Anti-HLA antibodies may be a subset of polyreactive immunoglobulins generated after viral superinfection

Chronic rejection remains an obstacle to long-term allograft survival. Donor-specific anti-HLA antibodies (DSA) play a significant role in causing chronic antibody-mediated allograft rejection. Exposure to mismatched HLA antigens via transfusion, pregnancy, or transplanted tissue has been described in the literature as an immunogenic stimulus of anti-HLA antibodies. Yet anti-HLA antibodies also develop in the absence of traditional sensitization events and molecular mimicry has been postulated as a stimulus for these naturally occurring alloantibodies. While heterologous reactivity has been documented between virus components and allogeneic T cells, there is insufficient evidence to support the development of anti-HLA antibodies from viral components. We hypothesized that anti-HLA antibodies may develop following viral coinfection or superinfection. The objectives of this investigation included: 1) developing an in-silico algorithm to identify viral peptide components that exhibit HLA-specific homology, and 2) identifying cellular changes that take place during ischemia/reperfusion injury which could facilitate the generation of novel anti-HLA antibodies from viral sources. We developed the neoepitope transplant rejection and autoimmune disease (NETRAD) algorithm to identify amino acid sequence homology between viral envelope proteins and HLA. The algorithm integrates post-translational protein modifications that are consistent with ischemia/reperfusion injury. Seventy-two HLA-specific epitopes were demarcated as examples using this approach. In conclusion, we present in-silico evidence which supports the identification of anti-HLA antibodies as a subset of polyreactive antibodies generated from stress-modified viral envelope proteins. Remarkably, each targeted HLA epitope associated with a distinct anti-HLA antibody could be consistently attributed to a major envelope glycoprotein component of Epstein Barr virus. Transplant Immunology manuscript # TRIM-D-24-00351. Dryad data repository:https://doi.org/10.5061/dryad.qjq2bvqpq.