DFG Research Training Group "TJ-Train" (GRK 2318)
Tight junctions and their proteins
Molecular features and actions in health and disease

Project B2

Prof. Dr. Michael Hummel1    &   Prof. Dr. Britta Siegmund2

1Molecularpathology Section at the Institute of Pathology, Charité, CCM
2
Med. Klinik m.S. Gastroenterologie, Infektiologie & Rheumatologie, Charité, CBF, Hindenburgdamm 30, 12203 Berlin

Tracking a primary barrier defect in celiac disease


Candidate gene studies and genome-wide association studies (GWAS). In addition, an involvement of immune cells appears to play an important role. Support for this hypothetical primary barrier defect comes from functional studies revealing barrier dysfunction in inactive CD patients (i.e. under a gluten-free diet) and in first-degree relatives. Here we intend to combine different types of data from epithelial cells as well as isolated intestinal lymphocytes to better understand the malfunction of the intestinal barrier.

Aims of this project are (i) to assess mutations in candidate gene and to determine their impact for barrier function; (ii) to decipher the transcriptional consequences of genetic variants in sorted intra-epithelial cells and (iii) to functionally analyze barrier defects.

Methods: Barrier function analysis will be performed employing Ussing chambers. To identify DNA-based alterations we will apply an amplicon-based next-generation sequencing approach. To determine the transcriptional profile of the FACS-sorted intra-epithelial cells we will use the NanoString technology. All methods are established in our group.

PhD doctoral student

  • Danielle Cardoso da Silva

Participation with project B2

Project-related publications

If a paper is not accessible, please mail to  

  1. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C (2017) Mend your fences: The epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell. Mol. Gastroent. Hepatol. 4(1): 33-46 [PubMed] [WebPage] [PDF] (Review)

  2. Ritter J, Zimmermann K, Jöhrens K, Mende S, Seegebarth A, Siegmund B, Hennig S, Todorova K, Rosenwald A, Daum S, Hummel M, Schumann M (2017) T-cell repertoires in refractory coeliac disease. Gut (online before print, doi:10.1136/gutjnl-2016-311816)

  3. Lissner D, Schumann M, Batra A, Kredel LI, Kühl AA, Erben U, May C, Schulzke JD, Siegmund B (2015) Monocyte and M1 macrophage-induced barrier defect contributes to chronic intestinal inflammation in IBD. Inflamm. Bowel Dis. 21:1297-305

  4. Kredel LI, Batra A, Stroh T, Kühl AA, Zeitz M, Erben U, Siegmund B (2013) Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease. Gut 62: 852-862

  5. Batra A, Heimesaat MM, Bereswill S, Fischer A, Glauben R, Kunkel D, Scheffold A, Erben U, Kühl A, Loddenkemper C, Lehr HA, Schumann M, Schulzke JD, Zeitz M, Siegmund B (2012) Mesenteric fat-control site for bacterial translocation in colitis? Mucosal Immunol. 5: 580-591

  6. Schumann M, Kamel S, Pahlitzsch ML, Lebenheim L, May C, Krauss M, Hummel M, Daum S, Fromm M, Schulzke JD (2012) Defective tight junctions in refractory celiac disease. Ann. N.Y. Acad. Sci. 1258: 43-51

  7. Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I (2012) IkBNS protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity 37: 998-1008

  8. Gerling M, Glauben R, Habermann JK, Kühl AA, Loddenkemper C, Lehr HA, Zeitz M, Siegmund B (2011) Characterization of chromosomal instability in murine colitis-associated colorectal cancer. PLoS One 6:e22114

  9. Mühr-Wilkenshoff F, Friedrich M, Foss HD, Hummel M, Zeitz M, Daum S (2010) Immune modulation by non-hodgkin lymphoma in a patient with two primary intestinal T-cell lymphomas and long-standing celiac disease. Digestion 81(4): 231-234

  10. Glauben R, Batra A, Stroh T, Erben U, Fedke I, Lehr HA, Leoni F, Mascagni P, Dinarello CA, Zeitz M, Siegmund B (2008) Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice. Gut 57: 613-622

  11. Stroh T, Batra A, Glauben R, Fedke I, Erben U, Kroesen A, Heimesaat MM, Bereswill S, Girardin S, Zeitz M, Siegmund B (2008) Nucleotide oligonerization domains 1 and 2: regulation of expression and function in preadipocytes. J. Immunol. 181: 3620-3627

  12. Batra A, Pietsch J, Fedke I, Glauben R, Okur B, Stroh T, Zeitz M, Siegmund B (2007) Leptin-dependent toll-like receptor expression and responsiveness in preadipocytes and adipocytes. Am. J. Pathol. 170: 1931-1941

  13. Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TFE, Bernd HW, Cogliatti SB, Dierlamm J, Feller AC, Hansmann ML, Haralambieva E, Harder L, Hasenclever D, Kühn M, Lenze D, Lichter P, Martin-Subero JI, Möller P, Müller-Hermelink HK, Ott G, Parwaresch RM, Pott C, Rosenwald A, Rosolowski M, Schwaenen C, Stürzenhofecker B, Szczepanowski M, Trautmann H, Wacker HH, Spang R, Loeffler M, Trümper L, Stein H, Siebert R & Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe (2006) A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. New Engl. J. Med. 354: 2419-2430

  14. Siegmund B, Sennello JA, Jones-Carson J, Gamboni-Robertson F, Lehr HA, Batra A, Fedke I, Zeitz M, Fantuzzi G (2004) Leptin receptor expression on T lymphocyte modulates chronic intestinal inflammation in mice. Gut 53: 965-972

  15. Siegmund B, Lehr HA, Fantuzzi G (2002) Leptin: a pivotal mediator of intestinal inflammation in mice. Gastroenterology 122: 2011-2025

  16. Daum S, Weiss D, Hummel M, Ullrich R, Heise W, Stein H, Riecken EO, Foss HD & Intestinal Lymphoma Study Group (2001) Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut 49: 804-812