The Role of Innate Immunity in Orchestrating Th17 Cell Pathogenesis in Severe Schistosomiasis.
Ponichtera, Holly.
2014
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Abstract: In murine Schistosoma mansoni infection, the magnitude of immunopathology and proinflammatory cytokine production in response to live schistosome eggs is strain dependent. Whereas infected CBA mice develop severe disease characterized by hepatic egg-induced granulomatous inflammation that is associated with prominent Th17 and Th1 cytokine responses, milder lesions develop in the Th2-pola... read morerized cytokine environment of infected BL/6 mice. The initiation of pathogenic Th17 cell differentiation in CBA mice is largely dependent on dendritic cell (DC) production of IL-1 and IL-23 following stimulation with schistosome eggs; by contrast, low-pathology BL/6 mice fail to mount this proinflammatory cytokine pathway. While the preconditions necessary for the generation of Th17 cells induced by CBA DCs have been elucidated, the reasons for strain-dependent differences in antigen (Ag) presenting cell (APC) reactivity to live eggs are not well understood. Genome-wide genetic profiling disclosed dramatic differences in the expression of C-type lectin receptors (CLRs) by CBA and BL/6 bone marrow derived DCs (BMDCs). CLRs are a family of pattern recognition receptors (PRRs) that specifically bind carbohydrate Ags such as the fucose-containing glycans that are abundantly secreted by live schistosome eggs. Marked elevation of CD209a, a murine homologue of the well characterized human CLR DC-specific ICAM-3-grabbing non- integrin (DC-SIGN), was detected in infected CBA tissues including liver, spleen, and granuloma cells by means of quantitative real-time PCR (qRT-PCR), flow cytometric analysis, and immunohistochemistry. Functional assessment of CD209a-expressing APC subsets determined that CBA DCs, but not macrophages, B cells, or neutrophils, elicit Th17 cell differentiation in response to eggs. Additionally, inhibition of Th17 cell induction by CBA DCs pre-treated with mannose prior to egg stimulation suggested lectin-dependency. Further gene silencing in CBA DCs and over-expression in BL/6 DCs, demonstrated that CD209a is essential for IL-1 and IL-23 production as well as subsequent differentiation of Rort+ Th17 cells. Signaling analysis revealed that DC CD209a expression was associated with SRC, RAF-1, and ERK1/2 activation; importantly, CD209a expression was necessary for ERK1/2-dependent IL-23 and IL-1 production in response to eggs. These findings reveal a novel role for CD209a in mediating pathogenic proinflammatory Th17 cytokine responses in helminthic disease.
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Immunology.
Advisor: Miguel Stadecker.
Committee: Mercio Perrin, Stephen Bunnell, and Alexander Poltorak.
Keyword: Immunology.read less - ID:
- hq37w0851
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