Background/Purpose:  Complement activation is proposed as one of the major thrombophilic mechanisms in antiphospholipid syndrome (APS). Among three complement pathways (classical, alternative and lectin), activation of classical pathway triggered by the immune complexes (IC) composed of antiphospholipid antibodies (aPL) has been considered as the mainstream of the phenomenon. However, we have reported that in APS patients, the serum IC levels were relatively low, and antibodies against C1q, the first component of the classical pathway that boost the complement activation immunologically are highly present. Recently, in vitro reports revealed that beta-2 glycoprotein I, a major target of aPL, interacts with the factor H (FH), one of the complement regulatory factors (CRF). CRF are the group of proteins that suppress the excessive activation of complement pathway mainly in the alternative pathway, of which activation spontaneously cleaves C3 and spreads activation to the late complement components thus contributes to the acceleration of inflammation. Membrane cofactor protein (MCP) and FH are the two major CRF that inhibit the C3 cleavage. The former inhibits the cleavage on cell surfaces, and the latter soluble components. We evaluated them in APS patients.

Methods:  The patients with connective tissue diseases including APS that visited the Hokkaido University Hospital rheumatology clinic during 2000 and 2013 were enrolled. The solid-phase enzyme-linked immunosorbent assays (ELISA) were performed as to detect the excessive activations of different complement pathways qualitatively (Wieslab® Complement system Screen, Euro Diagnostic). Serum MCP levels (MCP ELISA kit, Cloud-Clone) and FH levels (factor H human ELISA kit, Human Innovative Research) were also tested. Autoantibodies against FH were determined by western-blotting which detects the antibodies in 10% of patients with atypical hemolytic uremic syndrome, according to the previous reports (Moore et al, Blood, 2010 etc.).

Results:  Twenty-six patients with primary APS (PAPS), 45 systemic lupus erythematosus (SLE), and 56 other autoimmune diseases (control) were enrolled. Serum complement levels of PAPS as well as SLE were low compared with control (C3: 85.9±35.6, 73.0±51.5 vs 109.4±42.8 mg/dl). In PAPS, 22/26 (84.6%) showed normal serum IC levels. Excessive complement activations over 99 percentile of normal healthy controls were observed in 5/26 for the classical pathway and 4/26 for the alternative pathway. The serum levels of MCP were in normal range in all the groups. On the contrary, serum FH levels were significantly depleted in PAPS as well as SLE compared with control (median 180.1, 146.1 vs 368.5 μg/ml, p < 0.0001). In PAPS, serum FH levels were positively correlated with serum C3 levels (p = 0.015, R²= 0.502), however no significant correlation with the presence of any aPL was confirmed. Autoantibodies against FH were not detected in any of the patients.

Conclusion:  Complement activation in APS patients were multifactorial partly due to activation of classical pathway with less contribution of the circulating IC and the activation of alternative pathways mainly due to depletion of FH.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/complement-activation-in-antiphospholipid-syndrome-due-to-the-multi-activated-pathways-of-the-complement-system/