Immunology Graduate Group

Edward J. Pearce, Ph.D.
Professor, Department of Pathobiology, School of Veterinary Medicine

Address: 318 Hill Pavilion
Office Phone: (215) 573-3493
Lab Phone: (215) 898-3545
Fax: (215) 746-2295
Email: ejpearce@mail.med.upenn.edu

Education

BSc  University of Wales, Aberystwyth , UK

PhD  National Institute of Medical Research/Brunel University, London, UK

Postdoctoral training: National Institutes of Health, Bethesda, USA

Current Laboratory Members

Connie Krawczyk, PhD

Tori Freitas, PhD

Fraser Marshall, PhD

Justin Taylor, Immunology Graduate Group Student

EuiHye Jung, Technical Support

Research Interests

Immune responses during infection

The biology of dendritic cells

The biology of parasites, with emphasis on helminths

Key Words

dendritic cells; gene regulation; helminth parasite; Th1/Th2; cytokines; protein kinases/phosphatases

 

Description of Research

Our research is focused on the immune response of the host to infection with the parasitic worm Schistosoma mansoni, and on the influence of the immune response on the biology of this pathogen.

Schistosomes are complex metazoan pathogens that infect hundreds of millions of people in developing countries, causing the neglected disease schistosomiasis. Disease develops by virtue of the fact that the eggs that schistosomes produce, which are intended for release from the host in order to allow transmission of infection, become trapped in target organs such as the liver, where they induce immune-mediated pathologic changes.

The laboratory is engaged in three lines of research:

The regulation of immune responses during chronic infection:

Schistosomes are long lived, causing chronic infections in their natural human and experimental mouse hosts.  As with other helminth infections, schistosomiasis is associated with the development of a strong Th2 response, which serves a crucial host-protective function as illustrated by the fact that IL-4 is required for mice to survive the acute phase of infection.  Ironically, the serious pathologic changes that develop during chronic infection are also due to the Th2 response, being primarily the result of the profibrotic properties of the Th2 cytokine IL-13.  It has been long-recognized that during schistosomiasis the parasite-induced Th cell response, as measured by in vitro antigen-stimulated T cell proliferation or cytokine secretion assays, peaks early and then declines despite ongoing infection, a process that is referred to as immunomodulation. The size of granulomatous lesions around parasite eggs trapped in host tissues mirrors the rise and fall of the Th response.  Immunomodulation in schistosomiasis appears to play a vital role in minimizing immunopathology in a setting where the immune system is incapable of eliminating the pathogen. We are engaged in studies to explore the underlying basis and functional significance of the diminished Th2 responses that characterize chronic schistosomiasis. We hypothesize that chronic schistosome infection leads to a state of Th2 cell dysfunction. We are investigating this using 4get IL-4 reporter mice, in which cells which can make IL-4 make GFP and thus can be monitored using flow cytometry and fluorescence microscopy.  These mice allow the detailed tracking of Th2 cells throughout infection. We are interested in whether Th2 cells from chronically infected mice are irreversibly dysfunctional or whether ongoing environmental signals are required to maintain them in this state. We are hopeful that these studies will generate new insights into the processes that allow the regulation of Th2 responses during chronic schistosomiasis. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses. 

The role of dendritic cells in the recognition of pathogens and the induction of the adaptive immune response.

It has become clear over the past decade that dendritic cells (DCs) play a pivotal role in providing the cues that determine the effector function bias of CD4 T cell responses.  The crucial element that shapes DC plasticity in this regard is now recognized to be the nature of the ‘conditioning’ information imparted by the particular pathogen that the DCs encounter.  The molecular basis of conditioning is best understood from studies of the maturation of DCs exposed to defined Toll like receptor (TLR) ligands, such as LPS, or CpG, which are components of organisms that usually induce Th1-like immune responses.  The Th1-biased nature of the data that has been used to construct the current model of DC maturation raised the obvious question of whether DCs are activated and function in a similar way in Th2-dominated settings. Experimental work using the mouse model of schistosomiasis has revealed that it is the egg stage of the parasite that is responsible for inducing the Th2 response that dominates during infection. Knowing this, we have focused on the interaction of egg molecules (“SEA” – soluble egg antigens) with DCs, and, as a counterpoint, compared the responses of DCs to Th1-inducing pathogens with known TLR-stimulatory properties (for example, the Gram+ bacterium Propionebacterium acnes (Pa)), or to molecules from these pathogens (for example LPS or CpG). We have made several significant findings: 1) SEA does not, in any conventional sense, stimulate DC maturation; 2) SEA-pulsed DCs are able to induce Th responses when injected into mice, and these responses are highly Th2-polarized; 3) SEA contains a potent inhibitor of TLR-initiated DC maturation; 4) DCs stimulated by TLRs inhibit Th2 cell development. 

In ongoing research in this project we are particularly interested in: 1) why SEA is such a strong Th2 antigen, and 2)  how different types of pathogens regulate expression of Notch ligands by DCs, and the effects of these events on DC biology and subsequent immune response development.

The long-term goal of our studies is to elucidate how DCs interpret pathogen-inherent signals to promote different types of effector Th cell response development, with a particular emphasis on understanding how schistosomiasis leads to the development of a Th2 response.  We believe that our work has distinct medical relevance, with the potential to facilitate the discovery of: 1) new schistosome-derived anti-inflammatory molecules; 2) methods to regulate Th2-mediated immunopathologies, and 3) rational prophylactic and therapeutic vaccine-relevant methods for deliberately polarizing Th responses in particular directions.

The molecular cell biology of schistosomes.

Little is known of the molecular basis of cell to cell communication in schistosomes, but targeted studies and genome sequencing efforts have revealed that, not surprisingly, these organisms contain some of the intercellular signaling systems that are found in higher order metazoa.  Amongst these, we are particularly interested in the transforming growth factor b (TGFb) pathways.  In1998 we discovered that S. masoni expresses a type 1 TGFb receptor (SmRK1; SmTbR1), and since that time we and others have identified in schistosomes many of the core components of the consensus TGFb signaling pathway.  However, the role of TGFb signaling in schistosomes remains to be defined and elucidating the role(s) of the pathway in schistosome biology is a major goal of the laboratory.  Central to our view of what the TGFb pathway might be doing in schistosomes has been our failure to identify a gene for a TGFb ligand in these organisms, which led us to hypothesize that the TGFb signaling pathway in schistosomes evolved to receive signals from host TGFb ligands, a concept that was given credence by findings that schistosome TGFb receptors can respond to human TGFb ligands.  Recently however, we made a breakthrough by identifying a schistosome TGFb family members, SmInAct,

We have found that the protein encoded by SmInAct is made only when females are paired with males in an immunologically competent setting. This is intriguing because egg production by female schistosomes is critically dependent on the presence of male parasites, without which females never fully develop, and (counterintuitively) on the contribution of signals from the host’s immune system. 

Using recently developed RNAi tools that allow gene function to be inhibited in schistosomes, we have been able to show that SmInAct plays a crucial role in egg development. We are currently examining how the expression of this gene is controlled since understanding this process has the potential to provide insight into the molecular nature of the interactions between male and female parasites and their hosts.  Moreover, the pivotal role of this gene in the egg makes it a potential target for blocking transmission and disease development.

Recent Publications

Sher A, Pearce EJ, Kaye, P.
Shaping the immune response to parasites: role of dendritic cells.
Curr Op Immunol. 2003 15:421-29.

Pearce EJ.
Progress towards a vaccine for schistosomiasis.
Acta Trop. 2003 May;86(2-3):309-13.

Straw AD, MacDonald AS, Denkers EY, Pearce EJ.
CD154 plays a central role in regulating dendritic cell activation during infections that induce Th1 or Th2 responses.
J Immunol. 2003 Jan 15;170(2):727-34.

La Flamme AC, MacDonald AS, Huxtable CR, Carroll M, Pearce EJ.
Lack of C3 affects Th2 response development and the sequelae of chemotherapy in schistosomiasis.
J Immunol. 2003 Jan 1;170(1):470-6.

Pearce EJ, MacDonald AS.
The immunobiology of schistosomiasis.
Nat Rev Immunol. 2002 Jul;2(7):499-511. Review.

MacDonald AS, Patton EA, La Flamme AC, Araujo MI, Huxtable CR, Bauman B, Pearce EJ.
Impaired Th2 development and increased mortality during Schistosoma mansoni infection in the absence of CD40/CD154 interaction.
J Immunol. 2002 May 1;168(9):4643-9.

MacDonald AS, Pearce EJ.
Cutting edge: polarized Th cell response induction by transferred antigen-pulsed dendritic cells is dependent on IL-4 or IL-12 production by recipient cells.
J Immunol. 2002 Apr 1;168(7):3127-30.

Beall MJ, Pearce EJ.
Transforming growth factor-beta and insulin-like signalling pathways in parasitic helminths.
Int J Parasitol. 2002 Apr;32(4):399-404. Review.

MacDonald AS, Araujo MI, Pearce EJ.
Immunology of parasitic helminth infections.
Infect Immun. 2002 Feb;70(2):427-33. Review. No abstract available.

MacDonald AS, Straw AD, Dalton NM, Pearce EJ.
Cutting edge: Th2 response induction by dendritic cells: a role for CD40.
J Immunol. 2002 Jan 15;168(2):537-40.

de Jesus AR, Silva A, Santana LB, Magalhaes A, de Jesus AA, de Almeida RP, Rego MA, Burattini MN, Pearce EJ, Carvalho EM.
Clinical and immunologic evaluation of 31 patients with acute schistosomiasis mansoni.
J Infect Dis. 2002 Jan 1;185(1):98-105.

Patton EA, La Flamme AC, Pedras-Vasoncelos JA, Pearce EJ.
Central role for interleukin-4 in regulating nitric oxide-mediated inhibition of T-cell proliferation and gamma interferon production in schistosomiasis.
Infect Immun. 2002 Jan;70(1):177-84.

 

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