Lamprey Variable Lymphocyte Receptors Mediate Complement-Dependent Cytotoxicity

Abstract

An alternative adaptive-immune system is present in the most basal vertebrates--lampreys and hagfish--the only surviving jawless vertebrates. These eel-like fish use leucine-rich repeat-based receptors for Ag recognition instead of the Ig-based receptors used in jawed vertebrates. We report that in Japanese lamprey (Lampetra japonica), variable lymphocyte receptor (VLR)B interacts with C1q and C3 proteins to mediate complement-dependent cytotoxicity for bacteria and tumor cells. The immune-based lysis involves deposition of VLRB and C1q-like protein complex on the surface of target cells, activation of C3, and ultimate disruption of cell wall integrity. The demonstration of functional interaction between VLRB and complement components in lamprey provides evidence for the emergence of cooperative innate and adaptive-immune responses at a pivotal point in vertebrate evolution, before or in parallel with the evolution of Ig-based Abs and the classical complement-activation pathway.

Re-evaluation of the Immunological Big Bang

“…This is possible, as another example NK cells have much in common with T cells regarding signaling and effector functions, but lack any somatically generated antigen receptor and thus may have pre-dated cells with rearranging receptors. It is difficult to see what function a primordial “B cell” might accomplish without an antigen receptor, as effector functions for B cells are found within the secreted antigen receptor, not the cell itself (true of VLRB as well, as shown in a recent study [36]). Perhaps the VLRB arose first, and indeed was used in a T-independent system [11], Kasahara, personal communication); indeed since B cells from ectothermic vertebrates and mammalian B1 cells are capable of phagocytosis, this lineage may have retained primitive myeloid cell characteristics [37,38].…”

Different Members of the IL-1 Family Come Out in Different Ways: DAMPs vs. Cytokines?

“…This is true both for the passive release by dying cells exploited by IL-1α and IL-33, since death represents the last step of a cell subjected to stress, and for the more complex secretion of IL-1β and IL-18 that are regulated by redox stress (Cruz et al, 2007; Dostert et al, 2008; Hewinson et al, 2008; Meissner et al, 2008; Tassi et al, 2009). Interestingly, both purinergic receptor stimulation and mechanical stress, cause a disturbance of redox homeostasis resulting in redox response (Wu et al, 2013); redox response is also required for inflammasome activation (Rubartelli, 2012). Interestingly, a recent study shows that mechanical stress, which as stated above induces IL-33 secretion, is sensed by NLRP3 inflammasome and leads to IL-1β processing and secretion (Wu et al, 2013).…”

“…Interestingly, both purinergic receptor stimulation and mechanical stress, cause a disturbance of redox homeostasis resulting in redox response (Wu et al, 2013); redox response is also required for inflammasome activation (Rubartelli, 2012). Interestingly, a recent study shows that mechanical stress, which as stated above induces IL-33 secretion, is sensed by NLRP3 inflammasome and leads to IL-1β processing and secretion (Wu et al, 2013). Mechanical stretch induces production of Reactive Oxygen Species (ROS) which are well-known players in the mechanism of NLRP3 inflammasome activation (Rubartelli, 2012).…”

Host-defense peptides of the skin with therapeutic potential: From hagfish to human

“…The system of adaptive immunity that characterizes the higher vertebrates is not fully developed in the Agnatha so that host-defense peptides of the innate immune system may be of particular importance in protecting the organism against infection [13]. Instead of the immunoglobulin based antigen receptors of gnathostomes, the Agnatha use variable lymphocyte receptors (VLRs) comprised of leucine-rich-repeat (LRR) segments for antigen recognition [121].…”