Immunological Profiling of Thymectomy Tissues in Myasthenia Gravis: The Role of Th17-Related Molecules and Follicular T Helper Cells
Doruk Arslan1, Utku Horzum2, Zeynep Ergul-Ulger1, Hamdullah Yanik2, Sakine Ulusoy2, Suleyman Ozturk2, Can Ebru Bekircan-Kurt1, Mustafa Yilmaz3, Sevim Erdem-Ozdamar1, Gunes Esendagli2, Ersin Tan1
1Hacettepe University, Department of Neurology, 2Hacettepe University Cancer Institute, Department of Basic Oncology, 3Hacettepe University, Department of Cardiovascular Surgery
Objective:
To determine the immunological profile of thymus of myasthenia gravis (MG) patients, focusing on the role of Th17-related molecules and follicular T helper (Tfh) cells.
Background:
Thymus plays an important role in shaping T-cell responses and MG have altered T-cell populations. Thymectomy may potentially lead to clinical improvement by modulating Tfh and Th17 activity.
Design/Methods:
Thymus tissues from MG patients and healthy donors were dissected into small pieces and enzymatically digested to single cell suspensions. Multicolor flow cytometric immunophenotyping and immunofluorescence analysis was performed. After in vitro stimulation of thymocytes purified according to CD4 and CD8 expression, ELISA arrays and proliferation assays were conducted.
Results:
Thymectomy materials obtained from MG patients had almost as many CD4+CD8+ double-positive TCRαβ+ T lymphocytes as in healthy thymus. Compared to healthy thymus tissue, CD4+CD8+ T cells of MG patients expressed higher levels of CD3, CXCR5, CD28, PD-1, TIM-3, LAG3, CD40L and IL4RA markers (p<0.05). A similar pattern was observed in CD4+CD8- and CD4-CD8+ T lymphocytes. Besides, higher levels of BCL6, STAT3 and STAT5 transcript levels were detected in MG compared to normal thymus tissues (p<0.05). However, FOXP3, RORC2 and GATA3 gene expression levels were relatively decreased in MG (p<0.05). CD4+CD8- T cells of MG patients produced primarily IFN-γ, IL-22, TNF-α, IL-21 and IL-10. CD4+CD8+ T cells secreted high levels of IL-2. Lastly, PD-1+CXCR5+ Tfh cell population was higher in MG thymus (p<0.05).
Conclusions:
Th17 cells (through STAT3 activation and IL-22 production) may contribute to the inflammatory environment of MG. In addition, Tfh cells (marked by BCL6, PD-1+CXCR5+ Tfh cells and IL-21) seems to play a key role in the production of pathogenic anti-AChR antibodies. Thus, Treg deficiency (decreased FOXP3) and elevated immune checkpoint markers contribute to the immunopathogenesis of MG.
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