The importance of non-HLA antibodies in transplantation

Abstract

The development of post-transplant antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, recent studies provide compelling experimental and clinical findings demonstrating that antibodies directed against autoantigens contribute to the process of antibody-mediated acute and chronic rejection. Important areas for investigation remain understanding the mechanisms underlying the production of autoantibodies in the setting of organ transplantation. Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens in the form of soluble antigens, extracellular vesicles or apoptotic bodies that are presented in context of the transplant recipient’s antigen presenting cells to stimulate autoantibody production. Th17 cells are essential in the orchestrating autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promoteallograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection and the development of targeted therapies to treat these rejections are sorely needed to improve both transplant and patient survival.

A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

“…Treatment with aCD20 decreased 119 reactivities ( Figure S4 and Table S6), including those associated with CR after IRI ( Figures 6B and 8F). IRI can expose cryptic autoantigens 48 and release damage-associated molecular patterns, which might have augmented this response. IRI-driven autoantibody formation by B cells may contribute to CR after IRI, but further work will be required to determine which B cell functions are necessary for this phenomenon.…”

“…These findings suggest that IRI triggers a humoral response that may promote fibrosis. IRI can expose cryptic autoantigens 48 and release damage-associated molecular patterns, which might have augmented this response. In contrast, F I G U R E 6 IRI augments autoantibody formation in lung allograft recipients.…”

Back signaling of HLA class I molecules and T/NK cell receptor ligands in epithelial cells reflects the rejection-specific microenvironment in renal allograft biopsies

“…Consistently with our findings, proliferation, apoptosis, and leukocyte recruitment were proposed in airway epithelial cells upon crosslinking of HLA class I 59 supporting our hypothesis that the impact of DSA is not restricted to the endothelium. In addition, recent studies have revealed a novel role for non-HLA antibodies to MHC class I-related chain A/B or angiotensin type 1 receptor [60][61][62]. Based on their polymorphism,63,64 CD155 and CD166 may represent further candidates for the development of non-HLA antibodies, because antibodies against epithelial cell antigens have been described in lung transplantation 65.…”

Obliterative portal venopathy: A histopathologic finding associated with chronic antibody‐mediated rejection in pediatric liver allografts

“…It is unclear whether the development of HLA DSA precedes the development of non‐HLA antibodies, or vice versa; autoantibodies may be triggered by alloimmunity, and autoimmunity may trigger alloantibodies. Regardless, allo‐ and autoantibodies may work synergistically in allograft damage and rejection . Further mechanistic studies on the role of non‐HLA antibodies are needed and may aid in the development of effective medical therapy for chronic AMR.…”