Mast cells induce autoantibody-mediated vasculitis syndrome through tumor necrosis factor production upon triggering Fcgamma receptors.
The generation of autoantibodies and deposition of immune complexes (ICs) in tissue play a primary role in autoimmune diseases. However, the IC-triggered response consists of complex mechanisms that make it difficult to identify the pathogenesis and develop specific therapy. We clarified here a sequential mechanism for the induction of hypersensitivity angiitis by analyzing the responsible Fc receptor (FcR), effector cells, and mediators in an animal model using FcR-deficient mice. In this model, rheumatoid factor-mediated skin vasculitis was induced in wild-type mice, whereas FcRgamma-deficient mice did not develop the vasculitis. Adoptive transfer of various FcR(+) cells into FcRgamma-deficient mice showed that mast cells but not macrophages derived from wild-type mice triggered skin vasculitis. Mast cells derived from either FcgammaRIII-deficient or tumor necrosis factor (TNF)-deficient mice did not possess the inducibility of skin vasculitis. These results indicate that triggering of vascular inflammation was induced by mast cells through IC binding on FcgammaRIII. TNF produced by such activated mast cells was mainly responsible for the pathogenesis of autoantibody-mediated vasculitis. These findings illustrate the clinical significance of mast cells, Fcgamma receptors, and TNF in IC-induced vasculitis syndrome.
Watanabe
N
N
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
Akikusa
B
B
Park
S Y
SY
Ohno
H
H
Fossati
L
L
Vecchietti
G
G
Gessner
J E
JE
Schmidt
R E
RE
Verbeek
J S
JS
Ryffel
B
B
Iwamoto
I
I
Izui
S
S
Saito
T
T
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D011961:Receptors, Fc / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*; D014657:Vasculitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology
D001323:Autoantibodies; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha