Transcript Janeway's Immunology

Biophysical Immunology Laboratory
Thomas Vorup-Jensen
Institute for Medical Microbiology and Immunology
University of Aarhus
Denmark
[email protected]
Innate Immunity
Janeway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
Important soluble molecules supporting innate immunity effector
functions
Connection between molecular structure and function in the immune
System
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 in
solution (plasma)
Surface bound
complement factors
Recruitment of inflammatory cells
Conformational
change?
Enhanced
Phagocytosis
(faster clearing!)
Pathogen
Cascade deposition:
positive amplification
loop
Direct killing
by lysis
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”Target-binding” complement proteins are larger than the rest….
…but why?
Tanaka et al. (2010)
35 nm
Vorup-Jensen & Boesen (2011) Adv. Drug Discov. Rev. 63:1008-19
J Infect Chemother 16:383–387
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Innate Immunity
Janeway’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 supporting
to C3 activation
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Innate Immunity
Janeway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
The alternative pathway is activated spontaneous depostion of C3
on cell surface. Failure to down-regulate C3 activation leads to
opsonization of microbes.
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SAXS solution structure of MBL
Trimer of carbohydraterecognitiondomains
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Dong et al. J. Immunol. (2007) 178:3016-22
Atomic Force Microscopy
Mingdong Dong, Sailong Xu & Flemming Besenbacher
iNANO, University of Aarhus
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Constructing a MBL ligand-coated surface suitable for AFM
Mannose-amine immobilized on mica through coordinat
Mineral (mica) structure
O
NH3
O
NH3
O
NH3
SiO3-
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AFM imaging of rhMBL(I) on a mannosamine-coated surface
in liquid
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Dong et al. J. Immunol. (2007) 178:3016-22
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1,000 RU  1 ng protein/mm2
0.005 mcBSA molecules/mm2
SI = 600 RU
BSA
BSA
0.013 mcBSA molecules/mm2
SI = 1600 RU
BSA
BSA
BSA
0.033 mcBSA molecules/mm2
SI = 4000 RU
BSA
BSA
BSA
BSA
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Surface density of ligands
change MBL binding
kinetics
60 nm
d ~ 14 nm
d ~ 9 nm
d ~ 6 nm
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K  10-10 M and k  10-6 s-1
Organization of the cell wall of S. aureus:
a nm-scaled pattern?
50 nm
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Touhami A et al. (2004) J. Bacteriol. 186: 3286–3295.
Induced deficiency
in neutrophils
Primary
immunodeficiency
in the innate immune
system
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Innate Immunity
Janeway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
The lytic pathway may serve to from pores in target membranes. The
pore formation will eventually leads to cellular lysis.
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Time
(adaptive immunity)
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Innate Immunity
Janeway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
The complement system is an important mediator of cross-talk between
innate and adaptive immunity by mediating antigen uptake.
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iC3b is ”inactive” with regard to C3 conversion but may45bind
Complement 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)
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trialx.com
Innate Immunity
Janeway’s Immunobiology Chapter 2&3
Lecture II:(mainly) Soluble (humoral) factors
Important messages:
Failure to control complement activation leads to significant
health problems
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Innate Immunity
Janeway’s Immunobiology Chapter 2&3
Lectures I & II
Important messages:
Important soluble molecules supporting innate immunity effector
Functions
Cytokines & complement
Connection between molecular structure and function in the immune
system
Pattern recognition, conformational changes in MBL
Connection between cellular and humoral innate immunity
Opsonization facilitates antigen presentation to lymphocytes
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