The Role of Innate Immunity in Orchestrating Th17 Cell Pathogenesis in Severe Schistosomiasis.
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 ... read moreTh2-polarized 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-1β 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-1β and IL-23 production as well as subsequent
differentiation of Rorγt+ 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-1β production in
response to eggs. These findings reveal a novel role for CD209a in mediating pathogenic
proinflammatory Th17 cytokine responses in helminthic
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