patología , Estomatitis/etiología , Estomatitis/patología , Dedos del Pie/patología , Cicatrización de HeridasRESUMEN
Toll-like receptors (TLRs) are expressed by human microglia and translate environmental cues into distinct activation programs. We addressed the impact of TLR ligation on the capacity of human microglia to activate and polarize CD4 T cell responses. As microglia exist under distinct states of activation, we examined both ramified and ameboid microglia isolated from adult and fetal CNS, respectively. In vitro, ligation of TLR3 significantly increased major histocompatibility complex and costimulatory molecule expression on adult microglia and induced high levels of interferon-alpha, interleukin-12p40, and interleukin-23. TLR4 and, in particular, TLR2 had a more limited capacity to induce such responses. Coculturing allogeneic CD4 T cells with microglia preactivated with TLR3 did not increase T cell proliferation above basal levels but consistently led to elevated levels of interferon-gamma secretion and Th1 polarization. Fetal microglial TLR3 responses were comparable; in contrast, TLR2 and TLR4 decreased major histocompatibility complex class II expression on fetal cells and reduced CD4 T cell proliferation to levels below those found in untreated cocultures. All 3 TLRs induced comparable interleukin-6 secretion by microglia. Our findings illustrate how activation of human microglia via TLRs, particularly TLR3, can change the profile of local CNS immune responses by translating Th1 polarizing signals to CD4 T cells.
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Linfocitos T CD4-Positivos/fisiología , Polaridad Celular , Microglía/fisiología , Células TH1/fisiología , Receptor Toll-Like 3/fisiología , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Encéfalo/citología , Encéfalo/embriología , Antígenos CD40/metabolismo , Polaridad Celular/fisiología , Técnicas de Cocultivo , Citocinas/metabolismo , Antígenos de Histocompatibilidad/metabolismo , Humanos , Complejo Mayor de Histocompatibilidad , Transducción de Señal/fisiología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Nitric oxide (NO) and peroxynitrite (ONOO(-)) are potential mediators of the injury and cytotoxicity occurring over time to oligodendrocytes in multiple sclerosis (MS) lesions. Our in vitro results indicate that human adult CNS-derived oligodendrocytes are relatively resistant to NO-mediated damage. In contrast, human oligodendrocytes are highly susceptible to peroxynitrite-mediated injury. In situ, we found that inducible nitric oxide synthase (iNOS) was expressed in astrocytes and macrophages in all active demyelinating and remyelinating MS lesions examined, yet no correlation was found between numbers of glial cells expressing iNOS and the extent of oligodendrocyte cell death. Nitrotyrosine groups, indicative of the presence of peroxynitrite in vivo, could be detected on astrocytes, macrophages, and oligodendrocytes in MS lesions. High numbers of nitrotyrosine-positive oligodendrocytes were found in one MS case that featured extensive oligodendrocyte cell death. Our results indicate that NO alone is unlikely to induce oligodendrocyte injury, whereas its more potent byproduct peroxynitrite is a potential mediator of injury to oligodendrocytes in MS.
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Enfermedades Desmielinizantes/metabolismo , Esclerosis Múltiple/metabolismo , Vaina de Mielina/metabolismo , Óxido Nítrico/metabolismo , Oligodendroglía/metabolismo , Ácido Peroxinitroso/metabolismo , Astrocitos/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Células Cultivadas , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/fisiopatología , Humanos , Macrófagos/metabolismo , Esclerosis Múltiple/fisiopatología , Vaina de Mielina/patología , Óxido Nítrico/toxicidad , Donantes de Óxido Nítrico/toxicidad , Óxido Nítrico Sintasa de Tipo II/metabolismo , Oligodendroglía/efectos de los fármacos , Ácido Peroxinitroso/toxicidad , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
BACKGROUND: A proportion of patients with multiple sclerosis (MS) receiving systemic interferon beta therapy will develop serum neutralizing antibodies (NAbs) that can reduce the activity of the drug. Interferon-beta (IFN-beta) is produced by glial cells within the central nervous system. Although systemic interferon beta does not access the central nervous system, titers of serum NAbs may be sufficient that some will access the central nervous system. OBJECTIVE: To address whether serum samples that contain high titers of NAbs could inhibit glial cell production of chemokines and cytokines that are regulated by endogenous IFN-beta. DESIGN: We used an in vitro assay involving toll-like receptor 3 ligand (polyinosinic-polycytidylic acid) signaling to assess the effect of serum samples containing high titers of NAbs (1800-20 000 U) on production of the chemokine CXCL10 and the cytokine interleukin 6 by human astrocytes. RESULTS: Serum samples positive for NAbs significantly inhibited polyinosinic-polycytidylic acid-induced CXCL10 and IL-6 production by astrocytes. CONCLUSION: High-titer NAbs to interferon beta may block endogenous IFN-beta function and alter the chemokine/cytokine microenvironment within the central nervous system, thereby modulating the profile and course of the local inflammatory response.