The costimulatory immunogen LPS induces the B-Cell clones that infiltrate transplanted human kidneys

Abstract

The mechanism of chronic rejection of transplanted human kidneys is unknown. An understanding of this process is important because, chronic rejection ultimately leads to loss of the kidney allograft in most transplants. One feature of chronic rejection is the infiltration of ectopic B-cell clusters that are clonal into the transplanted kidney. We now show that the antibodies produced by these B-cells react strongly with the core carbohydrate region of LPS. Since LPS is a costimulatory immunogen that can react with both the B-cell receptor (BCR) and the Toll-like receptor 4 (TLR4), these results suggest a mechanism for the selective pressure that leads to clonality of these B-cell clusters and opens the possibility that infection and the attendant exposure to LPS plays a role in the chronic rejection of human kidney transplants. If confirmed by clinical studies, these results suggest that treating patients with signs of chronic rejection with antibiotics may improve kidney allograft survival.

Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies

“…Independent of immunosuppression, infections of the urinary tract or posttransplant alterations of the UMB may well lead to additional immune dysregulation and consequent immune‐mediated graft injury. In fact, two recent papers from our laboratory group demonstrate that antibodies produced by B cell clusters commonly found in the biopsies of IFTA subjects are not recognizing donor HLA antigens but rather are specific for Escherichia coli Lipopolysaccharide, a powerful immune activator through the canonical TLR4 receptor . Another of our studies identified the role of a new mycoplasma protein, obtained from a potential human urinary pathogen, as a powerful, polyclonal B cell activator .…”

Transplantation tolerance and its outcome during infections and inflammation

“…B-cell receptor specificity for bacterial lipopolysaccharide (LPS) has been recently identified in B cells infiltrating and expanding within human renal allografts undergoing chronic rejection (232). Since LPS can react in these cells with both the BCR and TLR4, these observations led the authors to speculate on the possibility that infection and the attendant exposure to LPS play a role in the chronic rejection of human kidney transplants.…”

A Structurally Distinct Human Mycoplasma Protein that Generically Blocks Antigen-Antibody Union

“…Clonal B-cell proliferation, as well as lymphomas and myelomas, can result from chronic infections with organisms such as Escherichia coli ( E. coli ) and Helicobacter pylori ( H. pylori ) (1–6). The main feature seems to be the approximation of two systems each capable of sustained replication where the replicating microbe induces proliferation and selection of members of the replicating B-cell repertoire.…”