β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome

Kenji Tanimura, Hui Jin, Tadahiro Suenaga, Satoko Morikami, Noriko Arase, Kazuki Kishida, Kouyuki Hirayasu, Masako Kohyama, Yasuhiko Ebina, Shinsuke Yasuda, Tetsuya Horita, Kiyoshi Takasugi, Koichiro Ohmura, Ken Yamamoto, Ichiro Katayama, Takehiko Sasazuki, Lewis L. Lanier, Tatsuya Atsumi, Hideto Yamada, Hisashi Arase

Research output: Contribution to journalArticle

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Abstract

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. b2-glycoprotein I (b2GPI) 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 b2GPI, 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 b2GPI/HLA class II complexes in the absence of phospholipids. In situ association between b2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against b2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that b2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis. (Blood. 2015;125(18):2835-2844)

Original languageEnglish
Pages (from-to)2835-2844
Number of pages10
JournalBlood
Volume125
Issue number18
DOIs
Publication statusPublished - Jan 1 2015

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Histocompatibility Antigens Class I
Antiphospholipid Syndrome
Autoantigens
HLA Antigens
Glycoproteins
Autoantibodies
Phospholipids
Immunoglobulin Heavy Chains
Peptides
Antiphospholipid Antibodies
Molecules
Pregnancy Complications
Cytotoxicity
Rheumatoid Arthritis
Membrane Proteins
Reference Values
Thrombosis
Blood
Immunoglobulin G
Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Tanimura, K., Jin, H., Suenaga, T., Morikami, S., Arase, N., Kishida, K., ... Arase, H. (2015). β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. Blood, 125(18), 2835-2844. https://doi.org/10.1182/blood-2014-08-593624

β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. / Tanimura, Kenji; Jin, Hui; Suenaga, Tadahiro; Morikami, Satoko; Arase, Noriko; Kishida, Kazuki; Hirayasu, Kouyuki; Kohyama, Masako; Ebina, Yasuhiko; Yasuda, Shinsuke; Horita, Tetsuya; Takasugi, Kiyoshi; Ohmura, Koichiro; Yamamoto, Ken; Katayama, Ichiro; Sasazuki, Takehiko; Lanier, Lewis L.; Atsumi, Tatsuya; Yamada, Hideto; Arase, Hisashi.

In: Blood, Vol. 125, No. 18, 01.01.2015, p. 2835-2844.

Research output: Contribution to journalArticle

Tanimura, K, Jin, H, Suenaga, T, Morikami, S, Arase, N, Kishida, K, Hirayasu, K, Kohyama, M, Ebina, Y, Yasuda, S, Horita, T, Takasugi, K, Ohmura, K, Yamamoto, K, Katayama, I, Sasazuki, T, Lanier, LL, Atsumi, T, Yamada, H & Arase, H 2015, 'β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome', Blood, vol. 125, no. 18, pp. 2835-2844. https://doi.org/10.1182/blood-2014-08-593624
Tanimura K, Jin H, Suenaga T, Morikami S, Arase N, Kishida K et al. β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. Blood. 2015 Jan 1;125(18):2835-2844. https://doi.org/10.1182/blood-2014-08-593624
Tanimura, Kenji ; Jin, Hui ; Suenaga, Tadahiro ; Morikami, Satoko ; Arase, Noriko ; Kishida, Kazuki ; Hirayasu, Kouyuki ; Kohyama, Masako ; Ebina, Yasuhiko ; Yasuda, Shinsuke ; Horita, Tetsuya ; Takasugi, Kiyoshi ; Ohmura, Koichiro ; Yamamoto, Ken ; Katayama, Ichiro ; Sasazuki, Takehiko ; Lanier, Lewis L. ; Atsumi, Tatsuya ; Yamada, Hideto ; Arase, Hisashi. / β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. In: Blood. 2015 ; Vol. 125, No. 18. pp. 2835-2844.
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abstract = "Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. b2-glycoprotein I (b2GPI) 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 b2GPI, 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 b2GPI/HLA class II complexes in the absence of phospholipids. In situ association between b2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against b2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that b2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis. (Blood. 2015;125(18):2835-2844)",
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