Integrated genetics of congenital defects of innate immunity

Primary immunodeficiency disorders involving innate immunity are characterized by recurrent and life-threatening infections. The aim of our work is to identify novel genetic defects in innate immunity and decipher their molecular pathophysiology. To this end, we will use a discovery engine consisting of an exclusive combination of genomic technologies, including SNP chip arrays and next generation sequencing, together with functional proteomic technologies. The engine will be complemented by biochemical, immunogical and imaging technologies to systematically assess the consequences of the genetic deficiencies and map the respective protein products onto molecular pathways. For these analyses, we will employ primary patient material as well suitable in vitro models. The proposed investigations are expected to contribute significantly to our understanding of the molecular processes that structure our innate immune system. This will not only enable a more comprehensive molecular classification system of primary immunodeficiencies, but also improve patient care by aiding molecular diagnosis in patients suffering from these disorders. Our investigations will serve as the basis for future development of targeted therapies such as gene therapy or pharmacological interventions targeting affected signaling pathways.

Inherited disorders of the immune system (so-called primary immunodeficiency disorders, PIDs) can enable the identification of essential components of the human immune system. Patients suffering from these diseases can have life-threatening infections and are thus in need to be treated timely upon diagnosis. A major problem from the patients point of view is that many PIDs have hitherto unknown genetic causes and thus cannot be easily diagnosed. In our work carried out within this FWF START grant, we have embarked on identifying novel disease etiologies, and on characterizing the disease- causing molecular pathologies to identify key components of human immunity.Within the 3.5 years since the initiation of the project we contributed significantly to the understanding of the molecular processes underlying proper and full functionality of the immune system through identification and molecular characterization of several novel PIDs. For instance, JAGN1 deficiency is a novel type of severe congenital neutropenia, marked by a lack of specific subsets of white blood cells, so-termed neutrophil granulocytes. We could show that patients with this disease have decreased numbers of neutrophils because these cells die prematurely due to the mutations in JAGN1 (Boztug K et al Nature Genet 2014). In additional work, we have been able to identify defects, which comprise both the innate and adaptive immune system. For instance, mutations in PRKCD cause a novel disease characterized by severe autoimmunity resembling systemic lupus erythematodes (Salzer E et al Blood 2013). Furthermore, we have identified NIK deficiency as a novel cause of combined T- and B-cell immunodeficiency (Willmann K et al Nature Comm 2014), and DOCK2 deficiency as a novel type of defect in actin polymerization leading to severe dysregulations in several subsets of leukocytes including neutrophil granulocytes (Dobbs K et al NEJM 2015). In addition to improvement of patient care those findings enable a more accurate molecular classification of primary immunodeficiencies. In several of these novel types of immunodeficiency, our understanding of the molecular disease mechanisms has helped to identify targeted therapies for the patients.The team has established various new international collaborations and the results have been presented to the scientific community at several top-class international conferences, e.g. the 15th biennial meeting of the European Society for Immunodeficiencies (ESID) 2012 in Florence, the Midwinter Conference 2014 in Seefeld, the 4th European Congress of Immunology (ECI) 2015 in Vienna, the 48th Annual Meeting of the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) 2015 in Amsterdam, the 7th International Conference on Autoimmunity 2015 in Chania, and the 9th European Workshop on Immune-Mediated Inflammatory Diseases (EWIMID)2015 in Amsterdam. We gratefully acknowledge funding and support through the FWF START program for the above-mentioned scientific projects.