glycoimmunology - novel insights into immunodeficiency ......stephan von gunten, md, phd, mme...
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Stephan von Gunten, MD, PhD, MMEInstitute of Pharmacology, University of Bern,
Bern, Switzerland
Clinical Immunology Course, Feb 22, 2018
Glycoimmunology - novel insights into immunodeficiency, autoimmune disease and cancer
von Gunten S et al.Nat Rev Immunol
2014
SiglecsImmuno-globulins
GlycomicsRESEARCH INTERESTSsvg
2005Blood
2009Shock
2009JACI
2007JACI
2008JACI
2006Blood
2003JACI
2012Glycobiology
2011Ann Rheum Dis
2011Allergy
2011PLoS One2012
Patent
2012Patent
2014J Clin Invest
2014Nat Chem Biol
2014J Immunol
2015Sci Transl Med
2015J Neuroinflammation
2015Mol Med
2017Sci Rep
Monosaccharide
Modified from Essentials of Glycobiology. 2nd edition.2009.
In vertebrates:Glucose, GlcNAc, Galactose, GalNAc,Mannose, Xylose, Glucuronic acid, Fucose, Sialic acid
Disaccharide 1
16
4
Complex carbohydrate
Glycoscience - History
1902 1937
W.N. HaworthH.E. Fischer
Fischer-Projection Haworth-Projection
Glucose
Nobel prize
Glykane, Glykoproteine und -lipide von Säugetieren
Varki A, Nature 2007
Sialinsäure(Neuraminsäure)
Glycoscience - History
L.F. LeloirGlycan biosynthesis
K. LandsteinerBlood groups
Carl and Gerty Cori Glycogen
1902
1930
1937
1947
1970
W.N. HaworthGlycochemistry
H.E. FischerGlycochemistry
Glycocalix: diversity
North SJ, von Gunten S et al. Glycobiology 2011
Basophils
Eosinophils
Mast cells
Fuster MM & Esko JD, Nat Rev Cancer 2005
Tumor biology:
Multifaceted role of sugar structures
Boligan KF et al. Cell Mol Life Sci, 2015
Tumor surface glycosylation
Sialinsäure
Role of sialic acid in recognition of «self» (molecular mimicry)
de novo synthesis(e.g. meningococci)
donor scavenging(e.g. gonococci)
precursorscavenging(e.g. H. influenzae)
trans-sialidasemechanism(e.g. trypanosomes)
Vimr E, Lichtensteiger C. Trends Microbiol 2002
3-Methylcholanthrene (MCA)-induced fibrosarcoma
Cohen M et al. J Immunol 2010
Sialic acids promote tumor progression and metastasis
B16F10 melanoma cells
Biochim Biophys Acta. 2014 Sweet escape: sialic acids in tumor immune evasion.Büll C1, den Brok MH1, Adema GJ2.
Büll C et al. Mol Cancer Ther 2013
Deciphering the glycan code
Läubli H & Borsig L, Sem Cancer Biol 2010Rabinovich GA & Croci DO, Immunity 2012
Selectins
Boligan KF et al. Cell Mol Life Sci, 2015
Glycan code
Sensor system (lectins,…)
Siglecs
Sialic acid-binding immunoglobulin-like lectins (Siglecs)
Jandus C et al. Biochem Pharmacol 2011 (modified)
Immunoreceptor tyrosine-based inhibition motif (ITIM)
Siglecs: Expression on immune cells
Illustration by Aldona von GuntenJandus C et al. Biochem Pharmacol 2011
von Gunten S et al.Nat Rev Immunol
2014
SiglecsImmuno-globulins
GlycomicsRESEARCH INTERESTSsvg
2005Blood
2009Shock 2009
JACI
2007JACI
2008JACI
2006Blood
2003JACI
2012Glycobiology
2011Ann Rheum Dis
2011Allergy
2011PLoS One2012
Patent
2012Patent
2014J Clin Invest
2014Nat Chem Biol
2014J Immunol
2015Sci Transl Med
2015J Neuroinflammation
2015Mol Med
Cancer Immunotherapy
Galluzi L et al. Oncotarget 2014
ANTIBODY CLASS SWITCHING RELIES ON T CELLS
Abbas AK et al. Cellular and Molecular Immunology,8th edition, Elsevier Saunders
T CELL INDEPENDENT
CONCEPTS ON CARBOHYDRATE-SPECIFIC ANTIBODIES
Gordon A N Engl J Med 2001
«Generally speaking, carbohydrates are classified as T-cell independent antigens…,
the inability of most carbohydrate antigens to recruit T-cell help results in a B-cell response lacking affinity maturation and weighted toward the production of IgM and IgG2 in human…»
Haji-Ghassemi O et al. Glycobiology 2015
MENINGOCOCCUS VACCINATION
Li S et al. Nat Immunol 2014
>25 yrs (USA)
MPSV4 = 4 PS(carbohydrate)
2005
MCV4 = 4 PS + diphteria toxoid
(conjugate)
CONCEPTS ON GLYCAN-SPECIFIC ANTIBODIES: CARBOHYDRATE-SPECIFIC T-CELLS
III (type III polysacch. group B Streptoc.:GBSIII)Carrier proteins: OVA, TT, HEL
CD4+T cells, spleen, BALB/c mice
Avci FY et al. Nat Med 2011
Antibody repertoire: glycan immunogenicity linked to structure
Schneider et al. Sci Transl Med 2015
Carbohydrate-based vaccines in development
Astronomo RD & Burton DRNat Rev Drug Discov 2016(modified)
Can
cer
Infe
ctio
us d
isea
se
Decreased CD56dimSiglec-9+ NK cell subset in peripheral blood of cancer patients
Jandus C & Boligan KF et al. J Clin Invest. 2014
Green: Melan-ARed: Siglec-7 ligands
Tissue section: Siglec-7 Ligands in melanomaFlow cytometry: Siglec-7 and -9 ligands on cell lines
Jandus C & Boligan KF et al. J Clin Invest. 2014
Siglec-7/-9 Ligand expression on tumor cells
Siglec-7/-9 Ligand expression on leukemia cells in patient peripheral blood
Jandus C & Boligan KF et al. J Clin Invest. 2014
The sialoglycan shield
Jandus C & Boligan KF et al. J Clin Invest. 2014
Desialylation of target cells enhances NK cell antitumor activities
Jandus C & Boligan KF et al. J Clin Invest. 2014
Degranulation Cytokine production
Siglec-7/-9 Ligand expression on tumor surface
Jandus C & Boligan KF et al. J Clin Invest. 2014
Hudak JE et al., Nat Chem Biol, 2014(modified)
(+ Siglec-7 ligand)
Davis DM. Trends Immunol 2002 (modified)
Adhesion Molecularreorganization
Mature IS
Supramolecular activation cluster (SMAC):
Central SMAC (cSMAC): signaling, secretionPeripheral SMAC (pSMAC): integrins
The immunological synapse (IS)
Berrien-Elliott et al. 2015
Illustration by Aldona von Gunten
Illustration by Aldona von Gunten
Natural killer (NK) cells
Cytotoxic T cells
Antibodies
Harvard Medical School, MA, USARichard D. Cummings
The Johns Hopkins University, MD, USARobert G. Hamilton
The Scripps Research Institute, CA, USAJim Paulson
Emory University, GA, USADavid Smith
Northwestern University, IL, USABruce S. Bochner
University of California San Diego, USAJane C. Burns
Russian Academy of Sciences Nicolai Bovin
Bulgarian Academy of SciencesAnastas PashovTchavdar Vassilev
Center of Molecular Immunology, CubaCirce Mesa
INSERM, Paris, FJagadeesh BayrySrini Kaveri
University of Cologne, GHinrich Abken
University of Freiburg, GBodo Grimbacher
von Gunten LaboratoryDenise Dorvignit PedrosoKayluz Frias BoliganMarc ZürcherMirela KremenovicOlivia Joan AdamsStefanie GräterQuentin Haas
Camilla JandusChristoph SchneiderFabiola SchorerMarc WehrliTankica Maneva TimchevaThomas Demoulins
Ariane MeisterAymar GanguinMelanie SchererChristine GallaszFabienne MoretJonathan EastlineKatarina FuchsMichael EastlineMuriel OttNadja SchneiderRebecca SträssleSarah LutzSinuhe NussbaumTobias Horn
University of Bern/Inselspital CHHans-Uwe Simon
Anne Angelillo-ScherrerDagmar SimonFabian BlankGabriela BärlocherLucy HathawayPeter JandusPeter VilligerRobert RiebenThomas KaufmannThomas HungerValentin Djonov
Inst Virology and Immunol (IVI), CHArtur SummerfieldKenneth C McCullough
University of Basel, CHHeinz Läubli
Hospital of Fribourg, CHUlf Kessler
University of Zurich, CHChristian MünzJan Lünemann
Ludwig Inst Cancer Res, Lausanne, CH Pedro Romero
Imperial College London, UKStuart M. Haslam