Complement Mediated Regulation of Autophagy and Maintenance of Alloreactive Memory B Cells

  • Leventhal, Jeremy S. (PI)

Project Details

Description

Donor specific antibodies (DSA) are pathogenic mediators of solid organ rejection for which no effective treatment exists. DSA are produced by plasma cells (PC) as well as by memory B cell (Bmem). While some therapies, including proteasome inhibitors, have efficacy in removing PCs that produce DSA, an incomplete understanding of Bmem biology has left the transplant community without effective strategies for inhibiting this component of the humoral immune system. The rationale for the proposed work is that better understanding of links among complement, Bmem autophagy and Bmem-dependent alloantibody responses will enable new strategies to prevent DSA in sensitized individuals. Autophagy, a cellular process overseeing degradation of intracellular constituents to maintain equilibrium, is of particular importance in Bmem. Our recently published findings support the hypothesis that survival of Bmem reactive to foreign antigens is dependent on Bmem intrinsic autophagy. We have made the novel observation that autophagy is regulated by complement, a part of the innate immune system. Mice lacking the complement regulator Decay Acceleration Factor (DAF) possess less Bmem whereas mice lacking the complement receptor C3aR1 possess more memory than control mice. Together, our data support testing of the novel hypothesis that: C3aR1 signaling on B cells inhibits autophagy by inactivating AMP kinase and activating mTOR. As DAF expression prevents local complement (C3a) activity, DAF inhibits C3aR1-mediated AMPK/mTOR inhibition/activation, among other signaling pathways, that cumulatively permit activation of the autophagy program that, in turn, is required for long term Bmem survival. We will test this hypothesis by quantifying Bmem and Bmem-mediated antibody responses after eliminating or increasing DAF expression in Bmem (aim 1), after eliminating C3aR1 in Bmem (aim 2), and by deciphering the changes in autophagy related signaling mechanisms that occur as a consequence of C3a-C3aR1 signaling (aim 3) The proposed work has the potential elucidate novel pathways and mechanisms required for the induction of autophagy in alloreactive Bmem. We expect that the mechanistic data generated by this project will provide insights into the pathways affecting, and necessary for, maintenance of DSA generating Bmem, results that have implications for antibody dependent transplant injury as well as for Bmem in other pathogenic contexts.
StatusFinished
Effective start/end date21/01/1930/06/20

Funding

  • National Institute of Allergy and Infectious Diseases: $423,750.00

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