What does elevated TARC/CCL17 expression tell us about eosinophilic disorders?

Catherine, Julien; Roufosse, Florence

doi:10.1007/s00281-021-00857-w

Cited by 34 publications

(41 citation statements)

References 207 publications

(235 reference statements)

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“…Accumulation in blood may also result from the action of thymus and activation-regulated chemokine (TARC/CCL17), a type 2 cytokine that binds to CCR4 and is involved in T H 2 cell trafficking in eosinophilic disorders [92]. TARC is synthesised by immune cells after stimulation of IL-4 following induction of STAT6, and this protein is also thought to be involved in eosinophil trafficking [93]. Increased TARC levels have been described in the bronchoalveolar lavage fluid of asthmatics and in EGPA lesions with eosinophilic infiltrations and CRT H 2 + T cells [94,95].…”

Section: Increased Eosinophil Levels With Dupilumab: the Story So Farmentioning

confidence: 99%

Eosinophilia Induced by Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes

Olaguíbel¹,

Sastre²,

Rodríguez³

et al. 2022

J Investig Allergol Clin Immunol

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Currently, five biological drugs for uncontrolled severe asthma treatment are marketed. They all block type 2 inflammatory pathways, either by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/13 pathway (dupilumab). Hypereosinophilia has been observed in between 4% and 25% of patients treated with dupilumab, being transient in most cases, but persistent cases of symptomatic hypereosinophilia consistent with eosinophil granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis or sudden worsening of asthma symptoms have been described. Cases of EGPA have been described with all biologics, including anti-IL-5, and with leukotriene receptors antagonists in publications or in the Eudravigilance database. In many cases of EGPA, it appears during systemic steroids tapering or after switching from an anti-IL-5 biologic to Dupilumab, suggesting that systemic steroids or the anti IL-5 were masking the vasculitis. This review aims to substantiate the plausible mechanisms of dupilumab-induced hypereosinophilia and review symptomatic hypereosinophilia cases associated with dupilumab therapy. Blockade of the IL-4/IL-13 pathway cause a reduction of eosinophil migration and blood accumulation by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in the bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1,500/mL), where an anti-IL-5/IL-5R is preferable. Also, when changing from an anti-IL-5/5R to an anti-IL-4/13R. Close monitoring of blood eosinophils and clinical evolution seems justified in these situations. Nevertheless, dual therapy with anti-IL-5/5R and anti-IL4/IL-13R may be needed for optimal control since both IL-5, and IL-4/13 pathways can simultaneously contribute to airway inflammation.

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Section: Increased Eosinophil Levels With Dupilumab: the Story So Farmentioning

confidence: 99%

Eosinophilia Induced by Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes

Olaguíbel¹,

Sastre²,

Rodríguez³

et al. 2022

J Investig Allergol Clin Immunol

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“…Different types of cell-mediated immunity have been previously described in detail ( 26 ). At study entry, children infected with RV were characterized by a higher expression of eotaxin-2 and TARC; the former promotes the migration of eosinophils into the lungs ( 27 ), and the latter selectively binds to CCR4, leading to the activation of a type 2 immune response via , e.g., Th2 cells, ILC2, and airway eosinophils ( 28 ). The expression of ENA-78, although counterintuitive is primarily a neutrophil chemoattractant, was higher in children infected with RV ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Cytokine expression in rhinovirus- vs. respiratory syncytial virus-induced first wheezing episode and its relation to clinical course

Hurme

Komulainen²,

Tulkki³

et al. 2022

Front. Immunol.

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Rhinovirus (RV) and respiratory syncytial virus (RSV) are common causes of bronchiolitis. Unlike an RSV etiology, an RV etiology is associated with a markedly increased risk of asthma. We investigated the cytokine profiles of RV- and RSV-induced first wheezing episode and their correlation with prognosis. We recruited 52 sole RV- and 11 sole RSV-affected children with a severe first wheezing episode. Peripheral blood mononuclear cells (PBMCs) were isolated during acute illness and 2 weeks later and stimulated in vitro with anti-CD3/anti-CD28. Culture medium samples were analyzed for 56 different cytokines by multiplex ELISA. Recurrences were prospectively followed for 4 years. In adjusted analyses, the cytokine response from PBMCs in the RV group was characterized by decreased expression of interleukin 1 receptor antagonist (IL-1RA), interleukin 1 beta (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) and increased expression of eosinophil chemotactic protein 2 (eotaxin-2), thymus- and activation-regulated chemokine (TARC), and epithelial-derived neutrophil-activating peptide 78 (ENA-78) in the acute phase and increased expression of fractalkine in the convalescent phase compared to those in the RSV group. An analysis of the change in cytokine expression between study points revealed an increased expression of fractalkine and IL-1β and decreased expression of I-309 (CCL1) and TARC in the RV group compared to those in the RSV group.. Considering hospitalization time, a significant non-adjusted group × cytokine interaction was observed in the levels of interferon gamma (IFN-γ), macrophage-derived chemokine (MDC), IL-1RA, and vascular endothelial growth factor (VEGF), indicating that a higher expression of cytokine was associated with shorter hospitalization time in the RSV group but not in the RV group. A significant interaction was also found in interleukin 6 (IL-6), but the cytokine response was not associated with hospitalization time in the RSV or RV group. In the RV group, increased expression of I-309 (CCL1) and TARC was associated with fewer relapses within 2 months, and decreased expression of interleukin 13 (IL-13) and increased expression of I-309 (CCL1) were associated with less relapses within 12 months. Differences in cytokine response from PBMCs were observed between RV- and RSV-induced first severe wheezing episode. Our findings also reveal new biomarkers for short- and medium-term prognosis in first-time wheezing children infected with RV or RSV.

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“…MIP-1β recruits leukocytes into injured tissues to perpetuate inflammatory processes ( Dumas et al, 2016 ). TARC, the last of the analytes to be increased on the Chemokine Plate, is associated with type 2 immune responses ( Catherine and Roufosse, 2021 ). Collectively, these changes correspond with the presence of both chronic and acute inflammatory processes.…”

Section: Discussionmentioning

confidence: 99%

Increased Serum Levels of Proinflammatory Cytokines Are Accompanied by Fatigue in Military T-6A Texan II Instructor Pilots

et al. 2022

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Tactical aviation imposes unprecedented physical challenges including repetitive exposure to hypergravity, hyperoxia, increased work of breathing, and profound cognitive workloads. Each stressor evokes outcomes ranging from musculoskeletal duress and atelectasis to physical and cognitive fatigue, the latter among the foremost threats to aviators. Whereas sleep loss is traditionally considered the primary cause of fatigue in aviators, converging experimental, observational, and medical studies have identified biochemical mechanisms promoting onset of fatigue. Those mechanisms, which fundamentally differ from sleep loss, revolve around increased proinflammatory cytokines, produced and released in response to tissue injury, chronic inflammatory disorders, allergens, or physical duress. This study’s objective was to inform our understanding of potential relationships between serum levels of proinflammatory cytokines and onset of fatigue within a cohort of aviators who experience multiple high-performance sorties on a daily basis.Methods: Active duty and reservist T-6A Texan II instructor pilots were studied on three separate days across their week-long flying schedule. Data collected included a physical assessment, subjective fatigue levels, venous blood samples for measures of chemistry and serum analytes, and urine samples for specific gravity.Results: Twenty-three persons were studied, of which 22 fulfilled minimum study requirements of completing two sorties. The study cohort was comprised of primarily males, age 37.95 ± 4.73 years with a BMI of 26.63 ± 3.15 kg/m2. Of 37 measurable serum analytes, 20 differed significantly (p < 0.05) between baseline values with those measured at the study endpoint. Thirteen of the aviators reported increased fatigue scores across their flying schedule whereas nine did not. Eleven blood serum analytes were associated with increasing levels of fatigue.Discussion: Fatigue in aviators has been attributed almost solely to sleep loss, nocturnal sorties, or disrupted circadian rhythmicity. In contrast, our study findings suggest an alternative mechanism that can promote onset of fatigue: increased blood levels of proinflammatory cytokines. Specific mechanisms triggering synthesis and release of those cytokines and other analytes are yet to be determined. However, their expression patterns suggest responses to both chronic and acute inflammation, hyperoxia, or bronchopulmonary responses to inspiration of dry gas, positive airway pressure, or perhaps atelectasis.

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What does elevated TARC/CCL17 expression tell us about eosinophilic disorders?

Cited by 34 publications

References 207 publications

Eosinophilia Induced by Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes

Eosinophilia Induced by Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes

Cytokine expression in rhinovirus- vs. respiratory syncytial virus-induced first wheezing episode and its relation to clinical course

Increased Serum Levels of Proinflammatory Cytokines Are Accompanied by Fatigue in Military T-6A Texan II Instructor Pilots

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