Natural Killer Cell Degranulation Defect: A Cause for Impaired NK-Cell Cytotoxicity and Hyperinflammation in Fanconi Anemia Patients

Abstract

Fanconi anemia (FA) is a rare inherited syndrome characterized by progressive bone marrow failure (BMF), abnormal skin pigmentation, short stature, and increased cancer risk. BMF in FA is multifactorial and largely results from the death of hematopoietic stem cells due to genomic instability. Also, inflammatory pathology in FA has been previously reported, however the mechanism is still not clear. In literature, decreased NK-cell count and/or impaired NK-cell activity, along with other immunological abnormalities have been described in FA-patients ( 1 ). However, to the best of our knowledge, this is the first report showing a defective degranulation mechanism leading to abnormal NK-cell cytotoxicity in FA-patients, which may explain the development of a hyperinflammatory response in these patients. This may predispose some patients to develop Hemophagocytic lymphohistiocytosis (HLH) which manifests with prolonged fever, progressive cytopenias and organomegaly. Early diagnosis and initiation of immunosuppressive therapy in these patients will help to better manage these patients. We also propose FA genes to be listed as a cause of familial HLH.

Higher Incidence of B Cell Malignancies in Primary Immunodeficiencies: A Combination of Intrinsic Genomic Instability and Exocytosis Defects at the Immunological Synapse

“…Alternative strategies are emerging and could potentially replace HSCT for specific PID ( 165 ). Until such treatments become approved as first line therapies, regular monitoring of PID patients associated with new routine procedures is critical to potentially detect early signs of cancer ( 310 ), especially as NK cytotoxicity issues have recently been identified in other PID ( 311 – 313 ).…”

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

“…The causes of dysfunctional NK cells can be broadly divided into two main categories: (1) quantitative de iciencies with low numbers or absent NK cells and (2) qualitative de iciencies with abnormal function of NK cells. The etiological causes and the associations of quantitative as well as qualitative NK cell de iciencies are shown in tables 2 and 3 [31,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52].…”

Papel de MICA na endometriose

“…Dessa forma, a análise da expressão de CD107a é considerada uma medida de degranulação de vesículas intracelulares por essas células (Alter et al, 2004). Algumas doenças são descritas como associadas a um mecanismo deficiente de degranulação (Marcenaro et al, 2006;Shabrish et al, 2019). Em pacientes com anemia de Falconi, foi observada deficiência na expressão de CD107a por células NK estimuladas, em relação à expressão em CTRs saudáveis, que, associada a uma menor citotoxicidade dessas células e a altos níveis de IFN-γ, sugere haver uma relação com a hiperinflamação descrita na doença (Shabrish et al, 2019).…”