glycoimmunology - novel insights into immunodeficiency ......stephan von gunten, md, phd, mme...

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