High HLA-DP Expression and Graft-versus-Host Disease

Petersdorf, Effie W.; Malkki, Mari; Ó'hUigín, Colm; Carrington, Mary; Gooley, Ted; Haagenson, Michael; Horowitz, Mary M.; Spellman, Stephen R.; Wang, Tao; Stevenson, Philip A.

doi:10.1056/nejmoa1500140

Cited by 247 publications

(282 citation statements)

References 27 publications

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“…The physiologic significance of this haplotype can also be inferred on the basis of our data linking these risk alleles to decreased expression of HLA–DPB1 and HLA–DP and an increased frequency of cPR3 peptide–reactive T cells in patients with anti‐PR3 autoantibodies. Although understanding of the autoantigenic epitopes driving T cell responses in AAV is limited, our findings are consistent with prior data correlating alleles at linked HLA–DPB1 SNP loci to differential HLA–DPB1 /HLA–DP expression and with the association of such expression changes, as well as the HLA–DP GGPM/DEAV variance, with differential outcomes of specific immune challenges 28, 29. Further investigation is required to define the extent to which the risk haplotype–associated increase in levels of autoreactive T cells reflects the failure to eliminate such cells during thymic selection and/or whether another mechanistic aberrancy may be involved.…”

Section: Discussionsupporting

confidence: 89%

“…These variants are in LD with a SNP variant (rs9277534) in the downstream HLA–DPB1 3 ′‐untranslated region, for which the homozygous genotype is associated with lower levels of HLA–DPB1 and HLA–DP expression in immune cells compared to those in subjects with the alternate homozygous genotype 28, 29. We therefore assessed the relationship between the triallelic AAV risk haplotype and HLA–DPB1/ HLA–DP expression using PBMCs from healthy subjects carrying either risk or protective rs1042169 alleles.…”

Section: Resultsmentioning

confidence: 99%

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Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Merkel

Xie

Monach

et al. 2017

Arthritis & Rheumatology

139

154

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ObjectiveTo identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).MethodsA genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.ResultsAmong the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.ConclusionThis study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Merkel

Xie

Monach

et al. 2017

Arthritis & Rheumatology

139

154

View full text Add to dashboard Cite

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“…This paradigm has recently been extended to the MHC: noncoding variation in the HLA-DPB1 region is associated with enhanced clearance of hepatitis B virus infection (23), and with increased risk of graft-versus-host disease in mismatched hematopoietic cell transplant recipients (24). Similarly, quantitative variation in the expression of HLA-C can influence the clinical course of HIV infection and the risk of graft-versus-host disease (25,26).…”

Section: Discussionmentioning

confidence: 99%

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Cavalli

Hayashi

Jin

et al. 2016

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

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Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genomewide association study of 2,853 Caucasian vitiligo patients. The superenhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5-and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.A utoimmune diseases are a group of over 80 disorders that together affect 3-5% of the United States population (1, 2). Many autoimmune diseases are associated with genetic variation in the HLA class I and class II gene regions of the major histocompatibility complex (MHC) on chromosome 6p21.3. HLA class I molecules present peptide antigens on the surface of almost all cells, whereas HLA class II molecules present antigens on the surface of antigen-presenting cells, such as dendritic cells, mononuclear phagocytes, and B cells. Contributions of HLA molecules to autoimmunity have almost exclusively focused on antigenic diversity and specificity. Although polymorphisms in intergenic regions of the MHC might additionally affect the complex transcriptional regulation of HLA genes, the potential role of these noncoding regions in the pathogenesis of autoimmune diseases has received much less attention.Vitiligo is an autoimmune disease in which white spots of skin and overlying hair result from progressive destruction of melanocytes by autoreactive T cells (3). In previous genome-wide association studies of autoimmune vitiligo in European-derived Caucasian (EUR) populations, we have identified association with 27 different loci (4-6), most strongly with MHC class II r...

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“…The first is based on structural T-cell epitopes (TCEs) shared by subsets of HLA-DPB1 alleles (TCE model) 39,62,63 ; the second considers differences in HLA-DPB1 allele cell-surface expression levels (expression model). 64 The TCE model stems from experimental data showing that T cells alloreactive to HLA-DPB1*09:01 reproducibly cross-recognize other nonself HLA-DPB1 alleles from at least 3 distinct TCE groups. It was predicted that mismatches between HLA-DPB1 alleles from the same TCE group (designated permissive) would elicit less vigorous T-cell alloreactivity compared with alleles from different TCE groups (designated nonpermissive).…”

Section: 55-58mentioning

confidence: 99%

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

Fleischhauer

Shaw

2017

Blood

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When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UDs) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling HCT. Mismatched HLA-DP is targeted by direct alloreactive T cell responses with important implications for graft-versus-host disease and graft-versus-leukemia. This concise review details special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders.

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High HLA-DP Expression and Graft-versus-Host Disease

Cited by 247 publications

References 27 publications

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

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