Origin of the classical complement pathway: Lamprey orthologue of mammalian C1q acts as a lectin

Abstract

The lectin complement pathway in innate immunity is closely related to the classical complement pathway in adaptive immunity, with respect to the structures and functions of their components. Both pathways are initiated by complexes consisting of collagenous proteins and serine proteases of the mannose-binding lectin (MBL)-associated serine protease (MASP)͞C1r͞C1s family. It has been speculated that the classical pathway emerged after the lectin pathway, and that the activation mechanism of the latter was partially conserved. The classical and lectin pathways can be traced back to at least cartilaginous fish and ascidian (urochordata), respectively. To elucidate the evolution of the complement system, we isolated and characterized a GlcNAc-binding lectin from sera of lamprey (agnathans), the most primitive vertebrate that lacks the classical pathway. Lamprey GlcNAc-binding lectin was an oligomer consisting of 24-kDa subunits. cDNA and phylogenetic analyses revealed that the lamprey GlcNAc-binding lectin is an orthologue of mammalian C1q, a collagenous subcomponent of the first component involved in binding to immunoglobulins in the classical pathway. Lamprey C1q copurified with MASP-A, a serine protease of the MASP͞C1r͞C1s family, which exhibited proteolytic activity against lamprey C3. Surface plasmon resonance analysis showed that lamprey C1q specifically bound to GlcNAc, but not various other carbohydrates tested. These results suggest that C1q may have emerged as a lectin and may have functioned as an initial recognition molecule of the complement system in innate immunity before the establishment of adaptive immunity such as immunoglobulins in the cartilaginous fish.

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses

“…Mice deficient in C1q, MBL, or secreted IgM have impaired control of inflammatory responses and, in some cases, autoimmune predisposition (36)(37)(38)(39). The regulatory inhibitory signaling properties of the anti-AC IgM were shown to be dependent on the presence of C1q or MBL, two soluble macromolecules of the innate immune system that share a common primordial genetic ancestor (40). When deposited on the surface of an AC, these represent "eat me" signals that enhance apoptotic clearance (41); however, we found that by themselves these recognition molecules demonstrated no significant activity in our assays.…”

An Overview of the Immunological Defenses in Fish Skin

“…For that property they have potential antimicrobial activity in the skin mucus. Lectins interact with pathogenic surface structures that result in opsonisation, enhance phagocytic activity [194], or activation of the complement pathway [195]. Furthermore, agglutinins in fishes are reported to prevent polyspermy [196] and assist in wound healing [60].…”

Unique Phenotypes of C1s Deficiency and Abnormality Caused by Two Compound Heterozygosities in a Japanese Family

“…Peptide Institute) as previously described (21). The activity was expressed as fluorescence intensity determined at 380 nm for excitation and 460 nm for emission.…”