The HLA genomic loci map: expression, interaction, diversity and disease

Shiina, Takashi; Hosomichi, Kazuyoshi; Inoko, Hidetoshi; Kulski, Jerzy K.

doi:10.1038/jhg.2008.5

Cited by 653 publications

(578 citation statements)

References 179 publications

(201 reference statements)

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“…Furthermore, it suggests that studies performed using mass spectrometry may underestimate MHC-associated peptide repertoires. Peptide ligands for HLA-A*02:01 have not been identified from the large majority of the on average 18,000 proteins expressed in a cell (10). In concert with this, none of the 36 epitopes from CD20 and MPO that were discovered here were found in existing peptide databases, such as Syfpeithi (syfpeithi.de) and the Immune epitope database (iedb.org).…”

Section: Discussionmentioning

confidence: 82%

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

Kumari

Wälchli

Fallang

et al. 2013

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

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HLA molecules presenting peptides derived from tumor-associated self-antigens (self-TAA) are attractive targets for T-cell-based immunotherapy of cancer. However, detection of such epitopes is hampered by self-tolerance and limitations in the sensitivity of mass spectrometry. Here, we used T cells from HLA-A2-negative donors as tools to detect HLA-A2-bound peptides from two leukemiaassociated differentiation antigens; CD20 and the previously undescribed cancer target myeloperoxidase. A high-throughput platform for epitope discovery was designed using dendritic cells cotransfected with full-length transcripts of self-TAA and HLA-A2 to allow presentation of all naturally processed peptides from a predefined self-protein on foreign HLA. Antigen-reactive T cells were directly detected using panels of color-coded peptide-HLA multimers containing epitopes predicted by a computer algorithm. Strikingly, cytotoxic T cells were generated against 37 out of 50 peptides predicted to bind HLA-A2. Among these, 36 epitopes were previously undescribed. The allorestricted T cells were exquisitely peptide-and HLA-specific and responded strongly to HLA-A2-positive leukemic cells with endogenous expression of CD20 or myeloperoxidase. These results indicate that the repertoire of self-peptides presented on HLA class I has been underestimated and that a wealth of self-TAA can be targeted by T cells when using nontolerized T-cell repertoires.C ytotoxic T cells (CTLs) selectively kill target cells that express defined peptides in complex with MHC class I molecules on the cell surface. Most tumor-associated antigens (TAA) are wild-type self-proteins, and T cells that recognize peptides from these antigens with high affinity are deleted during thymic development. Thus, the utility of T cells for detection of self-peptides presented on self-HLA is limited by tolerance. This may be one reason why the number of epitopes identified from TAA after 2 decades of intense research amounts to less than 600 (1). The ability to rapidly identify new CTL epitopes would likely facilitate the development of effective immunotherapeutic strategies against cancer.MHC molecules can be isolated from cells and the associated peptides eluted for identification by MS. Ultimately, this approach may provide a description of the entire MHC-bound peptide repertoire: the immunopeptidome (2, 3). This is, however, a daunting task, and it is unclear whether current MS-based protocols already provide the required sensitivity. Indeed, although 100,000-750,000 peptide-MHC class I complexes are expressed for each allelic product on the cell surface (for HLA-A and HLA-B loci) (3, 4), the largest HLA ligandome identified to date contains 14,065 peptides (5). In contrast, the predicted number of different HLA class I ligands would be 352,000 using the well-renowned computer algorithm NetMHCpan, considering that on average, 4.4% of all nonamers bind HLA class I (6) and that a cell contains at least 8 × 10 6 distinct nonamers (7). Thus, there is a very large gap between the numb...

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Section: Discussionmentioning

confidence: 82%

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

Kumari

Wälchli

Fallang

et al. 2013

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

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“…We imputed genotypes through the extended MHC (7,8) p1, and phs000439.v1.p1; phs000203.v1.p1, and phs000289.v2. p1; phs000196.v2.p1, phs000303.v1.p1, phs000304.v1.p1, phs000368.v1.p1, phs000381.v1.p1, phs000387.v1.p1, phs000389.v1.p1, phs000395.v1.p1, phs000408.v1.p1, phs000421.v1.p1, phs000494.v1.p1, and phs000524.v1.p1).…”

Section: Methodsmentioning

confidence: 99%

“…1). To better localize causal variation in the region, we compared genotypes of 2,853 EUR vitiligo cases and 37,412 unaffected subjects, imputed through the extended MHC (7,8) using data from the 1,000 Genomes Project. In the MHC class II region, the greatest association was with rs9271597 [chr6:32591291; P = 3.15 × 10 −89 , odds ratio (OR) 1.77].…”

Section: Significancementioning

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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“…Because controlling FDR is heavily affected by the number of identified SNPs, we pruned SNPs in linkage disequilibrium (LD; r 2 > 0.8) and excluded the major histocompatibility complex (MHC; genomic position (hg 19): chr6:29,528,318-33,373,649 [14]), which harbors established lung cancer susceptibility SNPs and is known for long-range LD. By controlling conjunction FDR, we identified one genetic locus at 6p22.1, rs6904596 (A>G, minor allele frequency in caucasians ¼ 0.094), associated with both lung cancer and blood triglycerides (conjunction FDR ¼ 1.24E-02; P ¼ 5.50x10 -6 for lung cancer; P ¼ 1.…”

Section: Introductionmentioning

confidence: 99%