How can the diagnosis be improved so that an early identification of as many affected persons as possible can be achieved?

What is this research project about?

The fitness of the immune system and thus the susceptibility to infections shows a Gaussian distribution in the population. The variability of susceptibility to infectious diseases is based on genetic variation.

What is this research project about?

The fitness of the immune system is unevenly distributed in the population. On the one hand there are anecdotal reports on the “90-yr-old smoker, who has never been admitted to hospital”; on the other hand there are immunocompromised individuals who would not survive without medical intervention, sometimes necessitating even bone marrow transplantation. These individuals, with a profoundly impaired immune system, manifest with severe and often untypical (e.g. opportunistic) life-threatening infections and a predisposition to (mainly virally-induced) malignancies. In between these two extremes, however, there is a distribution of immune fitness, where patients with recurrent non-life threatening -but repeated or prolonged- infections, represent the majority of cases. In the last decades more than 350 different genes have been found to be mutated in immunodeficiency patients.

What’s the current status?

Depending on the cohort of study, the more than 350 genes associated with primary immunodeficiencies (PID), can only explain about 15-60% of cases. Certainly, there are probably more genes yet to be discovered, however, it is also likely that our search is not deep enough and that the monogenic model is insufficient to fulfill the diagnostic odyssey. Nowadays, Next-generation sequencing (NGS) technologies are routinely used in the clinic to obtain a genetic diagnosis. Most PID patients undergo targeted gene panel (TGP) sequencing or whole exome sequencing (WES), but still, a substantial number of them remain undiagnosed, as it is true for most Mendelian diseases. There may be many reasons for this; first, standard NGS bioinformatics pipelines are not specifically designed to detect copy number alterations (CNAs) or structural variants (SV), and these may be missed. Second, the use of TGP or WES limits the search to the coding part of the genome (2%). Third, other causative or contributing factors, which are excluded with the monogenic model, such as epigenetic profiles and the regulation of gene expression or the gut microbiome, have not been sufficiently studied.

What are the project goals?

The main objectives are:

  • Reducing the number of unsolved cases, since the majority of patients with immunodeficiency are currently undiagnosed
  • Improving our understating on how the epigenome works and its role in primary immunodeficiency disease.
  • Understanding the relationship between the gut microbiome and disease severity and comorbidity in PID patients with malignancies, autoimmunity or inflammation

How do we get there?

The percentage of positively diagnosed patients could increase, first, by reanalyzing WES data with custom bioinformatics pipelines or with the use of novel alternative methods like next generation mapping (NGM) to detect CNAs or SVs, including insertions, translocations and inversions, which are not detectable by commonly used techniques. Second, by investigating epigenetic patterns of DNA methylation and histone modification in a genome-wide approach. Third, by sequencing the gut microbiome we can study the phylogenic and functional diversity of the gut microbiota and its role in shaping the immune system. Finally, microbiome diversity and co-morbidity in patients with PID could be addressed with the analysis of intestinal immunoglobulins.

Projectleaders

Project title: Infection predisposition in primary immundeficiencies

Prof. Dr. Bodo Grimbacher

Projekt: A2

 
  Center for Chronic Immunodeficiency
  Freiburg
  +49 761 270-77731
  +49 761 270-77744
 
  Bodo.Grimbacher
@uniklinik-freiburg.de
  DOWNLOAD CV

Prof. Dr. Thomas Illig

Projekt: A2

 
  Institut für Humangenetik, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-4526
 
 
  Illig.Thomas@mh-hannover.de
  DOWNLOAD CV

Prof. Dr. Torsten Witte

Projekt: A2, B2

  Leitung der Arbeitsgruppe „Autoimmunität“
  Klinik für Immunologie und Rheumatologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-3623
 
 
  Witte.Torsten
@mh-hannover.de
  DOWNLOAD CV

Prof. Dr. Reinhold E. Schmidt

Projekt: A2

  Direktor
  Klinik für Immunologie und Rheumatologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-6656
  +49 511 532-9067
 
  immunologie
@mh-hannover.de
  DOWNLOAD CV

Prof. Dr. Doris Steinemann

Projekt: A2

 
  Team „Funktionelle Genomik“, Institut für Humangenetik, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-4669
  +49 511 532-4521
 
  Steinemann.Doris
@mh-hannover.de
  DOWNLOAD CV

Project A2 Publications

You will find project related publications here.

  1. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, Scheible R, Rusch S, Gasteiger LM, Grimbacher B, Mahlaoui N, Ehl S; ESID Registry Working Party and collaborators. J Allergy Clin Immunol Pract. 2019 Jul – Aug;7(6):1763-1770. doi: 10.1016/j.jaip.2019.02.004. Epub 2019 Feb 15.
  2. Evaluating laboratory criteria for combined immunodeficiency in adult patients diagnosed with common variable immunodeficiency. von Spee-Mayer C, Koemm V, Wehr C, Goldacker S, Kindle G, Bulashevska A, Proietti M, Grimbacher B, Ehl S, Warnatz K. Clin Immunol. 2019 Jun;203:59-62. doi: 10.1016/j.clim.2019.04.001. Epub 2019 Apr 17.
  3. Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency. Eskandarian Z, Fliegauf M, Bulashevska A, Proietti M, Hague R, Smulski CR, Schubert D, Warnatz K, Grimbacher B. Front Immunol. 2019 Apr 16;10:568. doi: 10.3389/fimmu.2019.00568. eCollection 2019. Erratum in: Front Immunol. 2019 Jun 28;10:1490.
  4. Corrigendum: Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency. Eskandarian Z, Fliegauf M, Bulashevska A, Proietti M, Hague R, Smulski CR, Schubert D, Warnatz K, Grimbacher B. Front Immunol. 2019 Jun 28;10:1490. doi: 10.3389/fimmu.2019.01490. eCollection 2019.
  5. The German National Registry of Primary Immunodeficiencies (2012-2017). El-Helou SM, Biegner AK, Bode S, Ehl SR, Heeg M, Maccari ME, Ritterbusch H, Speckmann C, Rusch S, Scheible R, Warnatz K, Atschekzei F, Beider R, Ernst D, Gerschmann S, Jablonka A, Mielke G, Schmidt RE, Schürmann G, Sogkas G, Baumann UH, Klemann C, Viemann D, von Bernuth H, Krüger R, Hanitsch LG, Scheibenbogen CM, Wittke K, Albert MH, Eichinger A, Hauck F, Klein C, Rack-Hoch A, Sollinger FM, Avila A, Borte M, Borte S, Fasshauer M, Hauenherm A, Kellner N, Müller AH, Ülzen A, Bader P, Bakhtiar S, Lee JY, Heß U, Schubert R, Wölke S, Zielen S, Ghosh S, Laws HJ, Neubert J, Oommen PT, Hönig M, Schulz A, Steinmann S, Schwarz K, Dückers G, Lamers B, Langemeyer V, Niehues T, Shai S, Graf D, Müglich C, Schmalzing MT, Schwaneck EC, Tony HP, Dirks J, Haase G, Liese JG, Morbach H, Foell D, Hellige A, Wittkowski H, Masjosthusmann K, Mohr M, Geberzahn L, Hedrich CM, Müller C, Rösen-Wolff A, Roesler J, Zimmermann A, Behrends U, Rieber N, Schauer U, Handgretinger R, Holzer U, Henes J, Kanz L, Boesecke C, Rockstroh JK, Schwarze-Zander C, Wasmuth JC, Dilloo D, Hülsmann B, Schönberger S, Schreiber S, Zeuner R, Ankermann T, von Bismarck P, Huppertz HI, Kaiser-Labusch P, Greil J, Jakoby D, Kulozik AE, Metzler M, Naumann-Bartsch N, Sobik B, Graf N, Heine S, Kobbe R, Lehmberg K, Müller I, Herrmann F, Horneff G, Klein A, Peitz J, Schmidt N, Bielack S, Groß-Wieltsch U, Classen CF, Klasen J, Deutz P, Kamitz D, Lassay L, Tenbrock K, Wagner N, Bernbeck B, Brummel B, Lara-Villacanas E, Münstermann E, Schneider DT, Tietsch N, Westkemper M, Weiß M, Kramm C, Kühnle I, Kullmann S, Girschick H, Specker C, Vinnemeier-Laubenthal E, Haenicke H, Schulz C, Schweigerer L, Müller TG, Stiefel M, Belohradsky BH, Soetedjo V, Kindle G, Grimbacher B. Front Immunol. 2019 Jul 19;10:1272. doi: 10.3389/fimmu.2019.01272. eCollection 2019.
  6. The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies. Jandus P, Boligan KF, Smith DF, de Graauw E, Grimbacher B, Jandus C, Abdelhafez MM, Despont A, Bovin N, Simon D, Rieben R, Simon HU, Cummings RD, von Gunten S. Blood. 2019 Nov 28;134(22):1941-1950. doi: 10.1182/blood.2019001705.
  7. Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity. Jägle S, Heeg M, Grün S, Rensing-Ehl A, Maccari ME, Klemann C, Jones N, Lehmberg K, Bettoni C, Warnatz K, Grimbacher B, Biebl A, Schauer U, Hague R, Neth O, Mauracher A, Pachlopnik Schmid J, Fabre A, Kostyuchenko L, Führer M, Lorenz MR, Schwarz K, Rohr J, Ehl S. Clin Immunol. 2019 Nov 23;210:108316. doi: 10.1016/j.clim.2019.108316.
  8. Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1. Schröder C, Sogkas G, Fliegauf M, Dörk T, Liu D, Hanitsch LG, Steiner S, Scheibenbogen C, Jacobs R, Grimbacher B, Schmidt RE, Atschekzei F. Front Immunol. 2019 Nov 14;10:2618. doi: 10.3389/fimmu.2019.02618. eCollection 2019.
  9. Structural Noninfectious Manifestations of the Central Nervous System in Common Variable Immunodeficiency Disorders. van de Ven A, Mader I, Wolff D, Goldacker S, Fuhrer H, Rauer S, Grimbacher B, Warnatz K. J Allergy Clin Immunol Pract. 2019 Dec 16. pii: S2213-2198(19)31026-8. doi: 10.1016/j.jaip.2019.11.039.
  10. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Rivière JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Pérez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarström L, Dogu F, Haskologlu S, İkincioğulları AI, Bal SK, Baris S, Kilic SS, Karaca NE, Kutukculer N, Girschick H, Kolios A, Keles S, Uygun V, Stepensky P, Worth A, van Montfrans JM, Peters AM4, Meyts I, Adeli M, Marzollo A, Padem N, Khojah AM, Chavoshzadeh Z, Stefanija MA, Bakhtiar S, Florkin B, Meeths M, Gamez L, Grimbacher B, Seppänen MR, Lankester A, Gennery AR, Seidel MG; Inborn Errors, Clinical, and Registry Working Parties of the European Society for Blood and Marrow Transplantation (EBMT) and the European Society of Immunodeficiencies (ESID). J Allergy Clin Immunol. 2019 Dec 27. pii: S0091-6749(19)32603-X. doi: 10.1016/j.jaci.2019.12.896.

Project A2
Publications