B cells, natural antibodies, and humoral rejection in kidney transplantation: innate immunity to donor-specific alloresponses

Antibody-mediated rejection (ABMR) remains the leading immunological cause of kidney allograft loss, yet its humoral origins are incompletely understood. The prevailing paradigm focuses on adaptive B-2 cell responses and de novo donor-specific antibodies (DSA) against HLA antigens, but this framework overlooks an earlier and increasingly recognised humoral tier: B-1 cells and the natural antibodies (NAbs) they constitutively produce. Emerging clinical evidence shows that class-switched IgG NAbs, amplified by inflammation, are associated with HLA sensitisation after transplantation and with long-term renal allograft failure. Innate-like polyreactive B cells have also been identified infiltrating renal allografts during rejection episodes, implicating them directly in intragraft humoral injury. Taken together, these findings suggest that humoral alloimmunity in kidney transplantation initiates well before DSA are detectable — through a cascade rooted in innate B cell biology that has yet to be systematically described. This Research Topic aims to establish a unified framework for humoral alloimmunity in kidney transplantation, one that brings together innate and adaptive B cell compartments — from natural antibodies produced by B-1 cells to DSA arising from germinal centres — and maps their sequential and overlapping contributions to renal allograft injury. A central objective is to consolidate evidence that IgM and class-switched IgG NAbs recognise post-ischaemic neoepitopes on renal endothelium, activate complement, and generate the inflammatory milieu that primes downstream adaptive alloresponses. The Topic also aims to examine how memory B cells, long-lived plasma cells, and intragraft tertiary lymphoid organs sustain DSA production and ABMR independently of peripheral humoral control, and why these compartments remain refractory to conventional immunosuppression. Finally, it will consider how current therapeutic strategies in kidney transplantation — including co-stimulatory blockade, complement inhibition, and desensitisation protocols — engage or fall short of addressing the innate humoral tier, and whether approaches targeting natural antibodies could improve outcomes in sensitised recipients and those at high immunological risk. This Research Topic welcomes original research articles, systematic reviews, meta-analyses, and perspective pieces focused on B cell and antibody biology in kidney transplantation. Topics of particular interest include: • The biology of B-1 cells and natural antibodies in the renal transplant setting • The role of IgM and IgG NAbs in ischaemia-reperfusion injury, complement-mediated endothelial damage, and HLA sensitisation • De novo DSA genesis, IgG subclass pathogenicity, and C1q-binding capacity in renal allograft outcomes • Memory B cell and long-lived plasma cell persistence under immunosuppression • Intragraft tertiary lymphoid organ formation and autonomous antibody production • Regulatory B cell phenotyping as a biomarker of operational tolerance • The impact of co-stimulatory blockade or biologics targeting complement on humoral alloimmunity Studies incorporating both experimental models and human kidney transplant cohorts are strongly encouraged.Topic Editor Takayuki Hirose has declared collaborative research with PorMedTech and has received honoraria for lectures from Takeda Pharmaceutical Company Limited and Astellas Pharma Inc. Topic editors: Takayuki Hirose, Erik Berglund Source: https://www.frontiersin.org/research-topics/82919/b-cells-natural-antibodies-and-humoral-rejection-in-kidney-transplantation-innate-immunity-to-donor-specific-alloresponses