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

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.

[1]  A. Butte,et al.  Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes. , 2011, Kidney international.

[2]  N. Schork,et al.  Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal , 2011, Proceedings of the National Academy of Sciences.

[3]  I. M. Elkehili,et al.  Urinary tract infection in renal transplant recipients , 2010 .

[4]  R. Écochard,et al.  Chronic Rejection Triggers the Development of an Aggressive Intragraft Immune Response through Recapitulation of Lymphoid Organogenesis , 2010, The Journal of Immunology.

[5]  M. Sarwal,et al.  The yin and yang of B cells in graft rejection and tolerance. , 2010, Transplantation reviews.

[6]  M. Banach,et al.  The role of Toll-like receptors in renal diseases , 2010, Nature Reviews Nephrology.

[7]  T. Mohanakumar,et al.  Antihuman leukocyte antigen antibody-induced autoimmunity: role in chronic rejection , 2010, Current opinion in organ transplantation.

[8]  C. MacKenzie,et al.  Antibodies raised against chlamydial lipopolysaccharide antigens reveal convergence in germline gene usage and differential epitope recognition. , 2010, Biochemistry.

[9]  M. Kuskowski,et al.  Escherichia coli Sequence Type ST131 as an Emerging Fluoroquinolone-Resistant Uropathogen among Renal Transplant Recipients , 2009, Antimicrobial Agents and Chemotherapy.

[10]  C. Hassan,et al.  Eradication Therapy for Helicobacter pylori in Patients With Gastric MALT Lymphoma: A Pooled Data Analysis , 2009, The American Journal of Gastroenterology.

[11]  F. Batista,et al.  BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. , 2009, Blood.

[12]  Li Li,et al.  Identifying compartment-specific non-HLA targets after renal transplantation by integrating transcriptome and “antibodyome” measures , 2009, Proceedings of the National Academy of Sciences.

[13]  I. Cohen,et al.  Induction of IgG3 to LPS via Toll-Like Receptor 4 Co-Stimulation , 2008, PloS one.

[14]  W. Hörl,et al.  Urinary tract infection in renal transplant recipients , 2008, European journal of clinical investigation.

[15]  M. Sarwal,et al.  Characterization of intra-graft B cells during renal allograft rejection. , 2008, Kidney international.

[16]  M. Huber,et al.  Enhanced B‐cell activation mediated by TLR4 and BCR crosstalk , 2008, European journal of immunology.

[17]  S. Segerer,et al.  B cells and tertiary lymphoid organs in renal inflammation. , 2008, Kidney international.

[18]  T. Randall,et al.  Ectopic lymphoid tissues and local immunity. , 2008, Seminars in immunology.

[19]  F. Moreso,et al.  Immunephenotype of Glomerular and Interstitial Infiltrating Cells in Protocol Renal Allograft Biopsies and Histological Diagnosis , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[20]  C. Raetz,et al.  Lipid A modification systems in gram-negative bacteria. , 2007, Annual review of biochemistry.

[21]  C. Cohen,et al.  The contribution of B cells to renal interstitial inflammation. , 2007, The American journal of pathology.

[22]  A. Marshak‐Rothstein.  Toll-like receptors in systemic autoimmune disease , 2006, Nature Reviews Immunology.

[23]  J. Michel,et al.  Lymphoid neogenesis in chronic rejection: the murderer is in the house. , 2006, Current opinion in immunology.

[24]  Shankar Subramaniam,et al.  Kdo2-Lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4 Published, JLR Papers in Press, February 14, 2006. , 2006, Journal of Lipid Research.

[25]  H. Mori,et al.  Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection , 2006, Molecular systems biology.

[26]  E. Zucca,et al.  Delving deeper into MALT lymphoma biology. , 2005, The Journal of clinical investigation.

[27]  S. Akira,et al.  RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement , 2005, The Journal of experimental medicine.

[28]  B. Foxman,et al.  Escherichia coli mediated urinary tract infections: are there distinct uropathogenic E. coli (UPEC) pathotypes? , 2005, FEMS microbiology letters.

[29]  J. Schold,et al.  Long‐Term Renal Allograft Survival: Have we Made Significant Progress or is it Time to Rethink our Analytic and Therapeutic Strategies? , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[30]  M. Shlomchik,et al.  Activation of autoreactive B cells by CpG dsDNA. , 2003, Immunity.

[31]  M. Sarwal,et al.  Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. , 2003, The New England journal of medicine.

[32]  M. Stolte,et al.  Etiology and therapy of Helicobacter pylori-associated gastric lymphomas , 2003, Annals of Hematology.

[33]  Jongdae Lee,et al.  Two Lipoproteins Extracted from Escherichia coli K-12 LCD25 Lipopolysaccharide Are the Major Components Responsible for Toll-Like Receptor 2-Mediated Signaling1 , 2002, The Journal of Immunology.

[34]  M. Shlomchik,et al.  Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors , 2002, Nature.

[35]  C. Stratton,et al.  CME CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens , 2005 .

[36]  B. Bloom,et al.  Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. , 1999, Science.

[37]  T. C. Diss,et al.  Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori , 1993, The Lancet.

[38]  G. Ramsay,et al.  A broadly cross-protective monoclonal antibody binding to Escherichia coli and Salmonella lipopolysaccharides , 1993, Infection and immunity.

[39]  A. Cross,et al.  The human antibody response during natural bacteremic infection with gram-negative bacilli against lipopolysaccharide core determinants. , 1989, The Journal of infectious diseases.

[40]  J. Larrick,et al.  Human monoclonal antibodies that recognize conserved epitopes in the core-lipid A region of lipopolysaccharides. , 1987, The Journal of clinical investigation.

[41]  A. Horn,et al.  Lipid‐A‐Antibodies–Indicators for the Risk of Renal Scarring in Children with Urinary Tract Infection , 1986, Acta paediatrica Scandinavica.

[42]  W. Bessler,et al.  A defined fragment of bacterial protein I (OmpF) is a polyclonal B-cell activator , 1986, Infection and immunity.

[43]  I. Mattsby‐Baltzer,et al.  Experimental Escherichia coli ascending pyelonephritis in rats: changes in bacterial properties and the immune response to surface antigens , 1982, Infection and immunity.

[44]  I. Mattsby‐Baltzer,et al.  Antibodies to lipid A during urinary tract infection. , 1981, The Journal of infectious diseases.

[45]  D. Lopatin,et al.  Mitogen-induced amplification of blastogenesis in lipopolysaccharide-precultured lymphocytes , 1980, Infection and immunity.

[46]  P. Godowski,et al.  Toll-Like Receptor 2 Ligands as Adjuvants for Human Th1 Responses , 2002 .

[47]  A. Ravid,et al.  Quantitative dot-blot assay for low titer anti-lipopolysaccharide antibodies in human plasma. , 1995, Journal of immunological methods.