The Miguel Stadecker Lab

Research Publications Immunology

 

Schistosomiasis - Immune Response & Immunopathology

Our laboratory studies the host immune response and immunopathology associated with schistosomiasis, a serious potentially fatal parasitic disease currently afflicting more than 200 million people in tropical regions of the world. Schistosomiasis is contracted by exposure to bodies of fresh water contaminated with parasitic helminths of the genus Schistosoma. The immunopathology in schistosomiasis consists of granulomatous and fibrosing inflammation against tissue-lodged parasite eggs. Our goal is to gain a better understanding of the cellular and molecular mechanisms that drive the immunopathological host response.

The intensity of egg-induced immunopathology is determined by the predominance of a net pro- vs. anti-inflammatory host cytokine environment orchestrated by CD4 T cells specific for schistosome egg antigens. We found that the novel subset of CD4 T cells producing interleukin (IL)-17 (Th17 cells) is a major force that drives severe inflammation. Current efforts are directed at determining the mechanisms responsible for the preferential development of Th17 cells in certain mouse strains, such as CBA, which are genetically prone to high pathology. These studies focus on analyzing live parasite egg interactions with dendritic cells (DCs) that prime and activate the pathogenic Th17 cells (Figure 1).

We discovered that DCs from high-pathology CBA mice express strikingly higher levels of the C-type lectin receptor (CLR) CD209a (SIGNR5), a murine homologue of human CD209 (DC-SIGN), in comparison with low-pathology BL/6 mice. Recent studies have shown that egg-stimulated DCs from CBA mice lacking CD209a produce markedly lower levels of the proinflammatory cytokines IL-1β and IL-23 and fail to activate pathogenic Th17 cells. The result is a marked reduction in egg-induced granulomatous inflammation in vivo to levels typically seen in BL/6 mice. (Figure 1).

Stadecker Fig 1 

Figure 1. Schistosome egg-induced immunopathology. Upper panels: Macroscopic and histologic depiction of granulomatous lesions around parasite eggs in livers from 7 week-infected mice. Left, large egg granulomas as seen in CBA mice; right, small granulomas as seen in BL/6 mice. Lower panels: Immune cell and cytokine profiles in 7 week schistosome-infected mice. Left: Egg-stimulated, CD209a-expressing antigen-presenting cells (APCs) generate a strong proinflammatory cytokine milieu resulting in the activation of mainly proinflammatory T cell subsets that mediate severe immunopathology. Right: Egg-stimulated APCs, devoid of CD209a, generate a largely anti-inflammatory cytokine milieu resulting in the activation of anti-inflammatory and regulatory T (T reg) cells and mild immunopathology. DC I: type I or classically activated dendritic cell; DC II: type II or alternatively activated dendritic cell; M I: type I or classically activated macrophage; M II: type II or alternatively activated macrophage. Others: other APCs including granulocytes, B cells and innate lymphoid cells. PRRs: pattern recognition receptors.

Mechanistically, CD209a synergizes with the related CLRs Dectin-2 and Mincle to attain maximal proinflammatory effect. CD209a activates a pathway involving the serine and threonine kinase Raf-1, whereas Dectin-2 and Mincle signal via the spleen tyrosine kinase (Syk). These findings demonstrate that CLR crosstalk results in marked enhancement of immunopathology induced by a helminth pathogen.

Additional focus in the lab is directed at identifying the sensitizing egg antigens/glycans, and further determining the genetic base of disease heterogeneity. We aim to investigate the innate and adaptive immunopathogenic mechanisms operating in genetically diverse host populations that develop dissimilar forms of schistosomiasis with the purpose of identifying means to prevent and/or ameliorate severe disease. Our research has strong connections with, and obvious implications for global health, as elevated Th17 cell responses are also associated with pathology in the human disease.

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December 1: Basic Science Division PhD Programs

February 15: Building Diversity in Biomedical Sciences

March 31: Post-Baccalaureate Research Program

May 1: Clinical & Translational Science, MS in Pharmacology & Drug Development

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