Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor.
Anti-lymphocyte antibodies (Abs) that suppress T-cell chemotactic and other responses to sphingosine 1-phosphate (S1P), but not to chemokines, were found in a lymphopenic patient with recurrent infections. Lymphocyte type 1 S1P receptor (S1P(1)) that transduces S1P chemotactic stimulation was recognized by patient Abs in Western blots of T cells, S1P(1) transfectants, and S1P(1)-hemagglutinin purified by monoclonal anti-hemagglutinin Ab absorption. The amino terminus of S1P(1), but not any extracellular loop, prevented anti-S1P(1) Ab suppression of S1P(1) signaling and T-cell chemotaxis to S1P. Human purified anti-S1P(1) Abs decreased mouse blood lymphocyte levels by a mean of 72%, suppressed mouse T-cell chemotaxis to S1P in vivo, and significantly reduced the severity of dextran sodium sulfate-induced colitis in mice. Human Abs to the amino terminus of S1P(1) suppress T-cell trafficking sufficiently to impair host defense and provide therapeutic immunosuppression.
Liao
Jia-Jun
JJ
Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Huang
Mei-Chuan
MC
Fast
Katharine
K
Gundling
Katherine
K
Yadav
Mahesh
M
Van Brocklyn
James R
JR
Wabl
Matthias R
MR
Goetzl
Edward J
EJ
D000368:Aged; D000818:Animals; D000941:Antigens / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology; D003092:Colitis / Q000276:immunology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D001323:Autoantibodies; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D020033:Protein Isoforms; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine