Nature 2002 Apr 11;416(6881):603-7
Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A.
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent.
When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences.
B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF).
Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family.
Inhibitor studies implicate TLR9.
These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles.
The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.