Reduction in regulatory T cells in preterm newborns is associated with necrotizing enterocolitis.


Journal

Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714

Informations de publication

Date de publication:
11 2023
Historique:
received: 25 10 2022
accepted: 01 05 2023
revised: 24 04 2023
medline: 6 11 2023
pubmed: 22 6 2023
entrez: 21 6 2023
Statut: ppublish

Résumé

Despite multifactorial pathogenesis, dysregulation of inflammatory immune response may play a crucial role in necrotizing enterocolitis (NEC). Regulatory T cells (Tregs) are involved in immune tolerance early in life. We aimed to investigate the predicting role of Tregs in developing NEC in neonates at high risk. We studied six newborns with a diagnosis of NEC (cases) in comparison with 52 controls (without NEC). We further classified controls as neonates with feeding intolerance (FI) and neonates without it (FeedTol). The rate of female and male neonates (sex defined as a biological attribute) was similar. We analyzed the blood frequency of Tregs (not overall numbers) at three time points: 0-3 (T0), 7-10 (T1), and 27-30 (T2) days after birth by flow cytometry. Neonates' sex was defined based on the inspection of external genitalia at birth. We observed, at T0, a significantly lower frequency of Tregs in NEC cases (p < 0.001) compared with both FI (p < 0.01) and FeedTol controls (p < 0.01). Multivariate analysis reported that the occurrence of NEC was independently influenced by Treg frequency at birth (ß 2.98; p = 0.039). Tregs frequency and features in the peripheral blood of preterm neonates, early in life, may contribute to identifying neonates at high risk of developing NEC. Regulatory T cells may play a pivotal role in regulating the immune response in early life. Reduction of Tregs in early life could predispose preterm newborns to necrotizing enterocolitis. Early markers of necrotizing enterocolitis are still lacking. We demonstrated a predicting role of assessment of regulatory T cells in the diagnosis of this gastrointestinal emergency. Early identification of newborns at high risk of necrotizing enterocolitis through measurement of regulatory T cells may guide clinicians in the management of preterm newborns in order to reduce the development of this severe condition.

Sections du résumé

BACKGROUND
Despite multifactorial pathogenesis, dysregulation of inflammatory immune response may play a crucial role in necrotizing enterocolitis (NEC). Regulatory T cells (Tregs) are involved in immune tolerance early in life. We aimed to investigate the predicting role of Tregs in developing NEC in neonates at high risk.
METHODS
We studied six newborns with a diagnosis of NEC (cases) in comparison with 52 controls (without NEC). We further classified controls as neonates with feeding intolerance (FI) and neonates without it (FeedTol). The rate of female and male neonates (sex defined as a biological attribute) was similar. We analyzed the blood frequency of Tregs (not overall numbers) at three time points: 0-3 (T0), 7-10 (T1), and 27-30 (T2) days after birth by flow cytometry. Neonates' sex was defined based on the inspection of external genitalia at birth.
RESULTS
We observed, at T0, a significantly lower frequency of Tregs in NEC cases (p < 0.001) compared with both FI (p < 0.01) and FeedTol controls (p < 0.01). Multivariate analysis reported that the occurrence of NEC was independently influenced by Treg frequency at birth (ß 2.98; p = 0.039).
CONCLUSION
Tregs frequency and features in the peripheral blood of preterm neonates, early in life, may contribute to identifying neonates at high risk of developing NEC.
IMPACT
Regulatory T cells may play a pivotal role in regulating the immune response in early life. Reduction of Tregs in early life could predispose preterm newborns to necrotizing enterocolitis. Early markers of necrotizing enterocolitis are still lacking. We demonstrated a predicting role of assessment of regulatory T cells in the diagnosis of this gastrointestinal emergency. Early identification of newborns at high risk of necrotizing enterocolitis through measurement of regulatory T cells may guide clinicians in the management of preterm newborns in order to reduce the development of this severe condition.

Identifiants

pubmed: 37344544
doi: 10.1038/s41390-023-02658-3
pii: 10.1038/s41390-023-02658-3
pmc: PMC10624602
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1789-1796

Informations de copyright

© 2023. The Author(s).

Références

Terrin, G., Stronati, L., Cucchiara, S. & De Curtis, M. Serum markers of necrotizing enterocolitis: a systematic review. J. Pediatr. Gastroenterol. Nutr. 65, e120–e132 (2017).
doi: 10.1097/MPG.0000000000001588 pubmed: 28379923
Ma, F. et al. Interleukin-6-mediated CCR9+ interleukin-17-producing regulatory T cells polarization increases the severity of necrotizing enterocolitis. EBioMedicine 44, 71–85 (2019).
doi: 10.1016/j.ebiom.2019.05.042 pubmed: 31129099 pmcid: 6604880
Carter, B. M. & Holditch-Davis, D. Risk factors for necrotizing enterocolitis in preterm infants: how race, gender, and health status contribute. Adv. Neonatal Care 8, 285–290 (2008).
doi: 10.1097/01.ANC.0000338019.56405.29 pubmed: 18827518 pmcid: 2677063
Neu, J., Mshvildadze, M. & Mai, V. A roadmap for understanding and preventing necrotizing enterocolitis. Curr. Gastroenterol. Rep. 10, 450–457 (2008).
doi: 10.1007/s11894-008-0084-x pubmed: 18799119
Vitali, R. et al. Fecal High-Mobility Group Box 1 as a marker of early stage of necrotizing enterocolitis in preterm neonates. Front. Pediatr. 9, 672131 (2021).
doi: 10.3389/fped.2021.672131 pubmed: 34178888 pmcid: 8222523
Weitkamp, J.-H. et al. Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut 62, 73–82 (2013).
doi: 10.1136/gutjnl-2011-301551 pubmed: 22267598
Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295–309 (2016).
doi: 10.1038/nri.2016.36 pubmed: 27087661
Zeng, H., Zhang, R., Jin, B. & Chen, L. Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol. Immunol. 12, 566–571 (2015).
doi: 10.1038/cmi.2015.44 pubmed: 26051475 pmcid: 4579656
Yagi, H. et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int. Immunol. 16, 1643–1656 (2004).
doi: 10.1093/intimm/dxh165 pubmed: 15466453
Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
doi: 10.1038/ni904 pubmed: 12612578
Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).
doi: 10.1084/jem.20060468 pubmed: 16818676 pmcid: 2118333
Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).
doi: 10.1016/j.immuni.2009.03.019 pubmed: 19464196
Hayakawa, S., Ohno, N., Okada, S. & Kobayashi, M. Significant augmentation of regulatory T cell numbers occurs during the early neonatal period. Clin. Exp. Immunol. 190, 268–279 (2017).
doi: 10.1111/cei.13008 pubmed: 28677152 pmcid: 5629449
Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63 (2007).
doi: 10.1084/jem.20061852 pubmed: 17200412 pmcid: 2118432
Dingle, B. M. et al. FoxP3+ regulatory T cells attenuate experimental necrotizing enterocolitis. PLoS ONE 8, e82963 (2013).
doi: 10.1371/journal.pone.0082963 pubmed: 24367573 pmcid: 3867412
Pang, Y., Du, X., Xu, X., Wang, M. & Li, Z. Monocyte activation and inflammation can exacerbate Treg/Th17 imbalance in infants with neonatal necrotizing enterocolitis. Int. Immunopharmacol. 59, 354–360 (2018).
doi: 10.1016/j.intimp.2018.04.026 pubmed: 29680746
Pang, Y., Du, X., Xu, X., Wang, M. & Li, Z. Impairment of regulatory T cells in patients with neonatal necrotizing enterocolitis. Int. Immunopharmacol. 63, 19–25 (2018).
doi: 10.1016/j.intimp.2018.07.029 pubmed: 30059947
Kim, J. H., Sampath, V. & Canvasser, J. Challenges in diagnosing necrotizing enterocolitis. Pediatr. Res. 88, 16–20 (2020).
doi: 10.1038/s41390-020-1090-4 pubmed: 32855507
Walsh, M. C. & Kliegman, R. M. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr. Clin. North Am. 33, 179–201 (1986).
doi: 10.1016/S0031-3955(16)34975-6 pubmed: 3081865 pmcid: 7131118
Terrin, G. et al. Early protein intake influences neonatal brain measurements in preterms: an observational study. Front. Neurol. 11, 885 (2020).
doi: 10.3389/fneur.2020.00885 pubmed: 32982918 pmcid: 7479306
Wertheimer, F., Arcinue, R. & Niklas, V. Necrotizing enterocolitis: enhancing awareness for the general practitioner. Pediatr. Rev. 40, 517–527 (2019).
doi: 10.1542/pir.2017-0338 pubmed: 31575803
Barnes, M. J. & Powrie, F. Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009).
doi: 10.1016/j.immuni.2009.08.011 pubmed: 19766083
Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).
doi: 10.1038/nature10208 pubmed: 21677746
He, Y. et al. Colonization of fecal microbiota from patients with neonatal necrotizing enterocolitis exacerbates intestinal injury in germfree mice subjected to necrotizing enterocolitis-induction protocol via alterations in butyrate and regulatory T cells. J. Transl. Med. 19, 510 (2021).
doi: 10.1186/s12967-021-03109-5 pubmed: 34922582 pmcid: 8684079
Ismail, R. I. H. et al. Gut priming with bovine colostrum and T regulatory cells in preterm neonates: a randomized controlled trial. Pediatr. Res. 90, 650–656 (2021).
doi: 10.1038/s41390-020-01344-y pubmed: 33446924
Pagel, J. et al. Increased regulatory T cells precede the development of bronchopulmonary dysplasia in preterm infants. Front. Immunol. 11, 565257 (2020).
doi: 10.3389/fimmu.2020.565257 pubmed: 33101284 pmcid: 7554370
Muñoz-Rojas, A. R. & Mathis, D. Tissue regulatory T cells: regulatory chameleons. Nat. Rev. Immunol. 21, 597–611 (2021).
doi: 10.1038/s41577-021-00519-w pubmed: 33772242 pmcid: 8403160
Delacher, M. et al. Precursors for nonlymphoid-tissue treg cells reside in secondary lymphoid organs and are programmed by the transcription factor BATF. Immunity 52, 295–312.e11 (2020).
doi: 10.1016/j.immuni.2019.12.002 pubmed: 31924477 pmcid: 7026712

Auteurs

Ilenia Pacella (I)

Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Maria Di Chiara (M)

Department Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy.

Rita Prota (R)

Department Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy.

Chiara De Luca (C)

Department Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy.

Annalisa Cardillo (A)

Department Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy.

Elena Potenza (E)

Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Alessandra Pinzon Grimaldos (AP)

Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Valeria Pinna (V)

Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Silvia Piconese (S)

Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy.
Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy.

Gianluca Terrin (G)

Department Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy. gianluca.terrin@uniroma1.it.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female
Humans United States Aged Cross-Sectional Studies Medicare Part C
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH