New Answers to Old Conundrums

Abstract

Antibody-mediated injury is a major cause of allograft dysfunction and loss. Antibodies to ABH(O) blood group antigens are classic mediators of ABO-incompatible graft rejection, whereas donor-specific anti-HLA antibodies and, more recently, autoantibodies are appreciated as important contributors to allograft inflammation and dysfunction. In August 2016, the International Summit of the Canadian National Transplant Research Program focused on recent advances in the field of antibody-mediated rejection. Here, we describe work presented and discussed at the meeting, with a focus on 3 major themes: the importance of (1) natural antibodies and autoantibodies, (2) tissue injury–derived exosomes and autoimmunity, (3) inflammasome activation and innate immune responses in regulating allograft inflammation and dysfunction. Finally, we explore novel areas of therapeutic intervention that have recently emerged from these 3 major and overlapping fields of transplantation research.

Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis

“…Our study is the first to relate inflammasome activation in CD14 ++ monocytes to Treg dysfunction in DAIH. The inflammasome complex is a critical mediator in various autoimmune diseases; Moreover, it is thought to be a pivotal pathway connecting tissue injury with inflammation and autoimmunity ( 13 ). This is elegantly demonstrated in mice with Abca1/g1 deficiency in dendritic cells (DCs) that have a lupus-like phenotype.…”

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

“…The cargo of macrophage-derived EVs includes several molecules with immunomodulatory functions, such as Hsp 70 (pro-inflammatory or tolerogenic effect depending on coexistent signals) (39), IL-1 β (DC migration and expansion of T/B lymphocytes) (40,41), TNFα, and several chemokines (CCL2, CCL3, CCL4, and CCL5) (44)(45)(46). Complement C3 fragments are expressed on EV surface and interact with T cells during antigen presentation (48).…”

“…In this scenario, endothelial cell generate both "classical" apoptotic bodies and smaller exosome-like vesicles; both are overloaded with caspase-3 and can propagate cell death. Additionally, these exosome-like vesicles carry activated 20S proteasome; this complex recruits adaptive immune cells and induces the production of auto-antibodies toward perlecan/LG3, angiotensin-1 receptor, and dsDNA, further aggravating vascular inflammation (46,127,131). Reperfusion has also been associated with the occurrence of a broad range of IgM "natural antibodies, " targeting "neo-epitopes" on ischemic tissues and activating complement (123).…”

“…Innate immune response generates graft tissue damage, which can favor continuous release of sequestered self-antigens through EVs, with secondary activation of self-reactive T lymphocytes and development of a tissue-restricted form of autoimmunity (46,72).…”