A Deep Dive into the Pathology of Gray Platelet Syndrome: New Insights on Immune Dysregulation

Ana C Glembotsky,1,2 Geraldine De Luca,1,2 Paula G Heller1,2 1Departamento Hematología Investigación, Instituto de Investigaciones Médicas “Dr. A. Lanari”, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; 2Departamento Hematología Investigación, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Instituto de Investigaciones Médicas (IDIM), Buenos Aires, ArgentinaCorrespondence: Paula G HellerDepartamento Hematología Investigación,Instituto de Investigaciones Médicas “Dr. A. Lanari”, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, Buenos Aires, 1427, ArgentinaTel +54 11 5287 3872Email paulaheller@hotmail.comAbstract: The gray platelet syndrome (GPS) is a rare platelet disorder, characterized by impaired alpha-granule biogenesis in megakaryocytes and platelets due to NBEAL2 mutations. Typical clinical features include macrothrombocytopenia, bleeding and elevated vitamin B12 levels, while bone marrow fibrosis and splenomegaly may develop during disease progression. Recently, the involvement of other blood lineages has been highlighted, revealing the role of NBEAL2 outside the megakaryocyte-platelet axis. Low leukocyte counts, decreased neutrophil granulation and impaired neutrophil extracellular trap formation represent prominent findings in GPS patients, reflecting deranged innate immunity and associated with an increased susceptibility to infection. In addition, low numbers and impaired degranulation of NK cells have been demonstrated in animal models. Autoimmune diseases involving different organs and a spectrum of autoantibodies are present in a substantial proportion of GPS patients, expanding the syndromic spectrum of this disorder and pointing to dysregulation of the adaptive immune response. Low-grade inflammation, as evidenced by elevation of liver-derived acute-phase reactants, is another previously unrecognized feature of GPS which may contribute to disease manifestations. This review will focus on the mechanisms underlying the pathogenesis of blood cell abnormalities in human GPS patients and NBEAL2-null animal models, providing insight into the effects of NBEAL2 in hemostasis, inflammation and immunity.Keywords: NBEAL2, gray platelet syndrome, α-granules, immune dysregulation, neutrophils