Set Up for Failure: Pre-Existing Autoantibodies in Lung Transplant

Figures

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  Figure 1. Pre-existing Autoantibody-mediated Graft Injury. Autoantibodies developed as a consequence of chronic end-stage pulmonary diseases (CPD), such COPD and ILD may pre-dispose to worse graft outcomes. Autoantibodies characteristic of COPD and ILD have been shown to not only correlate with disease severity pre-transplant but hold the potential to target the lung and induce injury post-transplantation. Pre-existing autoantibodies that have been described can promote pro-inflammatory responses via a variety of effector pathways, including complement activation and Fc gamma receptor mediated inflammation, the impact of which on graft rejection has not been fully explored.

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  Figure 2. Pre-existing autoantibodies could pre-dispose to heightened epitope spreading. The existence of lung targeted autoreactive antibodies generated pre-transplantation as a consequence of the recipient’s chronic lung diseases could exacerbate cellular injury. 1. Pre-existing lung autoreactive antibodies bind within the lung upon reperfusion and induce cell injury. 2. Injury to donor lung cells releases other self-antigens. 3. Self-antigens are internalized by antigen presenting cells and presented to T cells (4) and promote B cell production of autoreactive antibodies (5 and 6).

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  Figure 3. Pre-Existing Autoantibody Characteristics Impact Effector Functions. Autoantibodies bind to a variety of different antigens expressed on the cell surface of damaged cells or damaged/modified proteins that exist in the extracellular space. Upon binding, autoantibodies work to fine-tune the activation or suppression of the immune response. Inherent antibody characteristics such as antigen specificity, Ig class, IgG/A subclass, and glycosylation give autoantibodies the ability to regulate the immunological response to stimuli. Antigenic specificity is determined by the Fab’ portion of the antibody while effector function is dependent on the Fc portion of the antibody. Immune responses can be pro-inflammatory or anti-inflammatory based on the target antigen. Ig classes (IgM/G/A/E/D) have different immune activation capabilities and activate different immune pathways. For example, IgG and IgM are able to fix complement while IgA, IgD, and IgE are not. IgG/A subclasses are also capable of modulating effector functions. IgG1-4 have different complement fixation capabilities and interact with different FcyR’s, thereby, fine-tuning the immune response.

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  Figure 4. Antibody N-glycosylation can influence antibody effector functions. Antibodies are asymmetrically glycosylated on a conserved Asn297 residue within each of their Fc fragments. There are estimated to be at least 33 different glycosylation signatures that can be post-translationally added to an antibody. The fact that each antibody can be asymmetrically glycosylated on each Fc fragment suggests that there are many iterations of glycan modifications. Antigen-Antibody complexes can thus stimulate pro- or anti-inflammatory responses based on the combination of glycans added.