IgM anti-Fc gamma R autoantibodies trigger neutrophil degranulation.
Anti-Fc gamma R IgM monoclonal antibodies (mAbs) isolated from lipopolysaccharide-stimulated spleen cells from tightskin (TSK) mice were found to be polyspecific, reacting with a wide variety of molecules, including double-stranded DNA, topoisomerase, RNA polymerase, and different collagen types. Approximately 60% of the polyspecific IgM mAbs have anti-Fc gamma R specificity. These anti-Fc gamma R mAbs induce the release of hydrolases from both azurophil and specific granules of human neutrophils. 25-45% of the total cellular content (determined in Nonidet P-40 lysates) of neutrophil elastase, 10-25% of beta-glucuronidase, and 30-50% of alkaline phosphatase was released after incubation with the mAbs. The degranulation process was accompanied by dramatic morphological changes shown by scanning and transmission electron microscopy. The release of hydrolytic enzymes stimulated by the IgM anti-Fc gamma R mAbs was inhibited by preincubation of neutrophils with Fab fragments of either anti-human Fc gamma RII (IV.3) or anti-human Fc gamma RIII (3G8) mAbs. The binding of the anti-Fc gamma R TSK mAbs to human neutrophils was inhibited by Fab fragments of mAb 3G8. However, we found that the TSK anti-Fc gamma R mAbs do not bind to human Fc gamma RII expressed in either CHO cells or the P388D1 mouse macrophage cell line. Since the enzyme release could be inhibited by Fab fragments of mAb IV.3, we suggest that the signal transduction may require Fc gamma RII activation subsequent to crosslinking of the glycan phosphatidyl inositol-anchored Fc gamma RIII-1. These data demonstrate for the first time that polyspecific autoantibodies with Fc gamma R specificity can trigger neutrophil enzyme release via human Fc gamma RIII-1 in vitro and indicate a possible role for such autoantibodies in autoimmune inflammatory processes.
Boros
P
P
Department of Biochemistry, Mount Sinai School of Medicine, New York, New York 10029.
Odin
J A
JA
Muryoi
T
T
Masur
S K
SK
Bona
C
C
Unkeless
J C
JC
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D015550:Cell Degranulation; D003001:Cloning, Molecular; D005966:Glucuronidase / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009504:Neutrophils / Q000502:physiology* / Q000648:ultrastructure; D010196:Pancreatic Elastase / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG; D013045:Species Specificity; D014162:Transfection
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D007075:Immunoglobulin M; D011961:Receptors, Fc; D017452:Receptors, IgG; D005966:Glucuronidase; D010196:Pancreatic Elastase