Our laboratory is very translational: In the morning, the physicians from the group see patients with immunodeficiencies, take blood from them, and bring it to the Center for Translational Cell Research (ZTZ), in which our working group is housed. Here, we extract the genomic DNA and search for the mutations that could explain the immunodeficiency. For this we use next generation sequencing which enables us to read all human genes in one experiment. However, each person carries about 250 new mutations that are not present in their parents. How do you find out the disease-causing mutations among all these hundreds of variants?

For this purpose, we developed a database that identifies the genetic variants that may be causing the disease, similar to the search for a specific fingerprint in the database of the Federal Criminal Police Office. However, we often encounter mutations that have not yet been described or investigated. Therefore, in a next step, we have to confirm these genetic results through functional studies.

Moreover, we are interested in the role of the microbiome for the immune system. During the last decade it became clear that the microbiome plays a prominent role in shaping the immune system. Here we try to answer the question how the microbiome can affect the everyday disease course of our patients.

Finally, we started to research the impact of epigenetic changes to the immune system: We follow the hypothesis that an aberrant methylation of genes leads to immune deficiency or immune dysregulation. Epigenetics goes beyond genetics. Every cell has the same genetic information – its DNA. But what determines that the cells in the eye can see, and the cells in the nose can smell? It is the epigenetic regulation of genes which determines these differences, for instance by the process of DNA methylation. We are using cutting edge multi-omics profiling and integrative bioinformatic analysis to unravel the pathway underlying immune-mediated diseases. By combining genomic, epigenomic, transcriptomic, and proteomic analysis, we will exploit defined pathways to improve the diagnosis and the mechanistic understanding of the pathophysiology of our patients.

Keywords:

Inborn errors of immunity, primary immunodeficiency, autoimmunity, inflammation, immune dysregulation

10 selected publications:

• Treatment of Progressive Multifocal Leukoencephalopathy with Pembrolizumab.
  Rauer S, Marks R, Urbach H, Warnatz K, Nath A, Holland S, Weiller C, Grimbacher B (2019).
  N Engl J Med. (letter)380(17):1676-1677.
• ZNF341 controls STAT3 expression and thereby immunocompetence.
  Frey-Jakobs S, Hartberger JM, Fliegauf M, Bossen C, Wehmeyer ML, Neubauer JC, Bulashevska A, Proietti M, Fröbel P, Nöltner C, Yang L, Rojas-Restrepo J, Langer N, Winzer S, Engelhardt KR, Glocker C, Pfeifer D, Klein A, Schäffer AA, Lagovsky I, Lachover-Roth I, Béziat V, Puel A, Casanova JL, Fleckenstein B, Weidinger S, Kilic SS, Garty BZ, Etzioni A, Grimbacher B (2018).
  Sci Immunol. 15;3(24).
• Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency.
  Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, Winzer S, Bulashevska A, Scerri T, Leung E, Jordan A, Keller B, de Vries E, Cao H, Yang F, Schäffer AA, Warnatz K, Browett P, Douglass J, Ameratunga RV, van der Meer JW, Grimbacher B (2015).
  Am J Hum Genet. 97(3):389-403.
• Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.
  Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schäffer AA, Grüning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Seneviratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu S, Salzer U, Franke A, Sakaguchi S, Walker LSK, Sansom DM, Grimbacher B (2014).
  Nat Med. 20(12):1410-1416.
• Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.
  Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hätscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C (2009).
  N Engl J Med. 361(21):2033-45.
• A homozygous CARD9 mutation in a family with susceptibility to fungal infections.
  Glocker EO, Hennigs A, Nabavi M, Schäffer AA, Woellner C, Salzer U, Pfeifer D, Veelken H, Warnatz K, Tahami F, Jamal S, Manguiat A, Rezaei N, Amirzargar AA, Plebani A, Hannesschläger N, Gross O, Ruland J, Grimbacher B (2009).
  N Engl J Med. 361(18):1727-35.
• STAT3 mutations in the hyper-IgE syndrome.
  Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schäffer AA, Puck JM, Grimbacher B (2007).
  N Engl J Med. 357(16):1608-19.
• Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.
  Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rochstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B (2005).
  Nat Genet 37: 820-828.
• Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.
  Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer AA, Mages HW, Kroczek RA, Peter HH (2003).
  Nat Immunol. 4(3):261-8.
• Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder.
  Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM (1999).
  N Engl J Med. 340(9):692-702.