Deficient antigen-presenting cell function in multiple genetic complementation groups of type II bare lymphocyte syndrome.

Kovats, Susan; Nepom, Gerald T.; Coleman, Marilyn A.; Nepom, Barbara S.; Kwok, William W.; Blum, Janice S.

doi:10.1172/jci118023

Cited by 33 publications

(37 citation statements)

References 45 publications

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Section: Cell Linesmentioning

confidence: 99%

“…Human B lymphoblastoid cell lines 6.16 and BLS-1, and the human monocytes THP-1 were cultured in complete IMDM with 10% heat-inactivated fetal bovine serum, 50 U/mL penicillin and 50 lg/mL streptomycin [13,36,40,45]. 6.16, BLS-1 and THP-1 cells were transduced using retroviral vectors for constitutive expression of HLA-DR4 (DRB1*0401) with linked drug selection markers for hygromycin and histidinol resistance [36,40,45].…”

Section: Cell Linesmentioning

confidence: 99%

“…6.16, BLS-1 and THP-1 cells were transduced using retroviral vectors for constitutive expression of HLA-DR4 (DRB1*0401) with linked drug selection markers for hygromycin and histidinol resistance [36,40,45]. Expression of surface HLA-DR4 complexes on B cells and macrophages was confirmed by flow cytometric analysis using the DR4-specific monoclonal antibody 359-F10 [46].…”

Section: Cell Linesmentioning

confidence: 99%

“…Expression of surface HLA-DR4 complexes on B cells and macrophages was confirmed by flow cytometric analysis using the DR4-specific monoclonal antibody 359-F10 [46]. 6.16.DR4, BLS-1.DR4 and THP-1.DR4 cells were then transduced using retroviral vectors for constitutive expression of DM molecules [40,45,47]. Steady-state expression of DM molecules in 6.16.DR4.DM, BLS-1.DR4.DM and THP-1.DR4.DM cells was confirmed by western blot analysis using DM-specific antibody (JSB-DM) [47,48].…”

Section: Cell Linesmentioning

confidence: 99%

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII [261][262][263][264][265][266][267][268][269][270][271][272][273] , which binds to HLA-DR4 and activates CD4 + T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII 261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope to activate CD4 + T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide is internalized by APC and edited by HLA-DM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class IImediated CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope presentation and regulates CD4 + T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.Key words: CD4 + T cells Á HLA-DM Á HLA-DR Á Peptide presentation Á Type II collagen IntroductionType II collagen (CII) is the major protein component of articular cartilage [1]. It is thought that T and B cell responses to this autoantigen are associated with the development and pathogenesis of rheumatoid arthritis (RA) [2,3]. It is also widely believed that RA is genetically linked to HLA class II molecules, including some HLA-DR4 alleles, and that T cell responses in collagendependent RA are directed towards the immunodominant pathogenic epitope CII [261][262][263][264][265][266][267][268][269][270][271][272][273] [4,5]. Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur. J. Immunol. 2008. 38: 1961-1970 Immunomodulation in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5...

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Section: Cell Linesmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

See 2 more Smart Citations

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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“…This process is dependent on HLA-DM such that in HLA-DM-deficient cells, the SDS-resistant property of various HLA-DR, -DQ, and -DP molecules is generally lost (5,(7)(8)(9). Peptides eluted from DR3 on HLA-DM-deficient cells are predominantly derived from invariant chain (10,11).…”

mentioning

confidence: 99%

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

Ettinger

Liu

Nepom

et al. 2000

The Journal of Immunology

103

160

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Studies of the stability of HLA-DQ have revealed a correlation between SDS stability of MHC class II αβ dimers and insulin-dependent diabetes mellitus (IDDM) susceptibility. The MHC class II αβ dimer encoded by HLA-DQA1*0102/DQB1*0602 (DQ0602), which is a dominant protective allele in IDDM, exhibits the greatest SDS stability among HLA-DQ molecules in EBV-transformed B-lymphoblastoid cells and PBLs. DQ0602 is also uniquely SDS stable in the HLA-DM-deficient cell line, BLS-1. We addressed the molecular mechanism of the stability of DQ0602 in BLS-1. A panel of mutants based on the polymorphic differences between HLA-DQA1*0102/DQB1*0602 and HLA-DQA1*0102/DQB1*0604 were generated and expressed in BLS-1. An Asp at β57 was found to be critical for SDS stability, whereas Tyr at β30, Gly at β70, and Ala at β86 played secondary roles. Furthermore, the level of class II-associated invariant chain peptide bound to HLA-DQ did not correlate with SDS stability, suggesting that class II-associated invariant chain peptide does not play a direct role in the unique SDS stability of DQ0602. These results support a role for DQB1 codon 57 in HLA-DQ αβ dimer stability and IDDM susceptibility.

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Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

Penzotti¹,

Nepom²,

Lybrand³

1997

Arthritis & Rheumatism

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Deficient antigen-presenting cell function in multiple genetic complementation groups of type II bare lymphocyte syndrome.

Abstract: The absence of HLA class II

Cited by 33 publications

References 45 publications

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

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Deficient antigen-presenting cell function in multiple genetic complementation groups of type II bare lymphocyte syndrome.

Abstract: The absence of HLA class II

Cited by 33 publications

References 45 publications

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA1*0102/DQB1*0602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus

Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

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Product

Resources

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β57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA10102/DQB10602 αβ Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus