Centrum für Chronische Immundefizienz - CCI

We want to understand why some people's immune systems aren't able to control inflammation or fight infection like most people are. We are particularly interested in understanding how genetic factors and sensing of nucleotides or nucleic acids might explain this variability.

CV

Current Position

• Professor (W1), Genetic of Immune Dysregulation, MHH Hannover Medical School
• Head of the Genetic and Genomic Research Unit, Institute for Immunodeficiency (IFI), Medical Center and Faculty of Medicine, University of Freiburg
• Group leader Institute for Immunodeficiency (IFI), Medical Center and Faculty of Medicine, University of Freiburg and Department of Rheumatology and Clinical Immunology, MHH Hannover

Professional career

Academic qualifications

2010              PhD Clinical and Experimental Immunology, University of Genova, Italy
2006              Board Certification in internal Medicine, University of Rome “La Sapienza”
2001              Medical degree, University of Rome “La Sapienza”

University training and degree

1996-2001      Medical studies, University of Rome “La Sapienza”
1999-2001      Clinical Immunology and Allergology Unit, University of Rome “La Sapienza”

Informatic and Bioinformatic skills

Informatic: Firm knowledge of R, Python, Bash, SQL and database management, Linux.
Bioinformatic: Whole Exome Sequencing (WES), Whole Genome Sequencing (WGS), SAMtools, BEDtools, RNA sequencing, variant discovery, integration of multiple datasets, data visualization.

Research Focus

• Genetic of Immunedysregulation
• Development of tools and databases for genetic analysis of Inborn Error of Immunity
• ADA2 and DADA2

Current Projects

Genetic of Immunedysregulation

We want to understand why some people's immune systems aren't able to fight infection or control inflammation like most people are. We are particularly interested in understanding how genetic factors might explain this variability.

The genetic architecture of complex human diseases, including congenital immunodeficiencies, is likely influenced by multiple components. These include common and rare genetic variants, structural variants, and gene-gene and gene-environment interactions. As a result, on the one hand we have to expand the list of possible candidates, while on the other hand we have to revise our assumptions about monogenic or oligogenic causality in many situations.

In order to efficiently analyze the large amount of genetic data, we have developed the Gemma database. For our research work we use the immunogenetic platform Gemma - a database in which resources and research data are stored. With it, for example, genetic research reports can be created automatically and clinical metadata can be harmonized and recorded more quickly.

In addition, a subset of the publicly available data was collected in a satellite project (www.GeniaDB.net) made available on the Internet. Unlike other databases composed mainly of computational and linked information, GeniaDB will ensure that synthesized and evolving information is incorporated – clinical and genetic paradigms and pitfalls, as well as new concepts and considerations specific to each patient situation, gene and disease. GenIA will also be a practical tool for healthcare providers to help them improve their genetic and functional testing strategies, interpretation of genetic test results, and/or patient counseling. To help clinicians use GenIA for triaging differential diagnoses for unsolved patients, we developed a Shiny app called “GenIA PhenoMatcher” that generates lists of candidate genes, genetic conditions and the number and percentage of known patients for a given input of clinical manifestations.

Effects of neonatal wildling microbiota on the immune response to vaccination

Early-life immunization has significantly reduced the morbidity and mortality in infants. However, the efficacy of neonatal vaccination is variable and overall limited compared to adults. It is therefore increasingly appreciated that a better understanding of the mechanisms controlling early life im-mune response to vaccination is needed to improve the efficacy of pediatric vaccines. Increasing evidence, both in human and mice, indicate that the gut microbiota and microbiota-derived mole-cules exert significant effects on the development of the immune system already in utero (via the maternal microbiota) and then postnatally. This in turn suggests that the microbiota may influence vaccine efficacy and immunogenicity in infants and that its manipulation constitutes a possible way to improve vaccine performance. We have recently collected experimental evidence for this hy-pothesis by creating a new generation of oral vaccines built on the inhibition of microbiota-derived ATP in the intestine. Of note, while human studies are by necessity mostly correlative, studies con-ducted with mice raised under conventional specific pathogen-free (SPF) conditions also have ma-jor limitations. In particular, the microbial challenges of the natural world are not replicated in the laboratory SPF setting and have limited ability to resemble the human immune responses. We have recently overcome these limits by developing wildling mice via embryo transplantation of laboratory mice into female wild mice. We subsequently showed, in two preclinical studies, that, whereas SPF mice failed to mimic human responses to therapy, wildlings strikingly phenocopied patient out-comes. Here, we propose to use wildlings to study neonatal immune response to vaccines. In par-ticular we will address, 1)  immunogenicity and efficacy of neonatal vaccination in wildlings versus SPF mice, 2) how wildlings affect Mφ or DC help to GC reaction upon vaccination in neonatal mice, 3) the role of nucleic acid sensing (NAS) for wildling-induced impact on Mφ and DC-mediated help to GC reaction. The project aims for identifying fundamental insights into microbiota-mediated modulation of the immune response to vaccination in infants. This may ultimately lead to the development of novel strategies targeting the microbiota that will enhance vaccine effective-ness.

ADA2 and DADA2

Deficiency of adenosine deaminase 2 (DADA2) is a severe, congenital syndrome, which manifests with hematologic, immunologic and inflammatory pathologies. DADA2 is caused by biallelic mutations in ADA2, but the function of ADA2, and the mechanistic link between ADA2 deficiency and the severe inflammatory phenotype remains unclear. We aim at a better understanding of the mechanisms that link ADA2 and the activation of the immune response.

Collaborations

Germany

• Bodo Grimbacher, Center for Chronic Immunodeficiency (CCI)
• Torsten Witte, MHH Hannover Klinik für Rheumatologie und Immunologie
• Doris Steinemann, MHH Hannover, Institut für Humangenetik
• Nataliya DiDonato, MHH Hannover, Institut für Humangenetik
• Philipp Henneke, UNIVERSITY MEDICAL CENTER and FACULTY OF MEDICINE FREIBURG, Institute for Infection Prevention and Control & Institute for Immunodeficiency
• Stephan Rossart, Uniklinikum Erlangen,
• Eva Bartok, UNI Bonn

International Collaborations

• Ingrun Alseth, Oslo University Hospital
• Ole K Greiner Tollersrud, UiT The Arctic University of Norway.
• Max Warncke, Novartis Institute for Biomedical Research
• Elisabetta Traggiai, Novartis Institute for Biomedical Research

Funding

• CRC/TRR 359 Perinatal Development of Immune Cell Topology (PILOT)
• Cluster of Excellence RESIST (EXC 2155)
• Flex Funding, Cluster of Excellence RESIST

Team

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