van Die I, Cummings R. 2009. Glycan gimmickry by parasitic helminths: A strategy for modulating the host immune response? Glycobiology. 20:2-12.
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Glycan Gimmickry by Helminths
Outline
Introduction
Case 1: B. malayi and C. elegans
Case 2: S. mansoni
Conclusion
Introduction
Section Outline
Helminths
Dendritic Cells
Th1 and Th2 Responses
CLRs
Helminth Modulation
Questions and Significance
Helminths
Four billion people infected by parasites.
Helminths are soft-bodied, elongated invertebrate animals.
Helminths are large animals relative to microbes.
Helminths are masters in regulating the immune response.
Most helminths influence the immune system to mount on a Th2 cell response.
“Glycan gimmickry” is a proposed strategy used by parasites to manipulate the immune response.
Dendritic Cells
http://en.wikipedia.org/wiki/File:Antigen_presentation.jpg
Dendritic Cells
http://en.wikipedia.org/wiki/File:Lymphocyte_activation_simple.png
Th1 and Th2 Responses
Th1 response – characterized as pro-inflammatory with the production of cytokines IFN-.
Promotes cellular immune response
Th2 response – characterized as anti-inflammatory with the production of cytokines IL4, IL5, IL10, IL13.
Promotes humoral immune response
Th1 and Th2 Responses
Cytokines are extracellular signal proteins or peptides that act as a local mediators in cell–cell communication.
CLRs
DC-SIGN recognizes the following terminal fucose patterns:
LeX Galβ1-4[Fucα1-3]GlcNAc-
LeY Fucα1-2Galβ1-4[Fucα1-3]GlcNAc-
LDNF GalNAcβ1-4[Fucα1-3]GlcNAc-
MGL recognizes α- or β-linked GalNAc residue patterns:
LDN GalNAcβ1-4GlcNAc-
Tn GalNAcα1-O-Thr/Ser) antigens
MR recognizes patterns containing mannose.
CLRs
(van Die and Cummings 2009)
CLRs
(van Die and Cummings 2009)
Helminth Modulation
Helminths attenuate Th1 responses and induce Th2 and regulatory responses to promote their survival within hosts.
Modulation is somehow related to the expression of certain helminth glycans.
“Glycan gimmickry” is proposed as the strategy helminths employ to promote their survival whereby the expression of certain glycan patterns is actively used to target immune cell lectin receptors to skew the host’s immune response toward less inflammatory reactions.
Helminth Modulation
Glycan gimmickry as an alternative strategy to molecular mimicry as first proposed by Damian (1965).
Glycan gimmickry is thought to be beneficial to the host as well who may otherwise not survive the chronic infection brought about by the strong Th1 immune response.
Questions and Significance
Questions:
What are the underlying mechanisms involved in helminth-induced Th2 responses?
Why has the immune system evolved to tolerate this kind of glycan gimmickry?
Significance
Understanding the mechanisms involved in glycan gimmickry can help further our knowledge of how the immune system functions. This increased knowledge can then be used to develop new drugs to treat or prevent diseases.
Case 1: B. malayi and C. elegans
Section Outline
Introduction
Materials
Results and Discussion
Introduction
Salah T, Laetitia LG, Fahimeda A, Baxter M, Allen J. 2004. Both free-living and parasitic nematodes induce a characteristic Th2 response that is dependent on the presence of intact glycans. Infection and Immunology. 72:398–407.
Brugia malayi is a roundworm nematode that is a causative agent of lymphatic filariasis in humans. Lymphatic filariasis, also known as elephantiasis, is a condition characterized by swelling of the lower limbs.
Caenorhabditis elegans is a free-living, transparent nematode about 1 mm in length, which lives in temperate soil environments. It is used extensively as a model organism in research.
Introduction
The purpose of the study was to test the hypothesis that glycans on B. malayi induce the Th2 response.
Moreover, the study sought to investigate whether such induction may be common to all nematodes including non-parasitic species.
http://en.wikipedia.org/wiki/File:Elephantiasis.jpg
Materials
B. malayi antigen (BmA) or mixed-stage C. elegans antigen (CeA) were prepared by homogenizing each worm population in sterile ice-cold PBS on ice by using a glass-glass homogenizer.
Groups of mice were immunized with a single dose of native CeA or native BmA in CFA (experimental groups) or with PBS in CFA (control group).
Freund's adjuvant is a water in oil emulsion. The so-called complete form (CFA) is composed of inactivated and dried mycobacteria, usually Mycobacterium tuberculosis (the pathogenic agent of tuberculosis).
Materials
BALB/c mice
http://en.wikipedia.org/wiki/File:Lightmatter_lab_mice.jpg
Results and Discussion
Worm antigens caused CD4+ T cells to proliferate and secrete higher levels of IL4.
Results and Discussion
Periodate-treated B. malayi antigens (pBma).
Lane 1 is pBma; Lane 2 is mBma (mock).
Periodate treatment modified glycan structures but maintained protein backbone integrity
Results and Discussion
pBmA and pCeA did not increase IL4 levels as mBmA and mCeA did.
Results and Discussion
IL-4 classically induces sequential switching to immunoglobulin G1 (IgG1) and IgE, whereas IFN- is associated with switching to IgG2a.
Immunization with mBmA increased IgG1 levels.
Case 2: S. mansoni
Section Outline
Introduction
Materials
Results and Discussion
Introduction
van Liempt E, van Vliet SJ, Engering A, Garcia Vallejo JJ, Bank CM, Sanchez-Hernandez M, van Kooyk Y, van Die I. 2007. Schistosoma mansoni soluble egg antigens are internalized by human dendritic cells through multiple C-type lectins and suppress TLR-induced dendritic cell activation. Mol Immunol. 44:2605–2615.
The parasitic helminth Schistosoma mansoni is the causative agent of the chronic disease schistosomiasis, which affects 300 million people worldwide, particularly in tropical countries. The disease is characterized by granulomatous reactions around viable eggs entrapped in host tissues.
Introduction
The early stage of infection with S. mansoni leads to a Th1 response. As the infection progresses and eggs are released by the adult worms, the Th1 response declines and switches towards a Th2 response, driven by the egg antigens.
http://en.wikipedia.org/wiki/File:Schistosomiasis_itch.jpeg
Introduction
The ability of monocyte-derived iDCs pulsed with SEA or copulsed with SEA and TLR-ligands to mature and induce polarized T cell responses was examined.
The interaction of SEA with DC-expressed CLRs was also studied.
Results showed that DC-SIGN, MGL as well as the mannose receptor play a role in binding and subsequent internalization of SEA.
Co-localization of SEA with MHC II in the lysosomal compartments suggests that antigen processing and presentation can occur.
Materials
Lysophosphatidylserine (LPS) – induces Th1/Th2 response via TLR2/4-dependent mechanism.
Polyinosine–deoxycytidylic acid (Poly-I:C) – induces Th1 response via TLR3-dependent mechanism
Results
SEA does not promote DC maturation.
Results
SEA prevents DC maturation caused by LPS or Poly-I:C in a dose-dependent manner.
Results
Cytokine levels are also reduced when SEA is present.
Results
When SEA is added, TH1 response is skewed to TH2.
Results
SEA is internalized and is channeled to the endosomal compartments, then to the lysosomes, and finally to the MHC II molecules.
Conclusion
Conclusion
Helminths are soft-bodied, elongated invertebrate animals that infect about 4 billion people worldwide.
“Glycan gimmickry” is a proposed strategy used by parasites to manipulate the immune response.
Dendritic cells (DCs) are antigen-presenting cells (APCs) that trigger polarization of T-cells.
The Th1 response is pro-inflammatory while the Th2 is anti-inflammatory.
Cytokines are extracellular signals used mediate the type of response elicited.
CLRs are used by DCs to recognize helminth glycans. Some prominent CLRs include DC-SIGN, MGL and MR.
Conclusion
Inflammatory modulation is somehow related to the expression of certain helminth glycans.
Most helminths influence the immune system to mount on a Th2 cell response.
Understanding the mechanisms through which helminths influence the immune system may help us develop new drugs to treat diseases.
Case 1: B. malayi and C. elegans
Glycans in B. malayi and C. elegans induce Th2 response as manifested by the increase in IL4 levels.
Removal of glycans on the worm surfaces removed their capacity to induce the Th2 response.
Conclusion
Case 2: S. mansoni
SEA does not promote DC maturation.
SEA inhibits DC maturation induced by LPS or Poly-I:C.
SEA skews Th1 responses toward more Th2-like responses as evidenced by the shift in cytokine levels from INF- to IL4.
SEA is internalized by DCs and is channeled to the endosomal compartments, then to the lysosomes, and finally to the MHC molecules.
References
Salah T, Laetitia LG, Fahimeda A, Baxter M, Allen J. 2004. Both free-living and parasitic nematodes induce a characteristic Th2 response that is dependent on the presence of intact glycans. Infection and Immunology. 72:398–407.
van Die I, Cummings R. 2009. Glycan gimmickry by parasitic helminths: A strategy for modulating the host immune response? Glycobiology. 20:2-12.
van Liempt E, van Vliet SJ, Engering A, Garcia Vallejo JJ, Bank CM, Sanchez-Hernandez M, van Kooyk Y, van Die I. 2007. Schistosoma mansoni soluble egg antigens are internalized by human dendritic cells through multiple C-type lectins and suppress TLR-induced dendritic cell activation. Mol Immunol. 44:2605–2615.
End
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