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Inborn errors of innate immunity: systems genomics route to the core of the immune system

Mid-Term Report Summary - IMMUNOCORE (Inborn errors of innate immunity: systems genomics route to the core of the immune system)

Inherited disorders of the immune system (so-called primary immunodeficiencies, PIDs) comprise a heterogeneous group of disorders that are often life-threatening. The majority of PIDs have a genetic cause, often arising from single-gene defects. Importantly, understanding of different genetic disease etiologies has also shaped our understanding of the hierarchical organization of the human immune system, and has enabled the identification of non-redundant components therein. More than 300 different genetic causes of PIDs have been identified over the last 20 years despite the fact that, until recently, the identification of those underlying disease-causing mutations was often cost-intensive and time-consuming. Due to advancements in next generation sequencing technologies within the last years the identification of genetic mutations has become much more efficient.
This ERC Starting Grant-funded project has focused on the identification, and immunological characterization of informative (consanguineous) families followed by the identification of novel genetic defects and detailed functional work-up in order to unravel the underlying disease-causing pathomechanisms of PIDs involving the innate immune system, and to potentially identify molecular targets for precision treatment of such disorders.
Our most significant findings and contributions to the field of immunology and PID research are the identification and molecular characterization of several novel and previously undescribed PIDs. We have identified JAGN1 deficiency as a novel etiology of severe congenital neutropenia (Kostmann’s Disease) (Boztug K et al., Nature Genet 2014), NIK deficiency as a novel type of PID with impaired NFκB signaling (Willmann K et al., Nature Commun 2014), and DOCK2 deficiency as a novel PID with impaired actin polymerization leading to multiple quantitative and qualitative immune defects (Dobbs K et al., New Engl J Med 2015). In addition, we identified a previously undescribed mutation in LRBA as the cause of early-onset inflammatory bowel disease (Serwas NK et al., Inflamm Bowel Dis, 2015).
Since November 2013 (start of the ERC ImmunoCore funding period), we have provided proof-of-principle in several sub-projects, published in high-ranking scientific journals, that PIDs can be considered paradigmatic for the upcoming era of personalized medicine and tailored treatments, and gratefully acknowledge funding and support through the ERC StG for the above-mentioned scientific projects.