Vasoactive intestinal peptide binding autoantibodies in autoimmune humans and mice.
Autoantibodies capable of binding the immunoregulatory neuropeptide vasoactive intestinal peptide (VIP) were detected in the sera of a mouse strain prone to autoimmune disease due to the lpr mutation (MRL/lpr). The autoantibodies were not present in control wildtype MRL/lpr mice, but they were readily detected in humans without autoimmune disease. The binding was due to low affinity VIP recognition. Increased VIP binding activity was evident in patients with systemic lupus erythematosus but not systemic sclerosis, Sjögren's syndrome (SS), rheumatoid arthritis or autoimmune thyroiditis. Recombinant VIP binding Fv clones (fragment variable; the variable domains of the light and heavy chains antibody subunits joined with a peptide linker) were isolated from a phage display library prepared from lupus patients. One Fv clone displaying VIP-selective binding and several clones displaying cross-reactivity with unrelated peptides were identified. Replacement mutations in the VIP-selective clone were preferentially localized in the regions known to make contacts with the antigen, i.e. the complementarity determining regions, suggesting that the selective binding activity is due to immunological maturation of the antibodies. Frequent occurrences of autoantibody responses to VIP indicate that immunological tolerance to this neuropeptide can be readily broken. The depletion of VIP by specific antibodies in autoimmune disease may interfere with VIP regulation of T cells and inflammatory cells and result in further amplification of autoreactive immunological responses.
Bangale
Yogesh
Y
Department of Pathology and Medicine, Chemical Immunology Research Center, University of Texas Medical School, Houston, TX, USA.
Cavill
Dana
D
Gordon
Tom
T
Planque
Stephanie
S
Taguchi
Hiroaki
H
Bhatia
Gita
G
Nishiyama
Yasuhiro
Y
Arnett
Frank
F
Paul
Sudhir
S
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D011863:Radioimmunoassay; D012595:Scleroderma, Systemic / Q000276:immunology*; D014660:Vasoactive Intestinal Peptide / Q000276:immunology*
D001323:Autoantibodies; D007128:Immunoglobulin Fragments; D014660:Vasoactive Intestinal Peptide