Significant Correlation of Antibody Repertoire Perturbations to Clinical Manifestations in Lupus Nephritis

Background: Lupus nephritis (LN), characterized by immune complex formation through autoantibodies recognizing multiple autoantigens and kidney deposition, is a major cause of morbidity and mortality that affects up to 60% of the SLE population during disease. However, detailed antibody repertoire profiling of all 5 isotypes and 9 subtypes remains unclear. Moreover, whether and the extent to which antibody repertoire features associate with important clinical manifestations of LN is unclear. <div id="gtx-trans" style="position: absolute; left: 588px; top: 55.3906px;"> <div class="gtx-trans-icon"> </div> </div> Methods: PBMC samples for 58 LN patients and 58 healthy controls were collected. Using a highly accurate repertoire sequencing strategy developed in our lab, we acquired antibody repertoires of all nine subtypes with single experiment. The base errors and amplification bias intrinsic to antibody repertoire sequencing were further corrected using the bioinformatics pipeline of DUMPArts. The isotype specific repertoire features were then compared between patients and healthy controls. <div id="gtx-trans" style="position: absolute; left: 557px; top: 55.3906px;"> <div class="gtx-trans-icon"> </div> </div> Results: Preferential up- and down-regulation of various IGHV genes in IgM, IgD, IgG, and IgA and subtypes of IgG and IgA indicate the perturbation of antibody repertoire for both naïve and activated B cells. The CDR3s of LN patients were significantly shorter than those in healthy controls in almost all isotypes. The SHMs were lower in repertoires of activated isotypes for LN patients while the SHMs in IgD repertoire were significantly higher, which suggests IgD+ B cells may be important for the disease severity. Evidenced clonal expansion in IgM and IgD compared to the activated isotypes (IgG, IgA, IgE). Combined repertoire-based features and support vector machine (SVM) model could distinguish LN patients from healthy donors with high accuracy. <div id="gtx-trans" style="position: absolute; left: 631px; top: 96.9844px;"> <div class="gtx-trans-icon"> </div> </div> Conclusion: Our results demonstrated multi-faceted nonunanimous perturbations of the antibody repertoire. The findings of significant changes in naïve repertoire compartment, especially changes in IgD. Repertoire features might serve as a biomarker for disease severity. Funding: Government Support – Non-U.S.