The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

Abstract

C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE.

MASP-1 and MASP-2 Do Not Activate Pro–Factor D in Resting Human Blood, whereas MASP-3 Is a Potential Activator: Kinetic Analysis Involving Specific MASP-1 and MASP-2 Inhibitors

“…One possibility is that fluid-phase activation of lectin pathway proteases occurs slowly at a constant rate, but active MASP-1 and MASP-2 are rapidly inactivated by their natural inhibitors like C1 inhibitor and antithrombin (37). This assumption is supported by the presence of MASP-1-C1-inhibitor and MASP-1-antithrombin complexes in normal serum and plasma (38). Importantly, as active MASP-3 is not inhibited by C1 inhibitor (39) or any other identified serpin, it could slowly accumulate in such a scenario.…”

The emerging roles of mannose‐binding lectin‐associated serine proteases (MASPs) in the lectin pathway of complement and beyond

“…Very recently two independent publications corroborated the role of antithrombin in lectin pathway regulation detecting MASP‐1–antithrombin complexes in the blood of patients having various diseases [e.g. hereditary angioedema (HAE), systemic lupus erythematosus, polytrauma] . The latter publication also demonstrates that blood clotting activates the lectin pathway .…”

“…Taken into account the high autoactivation potential of MASP‐1, it is also possible that MASP‐1 contributes to the elevated baseline level of bradykinin observed in the blood of the HAE patients . Indeed, a recent publication reported that that there is a significant amount of circulating MASP‐1‐C1 inhibitor complex in the resting blood of healthy individuals . This means that MASP‐1 is being continuously (auto)activated in the plasma at a slow rate (similarly to the “tick over” of C3), but the active MASP‐1 is present only for a limited period of time, as it is inactivated by C1 inhibitor (and possibly by antithrombin).…”

“…hereditary angioedema (HAE), systemic lupus erythematosus, polytrauma]. 75,76 The latter publication also demonstrates that blood clotting activates the lectin pathway. 76…”

Pathophysiology of Bradykinin-Mediated Angioedema: The Role of the Complement System

“…MASP-1 has been recently shown to cleave bradykinin from HMWK [17] and its levels, together with the complex MASP1-C1-INH, have been related to disease severity in C1-INH-HAE [18].…”