Arbeitsgruppe Prof. Dr. Hadaschik
Our group focusses on the immunology of autoimmune skin diseases.
In a healthy organism the activity of autoreactive CD4+ T cells is usually suppressed by regulatory T cells (Treg) to protect against autoimmunity. Treg are generated in the thymus, circulate in the periphery where they suppress activated autoreactive CD4+ T cells, which have escaped thymic deletion, to maintain peripheral tolerance.
Scurfy mice have a mutation in the FoxP3 gene, which is crucial for the function of regulatory T cells. The missing Treg-control leads to uncontrolled proliferation of autoreactive CD4+ T cells. Scurfy mice spontaneously develop CD4+ T cell-mediated autoimmune inflammation finally leading to multiorgan failure. Interestingly, all Scurfy mice develop severe erosive skin disease. In addition, patients with the rare “immunodysregulation, polyendocrinopathy, enteropathy, x-linked (IPEX) syndrome”, caused by the same functional defect in Treg as in Scurfy mice, suffer from similar symptoms as scurfy mice: They develop multiorgan autoimmune inflammation and the majority (>70%) of patients develops severe skin disease.
The autoimmune disease in Scurfy mice occurs spontaneously, so that it reproduces the pathogenesis of autoimmune reactions in the human system. Therefore, the Scurfy mouse is a suitable model to investigate the control function of Treg for autoimmune-mediated skin diseases in humans.
We are interested in the autoimmune disease, which develops in the absence of functional of regulatory T cells.
Autoantigens in Autoimmune Skin Disease in Absence of Treg
We previously identified Keratin 14 (K14) as new autoantigen in the skin, which is attacked by autoreactive T cells and B cells in the Scurfy mouse (Huter et al 2010). Patients with IPEX syndrome, harboring the same genetic defect as scurfy mice, also show reactivity to K14. Currently we are investigating the relevance of K14 as autoantigen in different autoimmune skin diseases such as atopic dermatitis, psoriasis, lupus erythematodes and lichen ruber.
Funding: Else-Kröner Fresenius Stiftung, Research Grant
Staff: X. Wei, doctoral Student, S. Martinache, BTA
Differentiation Factors for Th2-deviated Autoimmune Skin Disease in Scurfy mice
The autoreactive CD4+ T cells in inflamed Scurfy skin show a strong Th2-polarization as indicated by their cytokine profile (IL4, IL5 and IL13). In this project we focus on the mechanisms of Th2 differentiation of CD4 T cells of scurfy mice. We identified thymic stromal lymphopoietin (TSLP) as potential differentiation factor. In addition the Th2-associated cytokine IL31 is differentially expressed in Scurfy skin in comparison to WT skin. The results of this project will broaden the understanding of the pathology of Th2-biased allergic disease as atopic dermatitis and asthma and might further impact on future therapeutic strategies.
Funding: EU Marie Curie International Reintegration Grant (IRG)
Staff: X. Wei, doctoral Student, B. Heckmann, BTA
Autoimmune Blistering Diseases in the Absence of Regulatory T cells
Autoimmune blistering diseases (ABD), such as bullous pemphigoid (BP) or pemphigus vulgaris (PV), are severe autoimmune diseases of the skin that are caused by autoantibodies against structural proteins of the skin. The binding of autoantibodies in the skin leads to blistering and depending on the location of blister formation the different AMBD are diagnosed. This project aims at analyzing the role of regulatory T cells for the pathophysiology of ABD. We have preliminary data indicating the spontaneous development of different ABD in the absence of functional regulatory T cells.
Funding: DFG Research Grant
Staff: X. Wei, doctoral student, B. Heckmann, BTA
Role of Neutrophil Extracellular Trap Formation in Psoriasis
Neutrophil granulocytes are a histologic hallmark of psoriasis, yet their pathophysiological function in this very common disease is not well understood. Recent work points towards an important role of neutrophil granulocytes, particularly of neutrophil extracellular trap formation, in the pathogenesis of autoinflammatory/autoimmune diseases like lupus erythematodes and psoriasis. Our group aims at further elucidating neutrophil function in psoriasis and as a therapeutic target using the instruments of clinical and basic research. Currently, we are investigating the effects of common psoriasis therapeutics on key neutrophil functions, in particular neutrophil extracellular trap formation, polarization/chemotaxis, and apoptosis, using in vitro and ex vivo approaches. In parallel, we are clinically characterizing leucocyte dynamics in psoriasis patients under medical treatment and correlating these dynamics to clinical response.
Funding: Department funds
Staff: J. Hoffmann, research fellow, S. Martinache, BTA, B. Heckmann, BTA
Huter EN, Natarajan K, Torgerson T, Glass DD and Shevach EM. Autoantibodies in Scurfy mice and IPEX patients recognize Keratin 14. J. Invest. Dermatol. 2010; 130:1391-9.
Huter EN, Stummvoll GH, DiPaolo RJ, Glass DD, Shevach EM. Cutting Edge: Antigen-specific TGFb-induced Regulatory T cells Suppress Th17-Mediated Autoimmune Disease. Int. Immunopharmacol. 2009; 9:540-45.
Huter EN, Stummvoll GH, DiPaolo RJ, Glass DD, Shevach EM. Cutting Edge: Antigen-specific TGFb-induced Regulatory T cells Suppress Th17-Mediated Autoimmune Disease. J. Immunol. 2008; 181:8209-13.
Huter EN, Punkosdy GA, Glass DD, Cheng LI, Ward JM, Shevach EM. TGF-beta-induced Foxp3+ regulatory T cells rescue scurfy mice. Eur. J. Immunol. 2008; 38:1814-21.