Th17 cells have been implicated in the pathogenesis of numerous inflammatory and autoimmune conditions. At the ocular surface, Th17 cells have been identified as key effector cells in chronic... Show moreTh17 cells have been implicated in the pathogenesis of numerous inflammatory and autoimmune conditions. At the ocular surface, Th17 cells have been identified as key effector cells in chronic ocular surface disease. Evidence from murine studies indicates that following differentiation and expansion, Th17 cells migrate from the lymphoid tissues to the eye, where they release inflammatory cytokines including, but not limited to, their hallmark cytokine IL-17A. As the acute phase subsides, a population of long-lived memory Th17 cells persist, which predispose hosts both to chronic inflammation and severe exacerbations of disease; of great interest is the small subset of Th17/1 cells that secrete both IL-17A and IFN-gamma in acute-on-chronic disease exacerbation. Over the past decade, substantial progress has been made in deciphering how Th17 cells interact with the immune and neuroimmune pathways that mediate chronic ocular surface disease. Here, we review (i) the evidence for Th17 immunity in chronic ocular surface disease, (ii) regulatory mechanisms that constrain the Th17 immune response, and (iii) novel therapeutic strategies targeting Th17 cells. Show less
Background: Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of... Show moreBackground: Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.Objective: We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants.Methods: Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns.Results: Different adjuvants induce distinct IgG(+) GC B-cell responses with specific transcriptomes and expression levels of the alpha 2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3(-) follicular helper T (TFH) cell-inducing cytokine IL-6, here in particular induced by water-inoil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor-dependent IFN-gamma(+) TFH1 cells, IL-6/IL-23-dependent IL-17A(+) T-FH17 cells, and high ratios of TFH cells to Foxp31 follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor.Conclusion: This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC. Show less
This thesis provides novel insights into the role of IL-17 and Th17 cells in cervical cancer. While IL-17 was shown to be predominantly produced by innate myeloid cells such as neutrophils and... Show moreThis thesis provides novel insights into the role of IL-17 and Th17 cells in cervical cancer. While IL-17 was shown to be predominantly produced by innate myeloid cells such as neutrophils and correlated with poor survival, Th17 cells were generally a small cell population correlated with improved survival. Since IL-6 and IL-23 were also found to be strongly correlated with poor survival, we hypothesize that these cytokines may induce IL-17 production by myeloid cells. Th17 cells may counteract this pro-inflammatory response characterized by IL-6 and IL-17. The IL-6/IL-17 response was correlated with the absence of vaso-invasion. The immune responses described are tissue and context dependent, as indicated by the predominant correlation between Tregs and improved survival in cervical adenocarcinoma. In addition to innate and T lymphocytes responses, B lymphocytes may also play an important role in cervical cancer. Few studies have investigated this cell type. We found that B cells expressing TCL1A are strongly correlated with improved survival in squamous cervical cancer. These novel data will, together with the proposed future studies, provide a better understanding of the immune response in cervical cancer. This will advance our knowledge in cancer evolution, diagnostics, prognostics and therapeutics. Show less
