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Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization.

Authors
  • Ciudad, Marion1
  • Ouandji, Sethi1
  • Lamarthée, Baptiste2
  • Cladière, Claudie1
  • Ghesquière, Thibault1
  • Nivet, Martin1
  • Thébault, Marine1
  • Boidot, Romain3
  • Soudry-Faure, Agnès4
  • Chevrier, Sandy3
  • Richard, Corentin3
  • Maillet, Thibault5
  • Maurier, François6
  • Greigert, Hélène1
  • Genet, Coraline2
  • Ramon, André2
  • Trad, Malika2
  • Predan, Valérie7
  • Saas, Philippe2
  • Samson, Maxime1
  • And 2 more
  • 1 Department of Internal Medicine and Clinical Immunology, Referral Center for adult autoimmune cytopenia (CeReCAI) - Dijon University Hospital - F-21000 Dijon, France; Université de Bourgogne, INSERM, UMR1098, RIGHT -F-21000 Dijon. , (France)
  • 2 Université de Bourgogne, INSERM, UMR1098, RIGHT -F-21000 Dijon.
  • 3 Unit of Molecular Biology, Georges-François Leclerc Cancer Center - F-21000 Dijon.
  • 4 Department of Clinical Research and Innovation (DRCI), Clinical Research Unit-Methodological Support Network (USMR), Dijon Bourgogne University Hospital, Dijon.
  • 5 Department of Internal Medicine - Centre Hospitalier de Mâcon, Groupe Hospitalier Bourgogne Méridionale - F-71000 Macon.
  • 6 Department of Internal Medicine, Groupe Hospitalier UNEOS - F-57000 Metz.
  • 7 Department of Internal Medicine and Clinical Immunology, Referral Center for adult autoimmune cytopenia (CeReCAI) - Dijon University Hospital - F-21000 Dijon.
  • 8 Department of Internal Medicine and Clinical Immunology, Referral Center for adult autoimmune cytopenia (CeReCAI) - Dijon University Hospital - F-21000 Dijon, France; Université de Bourgogne, INSERM, UMR1098, RIGHT -F-21000 Dijon. [email protected]. , (France)
Type
Published Article
Journal
Haematologica
Publisher
Ferrata Storti Foundation
Publication Date
Feb 01, 2024
Volume
109
Issue
2
Pages
444–457
Identifiers
DOI: 10.3324/haematol.2023.282859
PMID: 37534543
Source
Medline
Language
English
License
Unknown

Abstract

Warm autoimmune hemolytic anemia (wAIHA) is a rare acquired autoimmune disease mediated by antibodies targeting red blood cells. The involvement of CD4 T-helper cells has been scarcely explored, with most findings extrapolated from animal models. Here, we performed quantification of both effector T lymphocytes (Teff) and regulatory T cells (Treg), associated with functional and transcriptomic analyses of Treg in human wAIHA. We observed a shift of Teff toward a Th17 polarization concordant with an increase in serum interleukin-17 concentration that correlates with red blood cell destruction parameters, namely lactate dehydrogenase and bilirubin levels. A decrease in circulating Treg, notably effector Treg, associated with a functional deficiency, as represented by their decrease capability to inhibit Teff proliferation, were also observed. Treg deficiency was associated with a reduced expression of Foxp3, the master transcription factor known to maintain the Treg phenotype stability and suppressive functions. Transcriptomic profiling of Treg revealed activation of the tumor necrosis facto (TNF)-α pathway, which was linked to increased serum TNF-α concentrations that were twice as high as in controls. Treg transcriptomic profiling also suggested that post-translational mechanisms possibly accounted for Foxp3 downregulation and Treg dysfunctions. Since TNF-α participates in the rupture of immune tolerance during wAIHA, its inhibition could be of interest. To this end, the effects of fostamatinib, a SYK inhibitor, were investigated in vitro, and we showed that besides the inhibition of erythrocyte phagocytosis by monocytes, fostamatinib is also able to dampen TNF-α production, thus appearing as a promising multitargeting therapy in wAIHA (clinicaltrials gov. Identifier: NCT02158195).

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