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.