ReviewHumoral immunity in chronic allograft rejection: Puzzle pieces come together
Highlights
► Humoral response plays a central role in the pathogenesis of chronic rejection. ► Alloantibody binding to graft microvasculature leads to microvascular inflammation. ► B cells present alloantigens to T cells within the graft, which amplifies rejection. ► A local humoral response develops in intragraft tertiary lymphoid tissue. ► B cells can participate in allograft tolerance.
Introduction
Progresses achieved over the last two decades have only marginally improved the long-term outcome of transplanted organs, as demonstrated by the stagnation of graft attrition rate beyond the first year post-transplantation [1], [2].
Among the main cause of late allograft failure is chronic rejection, which results from the inadequate control of the recipient immune response. Indeed, unlike T cells, which have progressively come under pharmacologic control, the humoral arm of recipient immune response remains insufficiently tamed by modern immunosuppressive armamentarium. As a result, B cells and alloantibodies are increasingly acknowledged as crucial mediators of chronic allograft injury.
The present article aims at connecting the concepts that recently emerged in the field of humoral alloimmunity. Putting these puzzle pieces together, the picture of chronic rejection pathogenesis begins to come into play.
Section snippets
The "humoral theory" of chronic rejection
Seminal clinical observations, made in the 1970s, have suggested a link between the presence of circulating donor-specific antibodies (DSA) and chronic rejection [3]. This hypothesis has then been substantiated by several experimental works [4], [5], notably the demonstration that immunodeficient scid mice given repeated doses of anti-MHC class I alloantibody develop fibrous intimal thickening of coronary arteries in cardiac allografts [6].
Finally, a recent large-scale prospective trial,
B cells as intragraft antigen-presenting cells
Binding of cognate antigen to B cell receptor (BCR) triggers membrane reorganisation, which results in the formation of an immunologic synapse that functions as a platform for internalization of the BCR-antigen complex [59]. Internalized antigen is degraded and subsequently exposed on the B-cell surface in association with major histocompatibility complex molecules for presentation to T cells. Of note, B cells are endowed with unique properties as antigen-presenting cells because i) they have
Conclusion
Chronic rejection represents currently the main obstacle to long-term survival of solid allografts. Accumulating evidence indicates that B cells are key players in chronic rejection pathophysiology. Beyond their widely acknowledged role in antibody production (following their differentiation in plasma cell), B cells are also endowed with critical, yet overlooked, antibody-independent functions, which place them at the center of immune regulation with the power to enhance or inhibit antigraft
Disclosures
The author has no conflicts of interest to disclose.
Acknowledgements
OT is supported by the CENTAURE Transplantation Research Network, the Hospices Civils de Lyon, the Societe de Nephrologie, the Societe Francophone de Transplantation, and the Fondation pour la Recherche Medicale.
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