Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization.
Fiche publication
Date publication
août 2023
Journal
Haematologica
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BOIDOT Romain, Pr BONNOTTE Bernard
Tous les auteurs :
Ciudad M, Ouandji S, Lamarthée B, Cladière C, Ghesquière T, Nivet M, Thébault M, Boidot R, Soudry-Faure A, Chevrier S, Richard C, Maillet T, Maurier F, Greigert H, Genet C, Ramon A, Trad M, Predan V, Saas P, Samson M, Bonnotte B, Audia S
Lien Pubmed
Résumé
Warm autoimmune hemolytic anemia (wAIHA) is a rare acquired autoimmune disease mediated by antibodies targeting red blood cells. The involvement of CD4 T helper (Th) 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 IL-17 concentration that correlates with RBC destruction parameters, namely LDH 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 Tregs revealed activation of the 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 AIHA, 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.
Référence
Haematologica. 2023 08 3;: