Journal of Genetic Syndromes & Gene Therapy
Open Access

Impairment of regulated exocytosis in rare human diseases with immunodeficiency: Lessons learned from Chediak-Higashi syndrome

Annual Congress on Rare Diseases & Orphan Drugs

October 26-27, 2016 Chicago, USA

Konrad Krzewski

National Institutes of Health, USA

Posters & Accepted Abstracts: J Genet Syndr Gene Ther

Abstract :

Several rare human diseases, including familial hemophagocytic lymphohistiocytosis, Hermansky-Pudlak syndrome, Griscelli syndrome or Chediak-Higashi syndrome (CHS), display similarities in terms of their clinical manifestations and immunologic mechanisms, for example the presence of hemophagocytosis and decreased or absent cytotoxic activity of Natural Killer (NK) cells. NK cells, a subset of lymphocytes involved in protection against tumors and microbial pathogens are best known for their ability to mediate cytotoxic elimination of abnormal cells. The killing of target cells is a complex process, culminating in the localized delivery of lysosome-related lytic granules to the cell-cell contact site (immunological synapse), where the granules navigate through the cortical actin meshwork before fusing with the plasma membrane and releasing their content. It has been proposed that defects in exocytosis of lytic granules, resulting in decreased cytolytic function of NK cells could be primarily responsible for the lack of elimination of over-activated cells and thus contribute to the persistent inflammation and uncontrolled cell proliferation observed in lymphohistiocytic syndromes. CHS is characterized by immunodeficiency and formation of giant lysosomes or lysosome-related organelles in several cell types. The treatment of CHS has been limited by the insufficient knowledge about the cellular mechanisms involved in disease development and progression. Using NK cells isolated from CHS patients and a newly generated human cellular model of CHS, we have gained new insights into the disease pathology, regulation of exocytosis and mechanisms underlying faulty granule secretion in CHS. We discovered that the large granules are functional but actin remodeling at the immunological synapse is a major factor limiting their release from CHS NK cells. Those data suggests that the faulty exocytosis in CHS is of a physical nature rather than a functional defect. Indeed, manipulation of cortical actin density or granule size allows restoring CHS NK cell function and offers new therapeutic strategy for CHS patients.

Biography :

Email: krzewskikj@niaid.nih.gov