Inhibition of antigen trafficking through scavenger receptor A.
B cell acquisition and presentation of specific autoantigens (auto-Ags) are thought to play an important and complex role in autoimmunity development. We previously identified scavenger receptor A (SR-A) as an early target in altering B cell-mediated autoimmunity. SR-A is highly expressed on professional antigen-presenting cells such as macrophages (MΦs) and dendritic cells (DCs). In this study, we demonstrate that SR-A is responsible for controlling B cell interactions with DCs/MΦs to promote Ag transfer from B cells to DCs/MΦs. We established a high-throughput ELISA-based screen to identify novel SR-A inhibitors, the specificity of which was determined by dose dependence and Biacore surface plasmon resonance testing. We identified small molecule inhibitors (SMIs) able to reduce SR-A-mediated Ag transfer in human cells. In particular, the SMIs prevented SR-A-positive cells from accumulating/loading Ag over time. Furthermore, we determined that one SMI, sennoside B, can reduce SR-A-mediated capture of B cells. Finally, SMI-mediated decreases in Ag transfer or accumulation reduced T cell proliferation in vitro and in vivo. These observations demonstrate that B cell-DC/MΦ interactions are conducive to promoting Ag trafficking between these cell types via SR-A. Inhibitors of SR-A may provide a novel therapeutic strategy in ameliorating autoimmune disease development.
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Maurice T
MT
Raycroft
Bohdan P
BP
Harvey
Matthew J
MJ
Bruck
Mark J
MJ
Mamula
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D051117:Scavenger Receptors, Class A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012676:Senna Extract; D000081226:Sennosides; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D000880:Anthraquinones; D000941:Antigens; D001324:Autoantigens; D051117:Scavenger Receptors, Class A; D000081226:Sennosides; D054852:Small Molecule Libraries; D012676:Senna Extract