Anti-HLA antibodies may be a subset of polyreactive immunoglobulins generated after viral superinfection
Year: 2025
Type: article
Abstract: 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 (under curation). • The NETRAD algorithm delineates HLA epitopes from superinfecting viral components. • EBV components appear essential to generate anti-HLA antibodies. • Ischemia-reperfusion injury trigger key post-translational modifications. • Post-translational modifications can facilitate the generation of HLA-homologous neoepitopes. • While the antigenicity of HLA proteins can be confirmed in both historical and current literature, the imputation of immunogenicity upon HLA cannot be reliably confirmed, thereby warranting the premise of viral superinfection as a precursor to the generation of anti-HLA antibodies.
Source: Transplant Immunology
Authors: Steven D. Heron, Jim Shaw, Johannes Dapprich
Institution: Generation Biotech (United States)
Language: English
Subfield: Transplantation
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,440
OpenAlex ID: W4407425458