β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome.
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. β2-glycoprotein I (β2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact β2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize β2GPI/HLA class II complexes in the absence of phospholipids. In situ association between β2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against β2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that β2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis.
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan;
Kenji
K
Tanimura
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan;
Hui
H
Jin
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan;
Tadahiro
T
Suenaga
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan;
Satoko
S
Morikami
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
Noriko
N
Arase
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan;
Kazuki
K
Kishida
Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan;
Kouyuki
K
Hirayasu
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan;
Masako
M
Kohyama
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan;
Yasuhiko
Y
Ebina
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan;
Shinsuke
S
Yasuda
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan;
Tetsuya
T
Horita
Department of Internal Medicine, Center for Rheumatic Diseases, Dohgo Spa Hospital, Matsuyma, Ehime, Japan;
Kiyoshi
K
Takasugi
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan;
Koichiro
K
Ohmura
Division of Genome Analysis, Medical Institute of Bioregulation, and.
Ken
K
Yamamoto
Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan;
Ichiro
I
Katayama
Institute for Advanced Study, Kyushu University, Fukuoka, Fukuoka, Japan;
Takehiko
T
Sasazuki
Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, CA; and.
Lewis L
LL
Lanier
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan;
Tatsuya
T
Atsumi
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan;
Hideto
H
Yamada
Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Honcho Kawaguchi, Saitama, Japan.
Hisashi
http://orcid.org/0000-0002-1153-3166
H
Arase
D000328:Adult; D000368:Aged; D017152:Antibodies, Antiphospholipid / Q000097:blood* / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology; D008297:Male; D046912:Multiprotein Complexes / Q000276:immunology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000276:immunology; D053482:beta 2-Glycoprotein I / Q000276:immunology* / Q000378:metabolism
D017152:Antibodies, Antiphospholipid; D001323:Autoantibodies; D000949:Histocompatibility Antigens Class II; D046912:Multiprotein Complexes; D053482:beta 2-Glycoprotein I