We would like to express our thanks for the comment on our current published report (1) from Dr. Gál and colleagues. In the comment, they note, “The authors’ findings in these mouse models are in perfect agreement with our previous results obtained with human … samples,” citing their previous publications in 2012 and 2016. However, we disagree with their comment on the historical background regarding MASP-1 and MASP-3 in the complement system, and it is possible that their comment may cause misunderstanding of the scientific novelty and importance of our paper in the field. In 1992, our group discovered the novel serine protease designated mannose-binding lectin (MBL)-associated serine protease (MASP) (2). In addition, we contributed to the discovery of MASP-3 in 2001 (3). Since then, we have investigated the roles of MASPs in the complement system. As a result, first, in 2008 we generated mice genetically deficient for both MASP-1 and MASP-3 and demonstrated that MASP-1 contributes to activation of the lectin pathway (LP) through the activation of MASP-2 (4). Second, in 2010 we showed that MASP-1 and/or MASP-3 plays an essential role in activation of the alternative pathway (AP) through activation of complement factor D (FD), possibly by MASP-1 (5). Third, in 2011 we revealed that MASP-3 can cleave a zymogen FD (pro-FD) to an active form FD in the presence of MBL-A and Staphylococcus aureus (6). That was the first demonstration of the physiological function of MASP-3. Subsequently, in 2016 Oroszlán et al. (7) showed that MASP-3 cleaved pro-FD to the active FD in resting human blood by in vitro addition of MASP-1– and MASP-2–specific inhibitors. Furthermore, they demonstrated in 2017 that MASP-1 activated MASP-3 via its catalytic activity by an in vitro experiment (8). Based on these publications, a suggestion had been widely disseminated stating that there is a cross-talk between the LP and AP through the activation of MASP-3 by MASP-1, as summarized by Oroszlán et al. (8). Of note, our current study (1) provided a clear-cut answer to this suggestion as we generated mice that were monospecifically deficient for MASP-1 or MASP-3, and clarified their independent roles in LP and AP activation. MASP-3 circulates mainly as an active form, can cleave pro-FD, and is involved in the AP activation even in the absence of MASP-1. Therefore, it is clear that, at least in mice, MASP-3 is an AP-specific serine protease, whereas MASP-1 is an LP-specific serine protease. Our findings led to the completion of the overall picture of the complement system other than the mechanism for MASP-3 activation. Nonetheless, an observation by Paréj et al. (9) that MASP-1 contributes to LPS-induced AP activation in human blood under the presence of a MASP-3–specific inhibitor should be further investigated in terms of minor species-specific evolutionary differences between mice and humans. We conclude our response to Dr. Gál and colleagues by stating that we definitively determined the independent roles of MASP-1 and MASP-3 in the complement system, with expectations of clarifying their roles in humans.
Footnotes
Abbreviations used in this article:
- AP
alternative pathway
- FD
factor D
- LP
lectin pathway
- MASP
MBL-associated serine protease
- pro-FD
zymogen FD.