Discrete MBL-MASP Complexes Show Wide Inter-Individual Variability in Concentration: Data from UK vs Armenian Populations

Abstract

K.R.M and R.B.S. contributed equally to this studyMannan-binding lectin (MBL) circulates in plasma in complex with MBL-associated serine proteases (MASP) -1, -2 and -3 and a smaller component, MApI9. When MBL binds to the surface of foreign material (microorganisms), MASP-l, -2, -3 are activated. MASP-2 then activates the complement system. MASP-l and -3 may activate other (unidentified) systems. MBL levels, MBL-bound MASP-l and MBL-bound MASP-2 activities have been evaluated in healthy individuals from UK and Armenian populations. MBL-bound MASP-2 activity declines in aging (P<O.04). MBL correlates with smoking (P<O.02). There were significant differences between the two populations in MBL-bound MASP-l activity and in MBL, but no difference in MBL-bound MASP-2 activity. When MASP activities were normalised to MBL (i.e, MASP-l activity/MBL, MASP-2 activity/MBL), normalised MASP-2 activity in UK individuals was more than 2 fold higher than in Armenians. The difference in normalised MASP-2 activity level between these two Caucasoid populations, suggests that concentration of the MBL-(MASP-2) complex, and therefore the function of activating complement, depends not only on the quantity of MBL in serum and its oligomeric state, but also on the quantity of MASP-2 in serum. It is likely that in individuals with high MBL concentration there is excess free MBL not occupied by MASPs, particularly not by MASP-2.

The Complement System in Schizophrenia

“…In individuals with high MBL concentration there may be excess free MBL not occupied by MASPs, particularly not by MASP-2. 78 The differently composed complexes have different functions. 79 The concentrations of these complexes show wide interindividual variation.…”

“…79 The concentrations of these complexes show wide interindividual variation. 78 Thus, complement activation depends not only on MBL concentration and oligomeric state, but also on the quantity of MASP-2 and MASP-1 in serum, as after some certain threshold MASP-1 can compete out MASP-2 from binding to MBL 78 Taking into account our recent findings on exploration of MBL-MASP and L-ficolin-MASP complexes in schizophrenia, 61,68,69 it is likely that subtle interplay between MBL, ficolins and MASPs determines complex composition and modulation of the lectin pathway, which could be a very dynamic process depending on the current immune status of the organism and, particularly for schizophrenia, on the stage and course of illness, or on the presence of secondary factors such as coincidental infections, the impact of chronic smoking or effects of poor hygiene. To further explore the associations between raised lectin pathway activity and schizophrenia, we are undertaking multifactorial exploration of the whole lectin pathway, including measurement of H-ficolin and MASP-2 serum concentrations and genotype analyses of the components, as well as H-ficolin-MASP-1 and H-ficolin-MASP-2 complex activities in the same sample cohort.…”

Activation of mannan‐binding lectin‐associated serine proteases leads to generation of a fibrin clot

“…Each MBL or FCN may associate with a homodimer of one of these proteases, so that, in the blood, there are varying amounts of complexes with composition MBL‐(MASP‐1) 2 , MBL‐(MASP‐2) 2 , MBL‐(MASP‐3) 2 and MBL‐(MAp19) 2 , and finally MBL with no proteases attached. The FCNs are likely to form a similar range of complexes 3,4 …”

Involvement of NK Cells against Tumors and Parasites

“…It was recently found that depletion of NK cells from mice using the anti-asialo GM1 antibody did not affect survival when a low dose (1 x 10 4 ) of T. cruzi trypomastigotes was used for infection; however, when a higher dose was used (5 x 10 5 ), NK-depleted mice had compromised survival compared with C57BL/6 mice (18)(19)(20)(21)(22)(23)(24)(25). Also in vivo and in vitro studies have shown that IL-12-stimulated NK cells can control parasitemia by IFN-γ secretion in the first days of infection with T. cruzi (26)(27)(28)(29).…”