Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Rupp, J.
Th1 cells in human diseases
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 76
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Reinisch Andreas
- Stradner Martin Helmut
- Altmetrics:
- Abstract:
- T-helper 1 (Th1) cells play a major role in human health and are implicated in different diseases. Here we focused on an infectious disease (coronavirus disease 2019, COVID-19) and an autoimmune disease (rheumatoid arthritis, RA). The approach of this study was to: I) identify T cell responses, in patients with acute COVID-19 and II) improve our understanding of how arthritis is initiated, the implication of Th1 cells, and to identify the arthritogenic immune cells by using a novel humanized mouse model of RA. Th1 belong together with CD8+ T cell to the antiviral subsets. Furthermore, it has been shown that prominent Th1 responses lead to viral clearance and are linked to good prognosis. Using multicolor flow cytometry, we profiled the T cell composition including markers for activation and proliferation. Comparing hospitalized COVID-19 patients to healthy controls, we see significant changes in the T cell distribution but also activation and proliferation. These alterations might be modulated by IL-6 levels in the plasma, which may impair viral clearance by blunting the antiviral T cell responses. In RA Th1 belong together with Th17 and regulatory T cells (Tregs) to the key subsets. However, the exact pathogenic pathway for developing this incurable and painful disease and how arthritogenic T cells trigger it is still elusive. HLA class II genes however, such as HLA-DRB1*0401 (HLA-DR4), confer the strongest genetic risk and suggest involvement of CD4+ T cells. Existing mouse models mimic specific aspects of the disease but do not fully recapitulate the human immune system. Thereby current research is limited and would profit from a humanized mouse (hu-mice) model. We aimed to identify arthritogenic cells by transferring HLA-DR4+ peripheral blood mononuclear cells (PBMC) of RA patients to immunodeficient NSG-DR4 mice. Thereby generating a novel mouse model with inflammatory joint disease, only triggered by the transfer of human immune cells. Human engraftment assessed using multicolor flow cytometry. Development of RA was monitored by examination of the joints, followed by micro computed tomography analysis and histology. Here, we show that DR4+ T cells of the peripheral blood of RA patients are capable of inducing an RA-like disease in NSG-DR4 mice. These mice recapitulate different hallmarks of the disease including immune cell infiltration, pannus formation, increased osteoclastogenesis, cartilage damage, and bone erosions. Th1 cells, dominated the human immune cell composition in hu-mice, while Tregs were diminished compared to donor PBMC composition. Based on our data we suggest that arthritogenic cells, found in the peripheral blood of RA patients, are capable of inducing an RA-like disease in NSG-DR4 mice.