Session Type: Abstract Submissions (ACR)
Systemic Lupus Erythematosus (SLE) is an autoimmune disease associated with the development of auto-antibodies particularly against nuclear antigens. Previous studies have revealed the possible role of type I interferon, IFN-α , in disease pathogenesis. Notably the formation of immune complexes (auto-antibodies with auto-antigens) can result in the production of IFN-α via Fc receptor signaling. Hereditary homozygous deficiency in the complement protein, C1q has shown a high penetrance of 88-93% in afflicted individuals resulting in disease development. Remarkably it was shown in recent years that C1q has the capacity to suppress immune complex mediated IFN-α production. Considering that in vivo C1q functions as the sensory adaptor in the C1 complex, we compared C1 with C1q in modulating immune complex-mediated IFN-α production from peripheral blood mononuclear cells (PBMCs).
Serum samples were obtained from 15 SLE patients and assayed for the presence of auto-antibodies (anti-nucleosome) via ELISA. The monocytic U937 cell line was UV-irradiated and the apoptotic supernatant was harvested after 24 hours. The apoptotic supernatant was incubated with SLE sera to form immune complexes. The immune complexes were pre-treated with C1 complex or, as controls, C1q or PBS. Human PBMCs, isolated from healthy donors by Ficoll- Hypaque density centrifugation were treated with the immune complexes for 24 hours and IFN-α production was measured by ELISA.
After screening 15 SLE patients for anti-nucleosome autoantibodies, 4 patients with disease activity (SLEDAI-2K ≥ 4) and high titer of anti-nucleosome (>60 R units/ml, where clinical cutoff ≥ 20 R units/ml) were selected. SLE sera were incubated with UV-irradiated U937 apoptotic supernatant to form SLE immune complexes. Human PBMCs were stimulated with SLE immune complexes and assayed for IFN-α production. Healthy control serum elicited 86.7 ± 8.0 R units/ml IFN-α (media control was 85.7 ± 3.5 R units/ml) , whereas SLE patient A elicited 674.7 ± 244.3 R units/ml IFN-α, SLE patient B elicited 243.8 ± 37.0 R units/ml IFN-α (p < 0.05), SLE patient C elicited 1115.8± 166.5 R units/ml IFN-α (p < 0.05), and SLE patient D elicited 142.6 ± 7.4 R units/ml IFN-α (p <0.05). SLE patient C immune complexes were treated with C1, C1q or PBS and C1 and C1q showed a dose-dependent inhibition in IFN-α induction (853.2 ± 16.3, 701.1 ± 1.0, 508.4 ± 18.6 and 192.1 ± 16.4 R units/ml respectively) as compared to PBS-treated SLE immune complex (1362.3 ±80.5 R units/ml). Furthermore, it was noted that, at equal molar concentration of C1 and C1q, C1-treated SLE immune complex suppressed immune complex-induced IFN-α production more effectively than C1q-treated immune complex.
C1 is the natural complex encompassing C1q and C1-treated SLE immune complexes exhibit suppressed IFN-α induction from human PBMCs. C1 appeared to be more potent than C1q in inhibiting immune complex-induced IFN-a production showing corporation among the complement classical pathway in providing enhanced protection against SLE pathogenesis as compared with C1q alone.
J. Y. Leong,
J. G. Yeo,
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppression-of-ifn-%ce%b1-production-from-systemic-lupus-erythematosus-immune-complexes-via-c1-complex-enzymatic-properties/