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

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).

Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments.

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. Although the primary triggering factors of ITP remain unknown, a loss of immune tolerance-mostly represented by a regulatory T-cell defect-allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcγRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. Moreover, the activation of the classical complement pathway participates to platelet opsonization and also to their destruction by complement-dependent cytotoxicity. Platelet destruction is also mediated by a FcγR-independent pathway, involving platelet desialylation that favors their binding to the Ashwell-Morell receptor and their clearance in the liver. Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes. The better understanding of ITP pathogenesis has provided important therapeutic advances. B cell-targeting therapies and thrombopoietin-receptor agonists (TPO-RAs) have been used for years. New emerging therapeutic strategies that inhibit FcγR signaling, the neonatal Fc receptor or the classical complement pathway, will deeply modify the management of ITP in the near future.