A novel interpretation of immune redundancy and duality in reperfusion injury with important implications for intervention in ischaemic disease.
The majority of ischaemia related injury occurs upon tissue reperfusion. Knock-out mouse models have recently shed light on the underlying molecular mechanisms, and suggest that this may be the result of an innate autoimmune response. Based on these new findings we present a novel model of immune redundancy and duality in reperfusion injury. Natural antibody, mannan-binding lectin and toll-like receptor 4 are three pre-formed innate immune receptors that recognise pathogenic molecular patterns. Removing either significantly ameliorates reperfusion injury. We propose that these three receptors serve as key parallel recognition elements that respond to the same or similar ischaemic neo-antigens, of which at least one may have a lipopolysaccharide-like motif. This would fit both with the ligand preference of the three receptors, and the observation that giving monoclonal antibody to lipopolysaccharide reduces reperfusion injury. The consequent injury caused by receptor activation appears to be mainly related to the complement anaphylatoxins, and less to phagocytes, oxidative radicals, and the membrane attack complex. C5a levels in particular are predictive of overall injury, and we suggest this anaphylatoxin causes most of reperfusion injury via both direct toxic effects and a generalised immune activation. The former is illustrated by the recent observation that excess C5a alone can cause cardiac dysfunction. As for the latter, there is evidence that adaptive immunity (especially CD4+ cells) and other serum cascades (coagulation and kallikrein) are involved, and may have been recruited by complement. Furthermore, excess C5a can cause innate immune overactivation that paralyses neutrophils, reduces complement lytic function, and leads to systemic inflammation. This is analogous to what happens in sepsis, and would explain the passive role in IRI of normal immune effectors. Finally, there is a duality complement's function in reperfusion, as some elements are conductive of damage, whilst others may help inflammatory resolution. Most important among the latter are the opsonins, like C3b and apparently C1q, which help macrophages clear apoptosing cells before they undergo secondary necrosis. This model has important implications for clinical interventions. Firstly, redundancy means that inhibiting multiple receptors may achieve a larger mortality reduction than the small and inconsistent one seen in the published monotherapy trials. Secondly, duality means that a non-specific inhibition of complement would reduce both injury and resolution. Therefore, a specific inhibition of the lectin pathway and/or an inhibition of the downstream effectors upon which the receptors converge (e.g. C5a) seem to be a better interceptive strategy.