Editorial: State-of-the-Art Research on C1q and the Classical Complement Pathway

摘要

The Editorial on the Research Topic State-of-the-Art Research on C1q and the Classical Complement Pathway Complement protein C1q is a fascinating innate immune molecule. C1q is the first subcomponent of the classical complement pathway. Its primary three-chain structure (A, B, and C chains), which is composed of a triple-helical collagen-like region and a C-terminal ligand-recognizing globular head (gC1q) domain, yields a tulip-like organization with six gC1q domains, each representing a heterotrimer (the C-terminal regions of the A, B, and C chains) ( 1 ). In addition to binding to immune complexes containing IgG and IgM, the gC1q domain also engages with a number of self and non-self ligands. A summary of the structural basis of C1q–ligand interactions has been elegantly presented in the review by Gaboriaud et al. For example, it shows that C1q can recognize multiple ligands on the apoptotic cell surface, which illustrates its versatile surface recognition properties. A common binding area for several of these non-immune ligands has been observed in the subunit C, which could play a role in restricting the activation of the classical complement pathway. It has become evident over the course of the last two decades that the gC1q domain is widely conserved across a diverse range of vertebrate and invertebrate proteins ( 2 ). The functions of these proteins can range from being immunological to structural. Through a review article, Ghebrehiwet et al. have cited two examples of C1q functions that are distinct from its involvement in the classical pathway: its ability to induce apoptosis in prostate cancer cells, and to modulate vascularization for fetal–maternal interaction. Given the existence of a C1q–TNF superfamily based on the remarkable structural similarities between C1q and TNF family members ( 1 ), a good argument has been made for a cytokine-like property of C1q. The complexity and diversity related to the functions of C1q family have been greatly exemplified by a structure–function review article by Colombatti et al. , who describe the functions associated with the gC1q domain of two C1q family members – such as EMILIN and multimerin. A slight structural variation from the prototypical structure, as revealed by the NMR solution structure, is insightful, purporting one residue in the interaction of gC1q domain with α_(4)β_(1)and α_(9)β_(1)integrins. In recent years, a number of functions of C1q have emerged that are complement independent. This is reflected in the local synthesis of C1q by various immune and non-immune cells. The diversity of C1q functions includes its involvement in dendritic cell maturation, immune modulation, cell differentiation, cancer progression, neuronal synapse pruning, and pregnancy. This has been extensively summarized by Kouser et al. In the backdrop of a recent observation that C1q gene knockout mice show nearly all features of preeclampsia, the role of C1q in normal and complicated pregnancies has become a burning issue in the reproductive immunology. In this issue, Madhukaran et al. have reported a link between the expression of the transcription factor PU.1 and C1q in human trophoblasts and stromal cells, similar to DCs and macrophages, using early decidual tissue. Given its involvement in a wide range of homeostatic functions, it is not surprising that C1q is central to many human diseases. C1q, as a key molecule in self-tolerance mechanisms, is involved in clearing immune complexes and apoptoticecrotic cells. C1q-deficient mice have been shown to have lupus-like symptoms. However, this issue is further confounded by the fact that anti-C1q autoantibodies are found in a number of pathological situations, more so in systemic lupus erythematosus (SLE). These autoantibodies are certainly required for the development of lupus nephritis. Since C1q itself is an IgG-binding protein, identification and characterization of anti-C1q autoantibodies is a challenging task. Mahler et al. have addressed the technicalities of this endeavor, while reassessing the pathological consequences of such autoantibodies in a disease context. In line with the involvement of C1q in tolerance and SLE, Ghebrehiwet et al. have addressed the importance of monocyte surface expressed C1q in association with C1r and C1s. This review examines the role of cell-bound C1q in capturing and processing circulating immune complexes and pathogen-associated molecular patterns (PAMPs). The ability of C1q to modulate PAMP-recognizing receptors (PRRs) makes it a potent and versatile immune surveillance molecule of the innate immunity. The final section of the issue is dedicated to the understanding of the mechanisms underlying activation of the classical pathway and their specific inhibition for therapeutic purposes. In an original research article, Wijeyewickrema et al. aim at further deciphering the interaction of the C1s protease with its C4 protein substrate. Previous studies had provided evidence for homol