Mechanistic Studies of Defects in Lymphocyte Cytotoxicity Underlying HLH
Yenan Bryceson PhD
Karolinska Institutet Center for Infectious Medicine – Stockholm, Sweden
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Familial hemophagocytic lymphohistiocytosis (FHL) is a devastating inherited disease affecting mainly infants and young children. It causes fever, enlarged liver and spleen, as well as reduced numbers of white blood cells. Without treatment FHL is invariably fatal. With the HLH-94 treatment protocol, based on chemotherapy and immunotherapy followed by bone marrow transplantation, the survival has increased to approximately 60%. Transplantation is the only curative curative treatment of FHL, but is associated with considerable risks. However, delay of treatment and transplantation can increase the risk of neurological dysfunction in FHL patients. Thus, rapid and accurate diagnosis of FHL is imperative.
The symptoms in FHL are caused by mutations in proteins that facilitate killing of target cells by specialized immune cells termed cytotoxic lymphocytes. When cytotoxic lymphocytes are unable to kill target cells, an infection can trigger an uncontrolled accumulation and activation of immune cells, mainly T cells and macrophages that infiltrate tissues and cause the symptoms associated with FHL. Mutations in genes encoding perforin, Munc13-4, syntaxin-11, and Munc18-2 have been associated with development of FHL. We and others have demonstrated that these proteins are implicated in release of lytic granules. However, how these proteins interact to facilitate release of granules for target cell killing is not clear. In addition, several other molecular components remain elusive. Our research aims at gaining insights into the mechanisms of lymphocyte cytotoxicity.
The outlined project pertains to the diagnosis and treatment of FHL. At the moment, diagnosis is best provided by identification of mutations, but sequencing of genes may take time and many cases remain unexplained by current knowledge. Further insights into the molecular mechanisms underlying FHL and better means of diagnosis are called for to assist in decisions concerning treatment of FHL patients and our research can thus help patients in several ways. First, understanding the molecular mechanisms of FHL can help explain the biological effect of specific mutations. Second, identification of new genes associated with FHL through studies of the molecular mechanism of granule trafficking and release can explain disease in FHL patients not identified by current methods. In this setting, a genetic diagnosis can aid in rapidly providing adequate treatment. Moreover, this can aid genetic counseling or, if desired, prenatal diagnostics. Finally, biological studies of the molecular pathways and proteins involved in granule trafficking and release, together with analyses of genotype and clinical phenotype can facilitate the establishment of functional criteria that can offer very rapid diagnosis and stratification of HLH patients. Such studies may in the future provide important platforms for decisions concerning treatment of diverse FHL patients and increase our understanding of patients with symptoms but as yet no clear diagnosis.