What genetic changes predispose people to infections?

What is this research project about?

Diagramm of the immunogentetic plattform Gemma

What is this research project about?

We aim to understand why the immune system of some individuals is unable to fight infections or control inflammation as the one of most of the people does. We are in particular interest in understanding how genetic could explain this variability.

For our research work, we use the immunogenetic platform Gemma – a database in which resources and research data are stored. It can be used, for example, to automatically generate genetic research reports and to harmonise and accelerate the collection of clinical metadata.

What’s the current status?

When suspecting Inborn Errors of Immunity, the genetic diagnosis is often negative or ambiguous and clear disease-causing mutations cannot be detected. We assume that this is due to both the technical limitations of current sequencing platforms and a lack of knowledge.

The figure illustrates the relationship between the number of people who receive a clinical diagnosis and the number of people for whom a genetic diagnosis is possible.

Example of genetic data queried from Gemma

What are the project goals?

We want to identify genetic alterations that predispose people to infections and immune-mediated diseases. The long-term goal is to ensure that all patients with congenital immunodeficiency around the world have an equal chance of genetic diagnosis.

How do we get there?

The genetic architecture of complex human diseases, which include Inborn Errors of Immunity, is likely to be influenced by several components. Among them are common and rare genetic variants, structural variants and gene-gene and gene-environment interactions. As a result, we need to expand the list of possible candidates on the one hand, while revising our assumptions about monogenic or oligogenic causality in many situations on the other.

In order to improve technology (e.g. optical genome mapping) and knowledge (clinical, genetic and molecular expertise as well as data) related to congenital immune disorders, we are currently establishing a joint “Freiburg-Hannover ImmunoGenetics Research Unit” (FH-IGRU). In this unit, we are combining the expertise and resources of the Institute of Human Genetics and the Department of Rheumatology and Immunology of the MHH with those of the Genetics and Genomics Unit of the CCI / IFI at the University Hospital of Freiburg.

In order to be able to efficiently analyse the large amount of genetic data, we have developed the immunogenetics platform GemmaDB. In addition, a subset of publicly available data has been made available on the internet in a satellite project (www.GeniaDB.net). Unlike other databases, which are mainly composed of computerised and linked information, GeniaDB will ensure that synthesized and evolving information is included – 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 counselling.

Homepage of the web based platform GenIA


Project title: Genetics of Immundysregulation

Prof. Dr. Michele Proietti

Project: A5

Project A5 Publications

Publications 2022

Evaluation of Laboratory and Sonographic Parameters for Detection of Portal Hypertension in Patients with Common Variable Immunodeficiency. Globig AM, Strohmeier V, Surabattula R, Leeming DJ, Karsdal MA, Heeg M, Kindle G, Goldacker S, von Spee-Mayer C, Proietti M, Bausch B, Bettinger D, Schultheiß M, Thimme R, Schuppan D, Warnatz K. J Clin Immunol.

Publications 2021

Multiple Immunostainings with Different Epitope Retrievals-The FOLGAS Protocol. von Schoenfeld A, Bronsert P, Poc M, Fuller A, Filby A, Kraft S, Kurowski K, Sörensen K, Huber J, Pfeiffer J, Proietti M, Stehl V, Werner M, Seidl M. Int J Mol Sci. 2021 Dec 25;23(1):223.

Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study. Rojas-Restrepo J, Caballero-Oteyza A, Huebscher K, Haberstroh H, Fliegauf M, Keller B, Kobbe R, Warnatz K, Ehl S, Proietti M *, Grimbacher B *. Front Immunol. 2021 Dec 17;12:786516.

Therapeutic targeting of endoplasmic reticulum stress in acute graft-versus-host disease. Haring E, Andrieux G, Uhl FM, Krausz M, Proietti M, Sauer B, Esser PR, Martin SF, Pfeifer D, Schmitt-Graeff A, Duyster J, Köhler N, Grimbacher B, Boerries M, Aumann K, Zeiser R, Apostolova P. Haematologica. 2021 Aug 19.

Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis. Frede N, Rojas-Restrepo J, Caballero Garcia de Oteyza A, Buchta M, Hübscher K, Gámez-Díaz L, Proietti M, Saghafi S, Chavoshzadeh Z, Soler-Palacin P, Galal N, Adeli M, Aldave-Becerra JC, Al-Ddafari MS, Ardenyz Ö, Atkinson TP, Kut FB, Çelmeli F, Rees H, Kilic SS, Kirovski I, Klein C, Kobbe R, Korganow AS, Lilic D, Lunt P, Makwana N, Metin A, Özgür TT, Karakas AA, Seneviratne S, Sherkat R, Sousa AB, Unal E, Patiroglu T, Wahn V, von Bernuth H, Whiteford M, Doffinger R, Jouhadi Z, Grimbacher B. J Clin Immunol. 2021 Nov;41(8):1804-1838.

Altered Spectrum of Lymphoid Neoplasms in a Single-Center Cohort of Common Variable Immunodeficiency with Immune Dysregulation. Wehr C, Houet L, Unger S, Kindle G, Goldacker S, Grimbacher B, Caballero Garcia de Oteyza A, Marks R, Pfeifer D, Nieters A, Proietti M, Warnatz K, Schmitt-Graeff A. J Clin Immunol. 2021 Aug;41(6):1250-1265. Epub 2021 Apr 19.

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. Wang L, Aschenbrenner D, Zeng Z, Cao X, Mayr D, Mehta M, Capitani M, Warner N, Pan J, Wang L, Li Q, Zuo T, Cohen-Kedar S, Lu J, Ardy RC, Mulder DJ,
Dissanayake D, Peng K, Huang Z, Li X, Wang Y, Wang X, Li S, Bullers S, Gammage AN, Warnatz K, Schiefer AI, Krivan G, Goda V, Kahr WHA, Lemaire M; Genomics England Research Consortium, Lu CY, Siddiqui I, Surette MG, Kotlarz D, Engelhardt KR, Griffin HR, Rottapel R, Decaluwe H, Laxer RM, Proietti M,
Hambleton S, Elcombe S, Guo CH, Grimbacher B, Dotan I, Ng SC, Freeman SA, Snapper SB, Klein C, Boztug K, Huang Y, Li D, Uhlig HH, Muise AM. Nat Genet. 2021 Apr;53(4):500-510. Epub 2021 Mar 29. Erratum in: Nat Genet. 2022 Feb;54(2):213.

Agammaglobulinemia with normal B-cell numbers in a patient lacking Bob1. J Allergy Clin Immunol. 2021 May;147(5):1977-1980. Kury P, Staniek J, Wegehaupt O, Janowska I, Eckenweiler M, Korinthenberg R, Japaridze N, Pendziwiat M, Helbig I, Verhoeyen E, Jung J, Garcia de Oteyza AC, Proietti M, Phirtskhalaishvili T, Rtskhiladze I, Nielsen PJ, Ehl S, Speckmann C, Rizzi M.  Epub 2021 Feb 9.

Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect. Haring E, Uhl FM, Andrieux G, Proietti M, Bulashevska A, Sauer B, Braun LM, de Vega Gomez E, Esser PR, Martin SF, Pfeifer D, Follo M, Schmitt-Graeff A, Buescher J, Duyster J, Grimbacher B, Boerries M, Pearce EL, Zeiser R, Apostolova P. Haematologica. 2021 Aug 1;106(8):2131-2146.

Publications of the Project A5