Natural IgM initiates an inflammatory response important for both hepatic ischemia reperfusion injury and regeneration

Abstract

Rationale: Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self-reactive IgM antibodies in activating complement after hepatic IR and liver resection.

Main Results: Natural IgM antibodies that recognize danger associated molecular patterns (neoepitopes) activate complement following both hepatic IR and liver resection. Antibody-deficient Rag1-/- mice were protected from hepatic IRI, but had increased hepatic injury and an impaired regenerative response after 70% partial hepatectomy (PHx). We identified two IgM mAbs that specifically reversed the effect of Rag1 deficiency in both models; B4 (recognizes annexin IV) and C2 (recognizes subset of phospholipids). Focusing on the B4-specific response, we demonstrated sinusoidal colocalization of IgM and C3d in Rag1-/- mice that were reconstituted with B4 mAb, and further that the annexin IV neoepitope is specifically and similarly expressed after both hepatic IR and PHx in wild-type mice. A single-chain Ab construct (scFv) derived from B4 mAb blocked IgM binding and reduced injury after IR in wild-type mice, although interestingly B4scFv did not alter regeneration following PHx, indicating that anti-annexin IV antibodies are sufficient, but not necessary for the regenerative response in the context of an entire natural antibody repertoire. We also demonstrated expression of the B4 neoepitope in post-ischemic human liver samples obtained after transplantation, and a corollary depletion in IgM recognizing the B4 and C2 neoepitopes in patient sera following liver transplantation.

Conclusion: These data indicate an important role for IgM in hepatic IRI and regeneration, with a similar cross-species injury-specific recognition system that has implications for the design of neoepitope targeted therapeutics. This article is protected by copyright. All rights reserved.

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