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Molecular mechanisms of pediatric immunodeficiency syndromes affecting natural killer cell cytotoxicity

Final Report Summary - NK IN HLH (Molecular mechanisms of pediatric immunodeficiency syndromes affecting natural killer cell cytotoxicity)

This project, between 2010 and 2012, set out to study the mechanisms of human genetic immune system deficiencies that affect cytotoxic lymphocytes, the cells responsible for killing virus-infected or tumourous cells. Patients with such deficiencies typically suffer from life-threatening sepsis-like conditions triggered by infection and caused by excessive proliferation of activated immune cells. Treatment includes chemoimmunotherapy and, in the case of genetic disease, subsequent hematopoietic stem cell transplantation, which has a survival rate of around 50 %. Only a handful of genes have yet been identified as causative of such immunodeficiencies, and a majority of clinical cases remain unexplained, creating difficulties for diagnosis. It is therefore critical to expand our understanding of these syndromes and the role of natural killer (NK) cells in the disease course. A more complete knowledge of these molecular mechanisms may provide opportunities for new therapies, and a full map of the proteins that regulate cytotoxicity will enable further genetic screening in patients with unexplained immunodeficiencies.

In order to achieve the aims of this project, we integrated cutting edge imaging techniques and other biochemical assays with advanced immunological assays. A cross-disciplinary approach utilised the latest techniques from both the cell biology and immunology fields provided great advantage in clarifying the mechanisms of NK cell granule maturation and release. In addition, patients with symptoms but no known genetic mutations were screened for novel mutations.

The key results of this project fall into several categories. Firstly, increased sensitivity and efficacy for diagnosis of patients with suspected immune deficiencies has been achieved, with improved cellular tests and genetic screening now available to patients around Europe and the world. We have described two novel genetic mutations, which explain the majority of FHL cases in Scandinavia. Multiparametric microscopy assays have also been developed, and used to examine cytotoxic granule exocytosis, providing a clearer picture of this process in healthy cells as well as patients suffering from genetic mutations. Two diagrams detailing the stages of this process and the molecules which have been mapped onto this pathway are included as an attachment. These results have been published in high level peer-reviewed journals, with additional publications under preparation.

In terms of the socio-economic and policy relevance of this project, this research has already provided concrete improvements in diagnostics and carrier testing and may also offer the possibility of prenatal testing. These tests have been implemented in Sweden, and the information has been disseminated worldwide through academic publications and conferences. In addition, the incremental increases in understanding of the biology underlying these defects may provide future improvements to clinical decisions and treatments. Moving forward, we are investigating the possibilities for screening of all newborns in Sweden for mutations found in the population.