Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke.
BACKGROUND
The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans.


RESULTS
Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes.


CONCLUSIONS
In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.
Comprehensive Stroke Center, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Medical School, University of Barcelona, Barcelona, Spain.
Alvaro
A
Cervera
Anna M
AM
Planas
Carles
C
Justicia
Xabier
X
Urra
Jens C
JC
Jensenius
Ferran
F
Torres
Francisco
F
Lozano
Angel
A
Chamorro
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D003176:Complement C3 / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D037601:Mannose-Binding Lectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D003176:Complement C3; C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin; D011994:Recombinant Proteins; C105296:MASP2 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases