Development of inhibitors in hemophilia A: an illustrated review

This illustrated review focuses on the development of inhibitors in patients with congenital hemophilia, which is the most serious treatment-related complication in these patients. Hemophilia A (HA) is an inherited X-linked bleeding disorder affecting 1:5000-10 000 newborn males worldwide. It results from the deficiency of coagulation factor VIII (FVIII), due to mutation(s) in its coding gene (F8). Treatment requires administration of FVIII-containing products either on demand or as prophylaxis, which can induce inhibitor development in 20%-35% of patients. Inhibitors are alloantibodies that neutralize the procoagulant activity of exogenous FVIII. During the initial administration of FVIII-containing products, patients with HA can develop a proinflammatory immune response with synthesis of anti-FVIII IgG1, which has no FVIII inhibitory activity. However, in patients with inhibitors, immune response shifts toward an anti-inflammatory/regulatory pattern favoring the synthesis of anti- FVIII IgG4 antibodies. Patients with inhibitors present with bleeding episodes that are difficult to control, and they have reduced response to FVIII replacement. Currently, immune tolerance induction is the available treatment for eradication of persistent high-titer inhibitors. Despite the clinical relevance, the immunological mechanisms for inhibitor development in patients with HA remains unexplained.</p

α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease

A diagnosis of motor Parkinson’s disease (PD) is preceded by a prolonged premotor phase with accumulating neuronal damage. Here we examined the temporal relation between α-synuclein (α-syn) T cell reactivity and PD. A longitudinal case study revealed that elevated α-syn-specific T cell responses were detected prior to the diagnosis of motor PD, and declined after. The relationship between T cell reactivity and early PD in two independent cohorts showed that α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased. Additional analysis revealed significant association of α-syn-specific T cell responses with age and lower levodopa equivalent dose. These results confirm the presence of α-syn-reactive T cells in PD and show that they are most abundant immediately after diagnosis of motor PD. These cells may be present years before the diagnosis of motor PD, suggesting avenues of investigation into PD pathogenesis and potential early diagnosis