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  • Review Article
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The importance of non-HLA antibodies in transplantation

Nature Reviews Nephrology volume 12, pages 484–495 (2016)Cite this article

Subjects

Key Points

  • Humoral immunity to self-antigens expressed on the allograft is associated with rejection and reduced long-term renal allograft survival

  • Autoantibodies can mediate graft damage via complement-dependent and complement-independent pathways.

  • Compelling experimental data suggest that autoantibodies are generated through multiple mechanisms, including presentation of donor-derived extracellular vesicles and apoptotic bodies by host antigen presenting cells

  • IL-17 and type 17 T helper (TH17) cell pathways might have a central role in autoantibody production in the setting of allotransplantation through development of tertiary lymphoid tissue (TLT)

  • TLT promotes B-cell survival and immunoglobulin isotype class switching

  • More investigation is required to elucidate the pathogenesis of autoantibodies and to develop targeted therapeutic strategies to prevent acute and chronic antibody-mediated rejection

Abstract

The development of post-transplantation antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, compelling experimental and clinical findings demonstrate that antibodies directed against autoantigens such as angiotensin type 1 receptor, perlecan and collagen, contribute to the process of antibody-mediated acute and chronic rejection. The mechanisms that underlie the production of autoantibodies in the setting of organ transplantation is an important area of ongoing investigation. Ischaemia–reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens (such as soluble antigens, extracellular vesicles or apoptotic bodies) that are presented to B cells in the context of the transplant recipient's antigen presenting cells and stimulate autoantibody production. Type 17 T helper cells orchestrate 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 promote allograft 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 such rejection, are sorely needed to improve both graft and patient survival.

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Figure 1: Allograft injury and potential mechanisms of autoantibody production.
Figure 2: Autoantigen presentation by extracelluar vesicles.
Figure 3: Effector mechanisms of T<cp:Subscript>H<cp:>17-cell-mediated autoantibody production.

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Acknowledgements

The authors' work is supported by the following grants: NIH RO1AI42819 and W.M. Keck Foundation (awarded to E.F.R).

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  1. Department of Pathology and Laboratory Medicine, UCLA Immunogenetics Center, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Los Angeles, 90095, California, USA

    Qiuheng Zhang & Elaine F. Reed

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  1. Qiuheng Zhang
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  2. Elaine F. Reed
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Both authors discussed the content, researched the data, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Elaine F. Reed.

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Zhang, Q., Reed, E. The importance of non-HLA antibodies in transplantation. Nat Rev Nephrol 12, 484–495 (2016). https://doi.org/10.1038/nrneph.2016.88

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