title: Human rheumatoid factor production is dependent on CD40 signaling and autoantigen.
abstract: High-affinity pathologic rheumatoid factor (RF) B cells occur in autoimmune diseases such as rheumatoid arthritis, but are deleted in healthy individuals. The reasons for the survival and differentiation of these autoreactive B cells in rheumatoid arthritis are not known. Previous studies in mice transgenic for a human IgM RF have shown that peripheral encounter with soluble human IgG leads to deletion of high-affinity RF B cells; however, deletion can be prevented when concomitant T cell help is provided. This study aimed to further discern the minimal factors necessary not only for the in vivo survival of RF B cells, but also for their differentiation into Ab-secreting cells. The combination of MHC class II-reactive T cells and Ag induced the production of RF in human IgM RF transgenic mice, while either stimulus alone was ineffective. Neutralizing Abs against CD40 ligand (CD40L), but not against IL-4 or IL-15, abrogated IgM-RF production. Moreover, blockade of CD40L-CD40 allowed IgG to delete the RF precursor cells. Most importantly, activating Abs to CD40 could substitute entirely for T cell help in promoting the survival of RF precursors and in stimulating RF synthesis in T cell deficient animals. The data indicate that CD40 signaling alone can prevent deletion of RF B cells by Ag and in the presence of IgG is sufficient to trigger RF synthesis. The results suggest that selective induction of apoptosis in high-affinity RF B cells may be achieved by blockade of CD40L-CD40 interaction.
authors.affiliation: Department of Medicine, The Sam and Rose Stein Institute for Research on Aging, University of California at San Diego, La Jolla 92093, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kyburz
authors.forename: M
authors.initials: M
authors.lastname: Corr
authors.forename: D C
authors.initials: DC
authors.lastname: Brinson
authors.forename: A
authors.initials: A
authors.lastname: Von Damm
authors.forename: H
authors.initials: H
authors.lastname: Tighe
authors.forename: D A
authors.initials: DA
authors.lastname: Carson
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001324:Autoantigens / Q000008:administration & dosage / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D023201:CD40 Ligand; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D019409:Interleukin-15 / Q000008:administration & dosage / Q000494:pharmacology; D015847:Interleukin-4 / Q000008:administration & dosage / Q000494:pharmacology; D008024:Ligands; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012217:Rheumatoid Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D001324:Autoantigens; D019013:CD40 Antigens; D015395:Histocompatibility Antigens Class I; D007106:Immune Sera; D007074:Immunoglobulin G; D019409:Interleukin-15; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D015847:Interleukin-4; D012217:Rheumatoid Factor