Glucocorticoid treatment in patients with newly diagnosed immune thrombocytopenia switches CD14(++)CD16(+) intermediate monocytes from a pro-inflammatory to an anti-inflammatory phenotype

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T-helper subset distribution and enhanced production of pro-inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T-cell phenotypes. Glucocorticoids (GCs) are commonly used for first-line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++CD16+ ) in untreated patients with newly diagnosed ITP, with these cells displaying a pro-inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti-inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC-induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy

TNF-mediated macrophage activation in the target organ is critical for clinical manifestation of uveitis

Clinically available anti-tumour necrosis factor (TNF) biologics, which inhibit both soluble (sTNF) and transmembrane forms (tmTNF) of TNF, eliminating all TNF signalling, have successfully treated autoimmune diseases including uveitis. These have potentially serious side effects such as reactivation of latent Mycobacterium tuberculosis and, therefore, more specific inhibition of TNF signalling pathways may maintain clinical efficacy while reducing adverse effects. To determine the effects of specific pharmacological inhibition of sTNF on macrophage activation and migration, we used a mouse model of uveitis (experimental autoimmune uveoretinitis; EAU). We show that selective inhibition of sTNF is sufficient to suppress EAU by limiting inflammatory CD11b(+) macrophages and CD4(+) T cell migration into the eye. However, inhibition of both sTNF and tmTNF is required to inhibit interferon-γ-induced chemokine receptor 2, CD40, major histocompatibility complex class II and nitric oxide (NO) up-regulation, and signalling via tmTNF is sufficient to mediate tissue damage. In confirmation, intravitreal inhibition of sTNF alone did not suppress disease, and inflammatory cells that migrated into the eye were activated, generating NO, thus causing structural damage to the retina. In contrast, intravitreal inhibition of both sTNF and tmTNF suppressed macrophage activation and therefore disease. We conclude that sTNF is required for inflammatory cell infiltration into target tissue, but at the tissue site inhibition of both sTNF and tmTNF is required to inhibit macrophage activation and to protect from tissue damage

Glucocorticoid treatment in patients with newly diagnosed immune thrombocytopenia switches CD14 ++ CD16 + intermediate monocytes from a pro‐inflammatory to an anti‐inflammatory phenotype

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T-helper subset distribution and enhanced production of pro-inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T-cell phenotypes. Glucocorticoids (GCs) are commonly used for first-line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++CD16+ ) in untreated patients with newly diagnosed ITP, with these cells displaying a pro-inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti-inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC-induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy