Abrogation of self-tolerance by misfolded self-antigens complexed with MHC class II molecules.

Specific MHC class II alleles are strongly associated with susceptibility to various autoimmune diseases. Although the primary function of MHC class II molecules is to present peptides to helper T cells, MHC class II molecules also function like a chaperone to transport misfolded intracellular proteins to the cell surface. In this study, we found that autoantibodies in patients with Graves' disease preferentially recognize thyroid-stimulating hormone receptor (TSHR) complexed with MHC class II molecules of Graves' disease risk alleles, suggesting that the aberrant TSHR transported by MHC class II molecules is the target of autoantibodies produced in Graves' disease.

Downregulation of HLA class II is associated with relapse after allogeneic stem cell transplantation and alters recognition by antigen-specific T cells.

Genomic deletion of donor-patient-mismatched HLA alleles in leukemic cells is a major cause of relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Mismatched HLA is frequently lost as an individual allele or a whole region in HLA-class I, however, it is downregulated in HLA-class II. We hypothesized that there might be a difference in T cell recognition capacity against epitopes associated with HLA-class I and HLA-class II and consequently such allogeneic immune pressure induced HLA alterations in leukemic cells.

Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer.

Mutations of KRAS gene are found in various types of cancer, including colorectal cancer (CRC). Despite intense efforts, no pharmacological approaches are expected to be effective against KRAS-mutant cancers. Macropinocytosis is an evolutionarily conserved actin-dependent endocytic process that internalizes extracellular fluids into large vesicles called macropinosomes.

Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90.

Radiotherapy is an essential part of multi-modal cancer therapy. Nevertheless, for certain cancer entities such as colorectal cancer (CRC) the indications of radiotherapy are limited due to anatomical peculiarities and high radiosensitivity of the surrounding normal tissue. The development of molecularly targeted, combined modality approaches may help to overcome these limitations.

Evolutionary basis of HLA-DPB1 alleles affects acute GVHD in unrelated donor stem cell transplantation.

HLA-DPB1 T-cell epitope (TCE) mismatching algorithm and rs9277534 SNP at the 3' untranslated region (3'UTR) in the HLA-DPB1 gene are key factors for transplant-related events in unrelated hematopoietic cell transplantation (UR-HCT). However, the association of these 2 mechanisms has not been elucidated. We analyzed 19 frequent HLA-DPB1 alleles derived from Japanese healthy subjects by next-generation sequencing of the entire HLA-DPB1 gene region and multi-SNP data of the HLA region in 1589 UR-HCT pairs.

Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells.

Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells.

MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers.

MACC1 was identified as a novel player in cancer progression and metastasis, but its role in death receptor-mediated apoptosis is still unexplored. We show that MACC1 knockdown sensitizes cancer cells to death receptor-mediated apoptosis. For the first time, we provide evidence for STAT signaling as a MACC1 target.

Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase.

A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC) can predict a lack of responses to anti-epidermal growth factor receptor-based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth.

Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis.

Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed.

BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells.

Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has a controversial role in cancer--both in protecting against tumor progression by isolation of damaged organelles, or by potentially contributing to cancer growth. The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context.

Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.

The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases.

High-risk HLA alleles for severe acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation.

HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation. To elucidate the effect of specific HLA alleles on acute graft-versus-host disease, we conducted a retrospective analysis using 6967 Japanese patients transplanted with T-cell-replete marrow from an unrelated donor. Using unbiased searches of patient and donor HLA alleles, patient and/or donor HLA-B*51:01 (patient: HR, 1.

Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals.

Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1(*) 05:01 and (*) 09:01, and three protective alleles, DPB1(*) 02:01, (*) 04:01, and (*) 04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection.

Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation.

Acute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In HLA-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minor H antigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD.

EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer.

Purpose: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.

Experimental Design: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined.

Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells.

Detachment of nonmalignant intestinal epithelial cells from the extracellular matrix (ECM) triggers their growth arrest and, ultimately, apoptosis. In contrast, colorectal cancer cells can grow without attachment to the ECM. This ability is critical for their malignant potential.

Solution structures of the DNA-binding domains of immune-related zinc-finger protein ZFAT.

ZFAT is a transcriptional regulator, containing eighteen C2H2-type zinc-fingers and one AT-hook, involved in autoimmune thyroid disease, apoptosis, and immune-related cell survival. We determined the solution structures of the thirteen individual ZFAT zinc-fingers (ZF) and the tandemly arrayed zinc-fingers in the regions from ZF2 to ZF5, by NMR spectroscopy. ZFAT has eight uncommon bulged-out helix-containing zinc-fingers, and six of their structures (ZF4, ZF5, ZF6, ZF10, ZF11, and ZF13) were determined.

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

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. β2-glycoprotein I (β2GPI) 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.

Biological significance of HLA locus matching in unrelated donor bone marrow transplantation.

We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell-replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation.

Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS.

Unlabelled: KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that (18)F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased (18)F-FDG accumulation.

Identification of a Hashimoto thyroiditis susceptibility locus via a genome-wide comparison with Graves' disease.

Background: Hashimoto thyroiditis (HT) and Graves' disease (GD) share some immunological features. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these two related diseases.

Aim: The aim of this study was to identify a non-HLA susceptibility locus that is specific to either HT or GD.

Associations of HLA class I alleles in Japanese patients with Crohn's disease.

Previous studies have suggested that the human leukocyte antigen (HLA) is involved in the etiology of Crohn's disease (CD); however, few reports are available on the association between HLA class I antigens and CD in Japan. In this study, we performed association analysis of HLA class I antigens in CD using 208 Japanese patients and 384 healthy controls. We identified novel positive associations between CD and HLA-A*02:01 (odds ratio (OR)=1.

Competition between human cells by entosis.

Human carcinomas are comprised of complex mixtures of tumor cells that are known to compete indirectly for nutrients and growth factors. Whether tumor cells could also compete directly, for example by elimination of rivals, is not known. Here we show that human cells can directly compete by a mechanism of engulfment called entosis.

Structural basis for the specific recognition of the major antigenic peptide from the Japanese cedar pollen allergen Cry j 1 by HLA-DP5.

The major allergen, Cry j 1, was isolated from Japanese cedar Cryptomeria japonica (Cry j) pollen and was shown to react with immunoglobulin E antibodies in the sera from pollinosis patients. We previously reported that the frequency of HLA-DP5 was significantly higher in pollinosis patients and the immunodominant peptides from Cry j 1 bound to HLA-DP5 to activate Th2 cells. In the present study, we determined the crystal structure of the HLA-DP5 heterodimer in complex with a Cry j 1-derived nine-residue peptide, at 2.