Immune modulation of human dendritic cells by complement

Abstract

Deficiency in complement proteins such as C1q is associated with the development of systemic lupus erythematosus (SLE). Here, we show that the differentiation of dendritic cells (DC) in the presence of C1q (C1qDC) gives rise to CD1a + /DC-SIGN + cells with high phagocytic capacity and low expression of CD80, CD83 and CD86. Further, when C1qDC were exposed to LPS, a significant reduction in the production of IL-6, TNF-a and IL-10 occurred with a limited up-regulation of CD80, CD83 and CD86. In addition, C1qDC were less responsive to activation by CD40L in terms of IL-12p70 secretion and CD86 expression. C1qDC showed an impaired ability to stimulate alloreactive T cells, with a reduced production of IFN-c. In conclusion, we have shown that C1q is a potent modulator of DC, resulting in cells characterized by an impaired capacity of cytokine production and an impaired up-regulation of costimulatory molecules, leading to a limited T cell response. Therefore, we hypothesize that, next to a pivotal role in the safe clearance of apoptotic cells, C1q regulates the threshold of DC activation and thereby prevents hyperactivation of the overall immune response.

Anti-CD20 monoclonal antibodies: historical and future perspectives

“…48,49 On consideration of all of these data, it appears that although complement can evoke potent CDC responses both in vitro and with xenografts in vivo, there is little direct evidence to suggest that this activity provides a substantial positive effect on rituximab-mediated depletion of B cells in humans.…”

The Classical and Regulatory Functions of C1q in Immunity and Autoimmunity

“…These C1q-activated DCs also stimulated T cell proliferation and the production of IFN-γ (96,97). In contrast, DCs cultured from monocytes in the presence of soluble C1q exhibited tolerogenic or immunosuppressive properties (98). These C1q-DCs expressed reduced co-stimulatory molecules and less cytokines and are also poorer in stimulating T cell proliferation and IFN-γ production (98).…”

“…In contrast, DCs cultured from monocytes in the presence of soluble C1q exhibited tolerogenic or immunosuppressive properties (98). These C1q-DCs expressed reduced co-stimulatory molecules and less cytokines and are also poorer in stimulating T cell proliferation and IFN-γ production (98). C1q has been reported to stimulate immature DC chemotaxis through gC1qR and gC1qR (99).…”

C1q Protein Binds to the Apoptotic Nucleolus and Causes C1 Protease Degradation of Nucleolar Proteins

“…IFN-␣ production is persistent in SLE patients and is pathogenic, but C1q binding to these complexes strongly inhibits IFN-␣ induction from plasmacytoid dendritic cells (12, 19 -21). Fourth, in a ligand-independent manner, C1q may directly induce tolerogenic properties in DCs (22,23). Therefore, multiple mechanisms may exist for C1q to inhibit lupus pathogenesis.…”