title: Sex matters: Systemic complement activity of female C57BL/6J and BALB/cJ mice is limited by serum terminal pathway components.
abstract: Experimental mouse models have been extensively used to elucidate the role of the complement system in different diseases and injuries. Contribution of gender has revealed an intriguing gender specific difference; female mice often show protection against most complement driven injuries such as ischemia/reperfusion injury, graft rejection and sepsis. Interestingly, early studies to the mouse complement system revealed that female mice have very low total complement activity (CH50), which is related to androgen regulation of hepatic complement synthesis. Here, our aim was to understand at which level the female specific differences in mouse complement resides. We have used recently developed complement assays to study the functional activities of female and male mice at the level of C3 and C9 activation, and furthermore assayed key complement factor levels in serum of age-matched female and male C57BL/6 mice. Our results show that the female mice have normal complement cascade functionality at the level of C3 activation, which was supported by determinations of early complement factors. However, all pathways are strongly reduced at the level of C9 activation, suggesting a terminal pathway specific difference. This was in line with C6 and C9 measurements, showing strongly decreased levels in females. Furthermore, similar gender differences were also found in BALB/cJ mice, but not in CD-1 mice. Our results clearly demonstrate that the complement system in females of frequently used mouse strains is restricted by the terminal pathway components and that the perceived female specific protection against experimental disease and injury might be in part explained by the inability promote inflammation through C5b-9.
authors.affiliation: Leiden University Medical Center (LUMC), Department of Nephrology, Leiden, The Netherlands.
authors.forename: Juha
authors.initials: J
authors.lastname: Kotimaa
authors.affiliation: Leiden University Medical Center (LUMC), Department of Nephrology, Leiden, The Netherlands.
authors.forename: Ngaisah
authors.initials: N
authors.lastname: Klar-Mohammad
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.affiliation: Hycult Biotech, Uden, The Netherlands.
authors.forename: Geurt
authors.initials: G
authors.lastname: Schilders
authors.affiliation: Hycult Biotech, Uden, The Netherlands.
authors.forename: Aswin
authors.initials: A
authors.lastname: Jansen
authors.affiliation: Hycult Biotech, Uden, The Netherlands.
authors.forename: Helma
authors.initials: H
authors.lastname: Rutjes
authors.affiliation: Leiden University Medical Center (LUMC), Department of Nephrology, Leiden, The Netherlands.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.affiliation: Leiden University Medical Center (LUMC), Department of Nephrology, Leiden, The Netherlands. Electronic address: Kooten@lumc.nl.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology*; D003183:Complement C6 / Q000276:immunology*; D003186:Complement C9 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012727:Sex Characteristics
chemical_list: D003176:Complement C3; D003183:Complement C6; D003186:Complement C9
keywords: Alternative pathway; C6; C9; Classical pathway; Complement system; Lectin pathway; Mouse gender dimorphism; Terminal pathway