Albrecht about her research:
“In rheumatic diseases the immune system is overactive. Immune cells attack self tissue and induce a longlasting inflammatory response that leads to progressive tissue damage. However, only a fraction of immune cells are pathogenic and participate in the inflammatory process. The majority of immune cells still is protective and clears infections with viruses or bacteria. Current therapies of chronic-inflammatory diseases suppress immune reactions and effectively resolve inflammation. However, the therapies lack selectivity. They also impair protective immune responses. The aim of our work was the identification of markers that allow discriminating between pathogenic and protective immune cells.

T helper (Th) cells act as control elements in the immune system: Upon encounter of the cognate antigen, e.g. a virus, they start to secrete selected cytokines and thereby control the immune response. The flexibility of Th cells in developing effector functions grants the adequate type of immune response. Th Type 1 (Th1) cells are characterized by the secretion of the pro-inflammatory cytokines Interferon-γ and Tumor Necrosis Factor (TNF)-α and protect against infections with intracellular pathogens. Autoreactive Th1 cells are enriched at the site of inflammation of patients suffering from chronic inflammatory diseases. Th1 cells are potent inducers of inflammation and are likely to play a key role in rheumatic diseases.

How can we model the differences between pathogenic and protective Th1 cells and thereby identify markers of pathogenic cells? In this work pathogenic Th1 cells were specifically generated in vitro. Starting from the hypothesis that pathogenic Th1 cells undergo a longlasting and repeated activation whereas protective Th1 cells represent rarely activated cells, the gene expression profiles of once and repeatedly activated Th1 cells were compared.

One gene that was exclusively expressed in repeatedly activated Th1 cells was the transcription factor “twist1”. Activity of “twist1” correlated with the number of antigenic stimulations and thereby reflects “cell age” and an active involvement in the inflammatory response. The ability of repeatedly activated Th1 cells to induce and maintain chronic inflammation was demonstrated in a mouse model of arthritis. Here, deletion of twist1 in the pathogenic Th1 cells enhances the inflammatory response. Twist1 represents an internal regulator of the pro-inflammatory capacity of Th1 cells by limiting the expression of pro-inflammatory cytokines.

Expression of “twist1” in human peripheral Th cells peaks in terminally differentiated effector memory Th cells and is the lowest in naïve Th cells. Th cells from the inflamed joint or gut tissue of patients with rheumatic diseases and inflammatory bowel disease express high levels of “twist1”. Expression of twist1 in Th cells at the site of inflammation highlights the role of chronic T cell activation in chronic inflammation and reflects the resistance of pathogenic Th cells to current therapeutic intervention. As a marker of pathogenic Th1 cells, twist1 may allow the development of novel therapies that selectively target the pathogenic Th1 cells.”

Source: Niesner, U, Albrecht, I, Janke, M, Doebis, C, Loddenkemper, C, Lexberg, MH, et al. Autoregulation of Th1-mediated inflammation by twist1. J Exp Med. 2008 Aug 4;205(8):1889-901