Analysis of the B cell receptor repertoire in six immune-mediated diseases.

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression.

ABO-incompatible (ABOi) kidney transplantation is an established therapy, though its implementation to date has been in part limited by the requirement for additional immunosuppression. Here, we describe the outcomes of 37 patients undergoing ABOi kidney transplantation utilizing perioperative antibody depletion and receiving an identical tacrolimus-based immunosuppressive regimen to contemporaneous ABO-compatible (ABOc) recipients, with the exception that mycophenolate was commenced earlier (7-14 days pretransplant). Antibody depletion was scheduled according to baseline anti-ABO antibody titer (tube IAT method: median 1:128, range 1:8 to 1:4096). Patient and graft survival for the 37 ABOi recipients was 100% after a median 26 months (interquartile range [IQR] 18-32). Eight rejection episodes (two antibody-mediated and six cellular) in ABOi recipients were successfully treated with biopsy-proven resolution. Latest median eGFR is 50 mL/min × 1.73 m² (IQR 40-64) for ABOi patients and 54 mL/min × 1.73 m² (IQR 44-66) in the ABOc patients (p = 0.25). We conclude that ABOi transplantation can be performed successfully with perioperative antibody removal and conventional immunosuppression. This suggests that access to ABOi transplantation can include a broader range of end-stage kidney disease patients.