VIPase autoantibodies in Fas-defective mice and patients with autoimmune disease.
The immunoregulatory neuropeptide vasoactive intestinal peptide (VIP) was cleaved by purified IgG from Fas-defective C3H/gld mice, lupus patients, and autoimmune thyroiditis patients. No VIPase activity was detected in IgG from control mice and humans. Kinetic analyses of VIPase IgG preparations suggested low-affinity recognition of VIP. Yet the VIPase activity was VIP selective, judged by lack of correlation with other protease activities expressed by the IgG and by noninterference of unrelated peptides in the activity. Recombinant Fv constructs selected from a human lupus phage show library displayed VIPase activity, confirming that the active site is located in the V domains. Inhibition of the VIPase activity by di-isopropylfluorophosphate suggested a serine protease-like mechanism of catalysis. Irreversible binding of a biotinyated phosphonate diester by the IgG and Fv preparations was observed, consistent with the presence of activated nucleophiles similar to those in enzymes capable of covalent catalysis. These observations show that VIP is a target for specific catalytic autoantibodies in autoimmune disease.
Bangale
Yogesh
Y
Chemical Immunology Research Center, Department of Pathology, University of Texas Medical School, 6431 Fannin, Houston, TX 77030, USA.
Karle
Sangeeta
S
Planque
Stephanie
S
Zhou
Yong-Xin
YX
Taguchi
Hiroaki
H
Nishiyama
Yasuhiro
Y
Li
Lan
L
Kalaga
Ravishankar
R
Paul
Sudhir
S
D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism*; D002384:Catalysis; D003001:Cloning, Molecular; D006801:Humans; D006868:Hydrolysis; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009154:Mutation; D009842:Oligopeptides / Q000378:metabolism; D013954:Thyroglobulin / Q000378:metabolism; D013967:Thyroiditis, Autoimmune / Q000276:immunology / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics
D001323:Autoantibodies; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D009842:Oligopeptides; D019014:fas Receptor; C055966:immunoglobulin Fv; D014660:Vasoactive Intestinal Peptide; C025273:prolyl-phenylalanyl-arginine-4-methylcoumaryl-7-amide; D013954:Thyroglobulin