Biophysical Immunology Laboratory
Thomas Vorup-JensenInstitute for Medical Microbiology and
ImmunologyUniversity of Aarhus
Innate ImmunityJaneway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
Important soluble molecules supporting innate immunity effectorfunctions
Connection between molecular structure and function in the immuneSystem
Connection between cellular and humoral innate immunity
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The (very) basic order of events in complement activation:three steps to inflammation
Complement factors insolution (plasma) Surface bound
complement factors
Pathogen
Cascade deposition:positive amplificationloop
Conformationalchange?
Recruitment of inflammatory cells
EnhancedPhagocytosis
(faster clearing!)
Direct killingby lysis
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”Target-binding” complement proteins are larger than the rest….
Vorup-Jensen & Boesen (2011) Adv. Drug Discov. Rev. 63:1008-19
35 nm
…but why?
Tanaka et al. (2010)
J Infect Chemother 16:383–387
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Innate ImmunityJaneway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
The classical pathway is activated through antibodies:Major molecular species involved are C1, C2 and C4 supportingto C3 activation
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Innate ImmunityJaneway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
The alternative pathway is activated spontaneous depostion of C3on cell surface. Failure to down-regulate C3 activation leads toopsonization of microbes.
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Dong et al. J. Immunol. (2007) 178:3016-22
SAXS solution structure of MBL
Trimer of carbohydrate-recognitiondomains
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Atomic Force Microscopy
Mingdong Dong, Sailong Xu & Flemming BesenbacheriNANO, University of Aarhus
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Constructing a MBL ligand-coated surface suitable for AFM
Mannose-amine immobilized on mica through coordination bonds
NH3
O
NH3
O
NH3
O
SiO3-
Min
eral
(m
ica)
str
uctu
re
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AFM imaging of rhMBL(I) on a mannosamine-coated surfacein liquid
Dong et al. J. Immunol. (2007) 178:3016-2226
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BSA BSA BSA
BSA BSA BSA
BSA
BSA
BSASI = 600 RU
SI = 1600 RU
SI = 4000 RU
1,000 RU 1 ng protein/mm2
0.005 mcBSA molecules/mm2
0.013 mcBSA molecules/mm2
0.033 mcBSA molecules/mm2
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Surface density of ligandschange MBL bindingkinetics
60 nm
KD 10-10 M and kd 10-6 s-1
d ~ 14 nm
d ~ 9 nm
d ~ 6 nm
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Organization of the cell wall of S. aureus: a nm-scaled pattern?
Touhami A et al. (2004) J. Bacteriol. 186: 3286–3295.
50 nm
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Primary immunodeficiencyin the innate immune system
Induced deficiencyin neutrophils
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Innate ImmunityJaneway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
The lytic pathway may serve to from pores in target membranes. Thepore formation will eventually leads to cellular lysis.
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Time
(adaptive immunity)39
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Innate ImmunityJaneway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
The complement system is an important mediator of cross-talk betweeninnate and adaptive immunity by mediating antigen uptake.
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iC3b is ”inactive” with regard to C3 conversion but may bindComplement receptors 3 & 4
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Hereditary angioedema: lack of C1INH
Treatment: blood transfusion or C1INH protein
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Systemic Lupus Erythematosus (SLE)
trialx.com
Innate ImmunityJaneway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
Failure to control complement activation leads to significanthealth problems
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Innate ImmunityJaneway’s Immunobiology Chapter 2&3
Lectures I & II
Important messages:
Important soluble molecules supporting innate immunity effectorFunctions
Cytokines & complement
Connection between molecular structure and function in the immunesystem
Pattern recognition, conformational changes in MBL
Connection between cellular and humoral innate immunityOpsonization facilitates antigen presentation to lymphocytes
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