Transport of misfolded endoplasmic reticulum proteins to the cell surface by MHC class II molecules

Yan, Jianhua; Arase, Noriko; Kohyama, Masanori; Hirayasu, Kouyuki; Sasajima, Tadahiro; Jin, Hui; Matsumoto, Maki; Shida, Kyoko; Lanier, Lewis L.; Saito, Takashi; Arase, Hisashi

doi:10.1093/intimm/dxs155

Cited by 59 publications

(49 citation statements)

References 30 publications

(36 reference statements)

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“…32 Furthermore, intact IgG heavy chain is transported to the cell surface by HLA class II molecules via association with the peptide-binding groove, and IgG heavy chain/ HLA class II complexes are recognized by autoantibodies in rheumatoid factor-positive sera from RA patients. 33 In contrast, autoantibodies in rheumatoid factor-positive sera from non-RA individuals did not bind to IgG heavy chain/HLA class II complexes, suggesting that IgG heavy chain complexed with HLA-DR is a specific target for autoantibodies from RA patients.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, however, we found that misfolded proteins are rescued from degradation and transported to the cell surface without processing to peptides when they associate with the peptide-binding groove of HLA class II molecules in the endoplasmic reticulum (ER). 32,33 Structural analyses of major histocompatibility complex (MHC) class II molecules have revealed that both ends of the MHC class II peptide-binding groove are open. Therefore, it is possible that MHC class II molecules might bind linear epitopes exposed on misfolded proteins.…”

Section: Introductionmentioning

confidence: 99%

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

Tanimura

Jin

Sasajima

et al. 2015

Blood

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Key Points• b2GPI complexed with HLA class II molecules was found to be a target for autoantibodies in APS.• More than 80% of patients with APS possess autoantibodies against b2GPI/HLA class II complexes.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 IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial or venous thrombosis and pregnancy complications, including recurrent spontaneous abortion.1,2 APS is associated with antiphospholipid (aPL) antibodies that bind to anionic phospholipid and serum protein complexes. [3][4][5] Interactions between aPL antibodies and vascular endothelial cells are thought to be involved in the pathogenesis of APS.6-9 b2-glycoprotein I (b2GPI) is the main phospholipid-binding molecule recognized by aPL antibodies 5,10,11 and is produced predominantly by hepatocytes, although some endothelial cells of blood vessels and placental villous tissue also express it.12,13 Plasma b2GPI circulates in a circular conformation with the aPL antibody epitopes being cryptic.14 When b2GPIassociates with anionic phospholipids such as cardiolipin (CL), the circular structure of plasma b2GPI is converted to a linear form, leading to exposure of the major epitope for aPL antibodies. [14][15][16][17][18][19] Therefore, b2GPI bound to negatively charged phospholipids or negatively charged plates is used clinically to detect antibodies. 20However, autoantibodies against the b2GPI associated with phospholipids are detected in less than half the patients with clinical manifestations of APS, [21][22][23] suggesting the existence of additional ta...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Tanimura

Jin

Sasajima

et al. 2015

Blood

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“…Unexpectedly, we discovered that these misfolded HLA class I molecules were transported to the cell surface by association with the peptide-binding groove of HLA class II molecules (8). Indeed, direct association between HLA class II molecules and misfolded HLA class I molecules was detected in HLA class II-expressing B-cell lines.…”

Section: −5mentioning

confidence: 94%

“…HLA-Cw3-pep-HLA-DRB1*04:04 containing a covalently attached peptide was generated by adding the peptide sequence (Cw3: GSHSMRYFYTAVSRPGR) and linker (GSGSGS) between the signal sequence and extracellular domain of these MHC class II cDNA as previously described (35). A cDNA for the mutHEL in which two cysteine residues at positions 30 and 64 were replaced with alanine was generated as described (8). V regions of RF61 RF mAb were synthesized according to the published sequence (accession numbers: for heavy chain, X54437; λ chain, X54438).…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, direct association between HLA class II molecules and misfolded HLA class I molecules was detected in HLA class II-expressing B-cell lines. Furthermore, the intact misfolded proteins transported to the cell surface by HLA class II molecules efficiently stimulated antigen-specific B cells (8). Accordingly, we hypothesized that misfolded proteins aberrantly transported to the cell surface by HLA class II molecules might be targets for autoantibodies detected in autoimmune diseases.…”

Section: −5mentioning

confidence: 99%

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Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility

Jin

Arase²,

Hirayasu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Specific HLA class II alleles are strongly associated with susceptibility to rheumatoid arthritis (RA); however, how HLA class II regulates susceptibility to RA has remained unclear. Recently, we found a unique function of HLA class II molecules: their ability to aberrantly transport cellular misfolded proteins to the cell surface without processing to peptides. Rheumatoid factor (RF) is an autoantibody that binds to denatured IgG or Fc fragments of IgG and is detected in 70–80% of RA patients but also in patients with other diseases. Here, we report that intact IgG heavy chain (IgGH) is transported to the cell surface by HLA class II via association with the peptide-binding groove and that IgGH/HLA class II complexes are specifically recognized by autoantibodies in RF-positive sera from RA patients. In contrast, autoantibodies in RF-positive sera from non-RA individuals did not bind to IgGH/HLA class II complexes. Of note, a strong correlation between autoantibody binding to IgG complexed with certain HLA-DR alleles and the odds ratio for that allele’s association with RA was observed (r = 0.81; P = 4.6 × 10−5). Our findings suggest that IgGH complexed with certain HLA class II alleles is a target for autoantibodies in RA, which might explain why these HLA class II alleles confer susceptibility to RA.

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Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase

et al. 2020

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In organ transplantation, donor‐specific HLA antibody (DSA) is considered a major cause of graft rejection. Because DSA targets primarily donor‐specific human leukocyte antigen (HLA) expressed on graft endothelial cells, the prevention of its expression is a possible strategy for avoiding or salvaging DSA‐mediated graft rejection. We examined the effect of various clinically used drugs on HLA class II expression on endothelial cells. Interferon‐γ (IFN‐γ)‐induced HLA class II DR (HLA‐DR) was downregulated by everolimus (EVR, 49.1% ± 0.8%; P < 0.01) and fluvastatin (FLU, 33.8% ± 0.6%; P < 0.01). Moreover, the combination of EVR and FLU showed a greater suppressive effect on HLA‐DR expression. In contrast, cyclosporine, tacrolimus, mycophenolic acid, and prednisolone did not exhibit any significant suppressive effect. FLU, but not EVR, suppressed mRNA of HLA‐DR. Imaging analysis revealed that HLA‐DR expressed in cytosol or on the cell surface was repressed by EVR (cytosol: 58.6% ± 4.9%, P < 0.01; cell surface: 80.9% ± 4.0%, P < 0.01) and FLU (cytosol: 19.0% ± 3.4%, P < 0.01; cell surface: 48.3% ± 4.8%, P < 0.01). These data indicated that FLU and EVR suppressed IFN‐γ‐induced HLA‐DR expression at the transcriptional and post‐translational level, respectively, suggesting a potential approach for alleviating DSA‐related issues in organ transplantation.

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Transport of misfolded endoplasmic reticulum proteins to the cell surface by MHC class II molecules

Cited by 59 publications

References 30 publications

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

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

Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility

Interferon‐γ‐induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG‐CoA reductase

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