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Review
. 2016 Aug;12(8):484-95.
doi: 10.1038/nrneph.2016.88. Epub 2016 Jun 27.

The importance of non-HLA antibodies in transplantation

Qiuheng Zhang  1 , Elaine F Reed  1
Affiliations
Review

The importance of non-HLA antibodies in transplantation

Qiuheng Zhang et al. Nat Rev Nephrol. 2016 Aug.

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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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Allograft injury and potential mechanisms of autoantibody production
Ischaemia-reperfusion injury (IRI)-induced damage to vascular endothelial and tubular epithelial cells triggers the release of damage associated molecular patterns (DAMPs), including nucleic acids, histones and high mobility group protein B1 (HMGB1). Ligation of Toll-like receptor (TLR) 2 and TLR4 on myeloid, dendritic, and vascular endothelial cells activates the MYD88 and NF-κB pathways, resulting in production of proinflammatory cytokines. Autoantibody-mediated inflammation activates complement and promotes further activation of autoreactive B cells and leukocyte recruitment through the production of C3a and C5a. Tissue damage caused by IRI, natural antibodies or HLA-DSA can also lead to the activation of autoreactive T and B cells and the subsequent production of autoantibodies. Complement can potentiate autoantibody production by lowering the threshold of B-cell activation through the binding of C3dg-coated antigen to complement receptor 2 (CR2) and the B cell receptor (BCR). MAC, membrane attack complex; TNF, tumour necrosis factor.
Figure 2
Figure 2. Autoantigen presentation by extracelluar vesicles
(1) Donor-derived extracellular vesicles containing major histocompatibility complex (MHC) class I and/or MHC class II molecules complexed to autoantigens released from the allograft can directly activate recipient autoreactive CD4+ and CD8+ T cells. Antigen presentation by free extracellular vesicles is much less efficient than presentation by professional antigen presenting cells (APCs). (2) Donor-derived extracellular vesicles can be internalized by recipient APCs and the processed donor antigens presented by these cells through the indirect recognition pathway to recipient autoreactive CD4+ and CD8+ T cells. (3) Antigen presentation through ‘cross-dressing’ of recipient APCs with donor MHC molecules activates recipient autoreactive CD4+ and CD8+ T cells. Cross-dressing occurs when donor-derived extracellular vesicles are internalized and recycled to the surface of recipient APCs without peptide–MHC reprocessing. Alternatively, donor derived extracellular vesicles EV can be captured and fused to the APC surface.
Figure 3
Figure 3. Effector mechanisms of TH17-cell-mediated autoantibody production
Type 17 T helper (TH17) cells secrete several effector molecules including IL-21, IL-22 and IL-17. Production of IL-17 in the allograft leads to leukocyte recruitment, resulting in graft damage and release of autoantigens. Production of IL-21 by TH17 cells can trigger formation of tertiary lymphoid tissue (TLT) and mediate B-cell differentiation and antibody class switch which is important for B cell maturation and autoantibody production.
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