title: Mycophenolic acid differentially impacts B cell function depending on the stage of differentiation.
abstract: Production of pathogenic Abs contributes to disease progression in many autoimmune disorders. The immunosuppressant agent mycophenolic acid (MPA) has shown clinical efficacy for patients with autoimmunity. The goal of these studies was to elucidate the mechanisms of action of MPA on B cells isolated from healthy individuals and autoimmune patients. In this study, we show that MPA significantly inhibited both proliferation and differentiation of primary human B cells stimulated under various conditions. Importantly, MPA did not globally suppress B cell responsiveness or simply induce cell death, but rather selectively inhibited early activation events and arrested cells in the G0/G1 phase of the cell cycle. Furthermore, MPA blocked expansion of both naive and memory B cells and prevented plasma cell (PC) differentiation and Ab production from healthy controls and individuals with rheumatoid arthritis. Finally, whereas MPA potently suppressed Ig secretion from activated primary B cells, terminally differentiated PCs were not susceptible to inhibition by MPA. The target of MPA, IMPDH2, was found to be downregulated in PCs, likely explaining the resistance of these cells to MPA. These results suggest that MPA provides benefit in settings of autoimmunity by directly preventing activation and PC differentiation of B cells; however, MPA is unlikely to impact autoantibody production by preexisting, long-lived PCs.
authors.affiliation: MedImmune, LLC, Gaithersburg, MD 20878, USA.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Karnell
authors.forename: Fredrick G
authors.initials: FG
authors.lastname: Karnell
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Stephens
authors.forename: Bhargavi
authors.initials: B
authors.lastname: Rajan
authors.forename: Chris
authors.initials: C
authors.lastname: Morehouse
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Bonnie
authors.initials: B
authors.lastname: Swerdlow
authors.forename: Mildred
authors.initials: M
authors.lastname: Wilson
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: Christopher
authors.initials: C
authors.lastname: Groves
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.forename: Rachel
authors.initials: R
authors.lastname: Ettinger
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D018920:Coculture Techniques; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid