title: Complementary Roles of the Classical and Lectin Complement Pathways in the Defense againstAspergillus fumigatus.
abstract: Aspergillus fumigatusinfections are associated with a high mortality rate for immunocompromised patients. The complement system is considered to be important in protection against this fungus, yet the course of activation is unclear. The aim of this study was to unravel the role of the classical, lectin, and alternative pathways under both immunocompetent and immunocompromised conditions to provide a relevant dual-perspective on the response againstA. fumigatus. Conidia (spores) from a clinical isolate ofA. fumigatuswere combined with various human serum types (including serum deficient of various complement components and serum from umbilical cord blood). We also combined this with inhibitors against C1q, mannose-binding lectin (MBL), and ficolin-2 before complement activation products and phagocytosis were detected by flow cytometry. Our results showed that alternative pathway amplified complement onA. fumigatus, but required classical and/or lectin pathway for initiation. In normal human serum, this initiation came primarily from the classical pathway. However, with a dysfunctional classical pathway (C1q-deficient serum), lectin pathway activated complement and mediated opsonophagocytosis through MBL. To model the antibody-decline in a compromised immune system, we used serum from normal umbilical cords and found MBL to be the key complement initiator. In another set of experiments, serum from patients with different kinds of immunoglobulin insufficiencies showed that the MBL lectin pathway contribution was highest in the samples with the lowest IgG/IgM binding. In conclusion, lectin pathway appears to be the primary route of complement activation in the absence of anti-A. fumigatusantibodies, whereas in a balanced immune state classical pathway is the main activator. This suggests a crucial role for the lectin pathway in innate immune protection againstA. fumigatusin immunocompromised patients.
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Rosbjerg
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Ninette
authors.initials: N
authors.lastname: Genster
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Katrine
authors.initials: K
authors.lastname: Pilely
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Mikkel-Ole
authors.initials: MO
authors.lastname: Skjoedt
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen , Copenhagen , Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
keywords: Aspergillus fumigatus; IgM; MBL; complement; immunocompromised; lectin pathway