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There is no doubt that HLA-DR molecules are acting as the products of HLA-linked immune response genes (Ir-genes), because (i) HLA-DR molecules are the restriction elements in the interaction between CD4+ helper T cells and antigen-presenting cells (APC) to respond to many antigens such as streptococcal cell wall antigen (SCW) (Nishimura & Sasazuki, 1983; Sone et al., 1985; Hizayama et al., 1986), schistosomal antigen (Sj) (Hirayama et al., 1987), Mycobacterium leprae antigen (ML) (Kikuchi et al., 1986) and so on; and (ii) anti-HLA-DR monoclonal antibodies completely abolish the immune response to those antigens (Nishimura & Sasazuki, 1983; Sone et al., 1985). However, genetic analysis of the immune response to those antigens in families or populations revealed that responsiveness is recessive and non-responsiveness to those antigens is a dominant genetic trait that is tightly linked to HLA (Sasazuki et al., 1980a, 1983; Watanabe et al., 1988). This is completely opposite to the situation under the Ir-gene control where responsiveness is dominant and non-responsiveness is recessive. In this paper, we report evidence of how we came across the concept of HLA-linked immune suppression genes (Is-genes) besides Ir-genes, and show evidence for the epistatic interaction between HLA-DR and DQ to determine the immune response to several antigens in humans. [ABSTRACT FROM AUTHOR]

Antiangiogenic therapies are promising approaches to cancer control, but the details of their effects on subsequent tumor progression are not fully understood. Such therapies have the potential to eventually generate extensive amounts of tumor ischemia, and we previously demonstrated that ischemic conditions induce K-ras mutations in cells with deficient mismatch repair (MMR) mechanisms. This suggested that similar effects on oncogene mutagenesis may accompany antiangiogenic therapy. To test this, MMR-deficient colorectal cancer cells (Dks-8) were xenografted into immune-deficient mice and treated with the antiangiogenic regimen of low-dose/metronomic cyclophosphamide for 2 weeks followed by a 2-week recovery period without therapy. This treatment resulted in transient tumor growth inhibition, increased hypoxia, and decreased microvessel density, and cancer cells from treated tumors acquired activating mutations of the K-ras oncogene (K-rasG13D). In vitro exposure of Dks-8 cells to the active metabolite of cyclophosphamide (4-hydroxycyclophosphamide) had no effect on the K-ras status, indicating that there was no direct action of this alkylating agent on K-ras mutagenesis. In addition, cells sorted from hypoxic regions of Dks-8 tumors were enriched in K-rasG13D mutants. Collectively, our studies suggest that increases in tumor hypoxia induced by antiangiogenic treatment may lead to K-ras mutation and consequently tumor progression, especially in susceptible individuals.Oncogene (2008) 27, 3729–3738; doi:10.1038/sj.onc.1211031; published online 28 January 2008 [ABSTRACT FROM AUTHOR]

With a view to establishing an accurate evaluation of the genetic predisposition to insulin-dependent type I diabetes (IDDM), we have built a model based on the characteristics of the relevant pockets of HLA-DR and -DQ molecules. Three independent populations were investigated. Group I and group II were Caucasoids, while group III was Japanese, including a total of 1,166 IDDM patients and 2,391 healthy controls. We formulate the hypothesis that suceptibility to IDDM is not only explained by the absence of Aspartate 57 (negative charge) from pocket 9 of DQB1 (P9DQ), but also by the presence of an electric charge (+/- vs. neutral), generated by residues 70, 71 and 74 in pockets 4 of DRB1 (P4DR) and DQB1 (P4DQ) molecules. The respective weight of each pocket, was evaluated in a multivariate analysis based on the logistic regression method. The 4 components (2 loci and 2 pockets) were systematically analysed in the computer model. It was clearly shown that the structural characteristics of pockets P9DQ-P4DR and, to a lesser degree that of P4DQ, account for IDDM predisposition. On applying the model to the whole international series, it appears that the highest risk concerns individuals with P9DQ non-Asp 57 and both the charged P4 of DRB1 and P4 of DQB1, conferring a 80% prediction of susceptibility. Conversely, P9DQ Asp and neutral P4DR and P4DQ give the lowest risk with a predictive value of 5%. This model of risk susceptibility prediction fits remarkably well with the observed distribution in a worldwide study. It allows a better evaluation of the respective role of HLA-DR and -DQ molecules as a major component of susceptibility to IDDM. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between HLA class II genes and methimazole-induced agranulocytosis in patients with Graves disease.Design: Case-control study.Setting: Kuma Hospital, which specializes in thyroid diseases, in Kobe, Japan.Subjects: 24 patients with Graves disease who had methimazole-induced agranulocytosis diagnosed by peripheral granulocyte counts of less than 0.5 x 10(9)/L, and 68 patients with Graves disease treated with methimazole, who were free from agranulocytosis. Controls were 525 healthy, unrelated Japanese student volunteers at Kyushu University in Japan.Measurements: All HLA class II genes were analyzed for polymorphisms at the DNA level by using the polymerase chain reaction sequence-specific oligonucleotide probes method. The allele frequencies in the agranulocytotic Graves disease group were compared with those in the nonagranulocytotic Graves disease and control groups.Results: A strong positive association was seen in DRB1*08032 between the agranulocytotic group and both the control and nonagranulocytotic Graves disease groups.Conclusion: The HLA DRB1*08032 allele was strongly associated with susceptibility to methimazole-induced agranulocytosis, suggesting that cellular autoimmunity may be involved in its development. [ABSTRACT FROM AUTHOR]

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. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules. [ABSTRACT FROM AUTHOR]

The article presents a report documenting the additions and revisions to the nomenclature of HLA specificities. It states that a number of HLA gene fragments have been reported and named which includes HLA-T previously known as HLA-16 and HLA-V previously known as HLA-75. It further discusses the conditions for acceptance of new genes and allele sequences for official names. It also presents lists of the serological specificities or antigens associated with the alleles.

T-box transcription factor, T-bet, has a central role in the differentiation of T-helper (Th) progenitor cells to Th1 or Th2 effector cells, partly by regulating the expression of genes such as interferon-γ (IFN-γ). However, the direct target genes, especially those mediating the transcriptional network initiated by T-bet, are not yet fully understood. By combining chromatin immunoprecipitation from Th1 cells with human cytosine-phosphate-guanine-island array analysis, Onecut 2 (OC2), which encodes a member of the ONECUT class of transcriptional activators, was identified as a direct target gene of T-bet. OC2 is expressed in Th1 but not Th2 cells and reporter assays showed that T-bet transactivates OC2 transcription through putative T-bet half-sites locating −451 to −347 of OC2 promoter region. Moreover, we found that OC2 binds and transactivates human T-bet promoter. These results suggest that not only cell-extrinsic regulation via the IFN-γ/STAT1 pathway, but also cell-intrinsic transcriptional positive feedback loop between T-bet and OC2 could be involved in Th1 development.Genes and Immunity (2008) 9, 302–308; doi:10.1038/gene.2008.18; published online 17 April 2008 [ABSTRACT FROM AUTHOR]

To systematically evaluate genetic susceptibility to type 2 diabetes (T2D) in “candidate” regions on chromosomes 1q, 3q and 12q, we examined disease association by using a total of 2,083 SNPs in two-step screening; a screening panel comprised 473 cases and 285 controls and an extended (or combined) panel involved 658 cases and 474 controls. For the total interval screened (40.9 Mb), suggestive evidence of association was provided for several annotated gene loci. For example, in the MCF2L2 gene on 3q, a significant association (a nominal P value of 0.00009) was observed when logistic regression analysis was performed for three associated SNPs (rs684846, rs35069869 and rs35368790) that belonged to different LD groups. Also, in the SLC15A4 gene on 12q, rs3765108 showed a marginally significant association with an overall estimated odds ratio of 0.79 ( P = 0.001). No significant association was found for known candidate gene loci on 3q, such as ADIPOQ and IGF2BP2. Using the available samples, we have observed disease associations of SNPs derived from two novel gene loci in the Japanese population through high-density searches of diabetes susceptibility in three chromosomal regions. Independent replication will clarify the etiological relevance of these genomic loci to T2D. [ABSTRACT FROM AUTHOR]

Allele and haplotype frequencies of the human leukocyte antigens (HLA) were studied in the Kinh Vietnamese population. We analyzed 170 unrelated healthy individuals. DNA-based HLA typing was performed using a microsphere-based array genotyping platform with sequence-specific oligonucleotide probes to distinguish HLA-A, -B, -C, -DRB1 and -DQB1 alleles. A total of 21 HLA-A, 37 HLA-B, 18 HLA-C, 25 HLA-DRB1, and 14 HLA-DQB1 alleles were identified. HLA-A*1101, A*2402, A*3303, B*1502, B*4601, Cw*0102, Cw*0702, Cw*0801, DRB1*1202, DQB1*0301, DQB1*0303, and DQB1*0501 were found with frequencies higher than 10%. Two representative haplotypes bearing two to five HLA loci were A*1101-B*1502 and A*3303-B*5801 for HLA-A-B; Cw*0801-B*1502 and Cw*0102-B*4601 for HLA-C-B; B*1502-DRB1*1202 and B*4601-DRB1*0901 for HLA-B-DRB1; DRB1*1202-DQB1*0301 and DRB1*0901-DQB1*0303 for HLA-DRB1-DQB1; A*1101-Cw*0801-B*1502 and A*3303-Cw*0302-B*5801 for HLA-A-C-B; A*1101-B*1502-DRB1*1202 and A*2901-B*0705-DRB1*1001 for HLA-A-B-DRB1, A*1101-Cw*0801-B*1502-DRB1*1202-DQB1*0301 and A*2901-Cw*1505-B*0705-DRB1*1001-DQB1*0501 for HLA-A-C-B-DRB1-DQB1. Allele distribution and haplotype analysis demonstrated that the Vietnamese population shares HLA patterns with southern Chinese, Thai, Javanese and Micronesians, while it also retains unique characteristics. [ABSTRACT FROM AUTHOR]

Abstract: Significant evidence of linkage to type 2 diabetes (T2D) has been shown in a relatively broad region on chromosome 20q, where the hepatocyte nuclear factor-4α (HNF4A) has been noted as a positional candidate. To systematically evaluate genetic susceptibility to T2D in the relevant region, we examined the disease association by using 1145 SNPs in two-step screening in the Japanese population. The marker screening enabled us to identify significant disease association in the lipopolysaccharide binding protein (LBP) but not in the HNF4A locus. In a 17.7-Mb interval screened, the strongest association was identified for a SNP, rs2232592, located in the intron of LBP, with an estimated odds ratio of 1.73 (95% CI 1.30–2.31) (P =0.0002) in the whole study panel involving 675 case and 474 control subjects. Our data suggest that the LBP gene may confer genetic susceptibility to T2D and this warrants further replication study. [Copyright &y& Elsevier]

Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, promotes the development of colorectal cancer, and is a key molecular target of non-steroidal anti-inflammatory drugs, compounds that reduce the relative risk of developing colon cancer. In this study, we showed that interferon γ (IFNγ) inhibits the expression of COX-2 protein in intestinal epithelial cells (IECs) through a pathway that requires Janus-activated kinase (JAK) activity. In contrast, we demonstrated that transcriptional inhibition of COX-2 by IFNβ or IFNγ occurs in cells with silenced signal transducer and activator of transcription 1 (STAT1) expression and that IFNs retained the ability to inhibit COX-2 transcription in cells with activated RasV12, in which IFNγ failed to induce STAT1. Thus, unlike the activity of JAK, STAT1 is not required for the inhibition of COX-2 expression by IFNγ. In contrast to COX-2, the activation of genes in response to IFNγ, such as interferon regulatory factor-1, was severely impaired by both STAT1 silencing and by constitutive Ras signaling. To determine whether there is a general differential requirement for STAT1 in gene activation and gene repression in response to IFNγ in intestinal cells, we performed genome-wide analysis of IFNγ target genes in an IEC line in which STAT1 expression was silenced by small interfering RNA. The results confirmed that the activation of the majority of genes by IFNγ required STAT1. In contrast, the repression of several genes, as we showed for COX-2 specifically, was largely unaffected in cells with silenced STAT1. Our results therefore demonstrate that in general gene activation by IFNγ is more sensitive to STAT1 deficiency than gene repression, and suggest that IFNγ activates and represses gene expression via distinct pathways that can be distinguished, at least in part, by their requirement for STAT1.Oncogene (2007) 26, 2071–2081. doi:10.1038/sj.onc.1210015; published online 2 October 2006 [ABSTRACT FROM AUTHOR]

Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro- and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachment-dependent activation of the transcription factor nuclear factor-κB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.Oncogene (2006) 25, 7680–7690. doi:10.1038/sj.onc.1209753; published online 26 June 2006 [ABSTRACT FROM AUTHOR]

The article reports that World Health Organization Nomenclature Committee for factor of the human leukocyte antigen (HLA) system has decided to publish an interim report listing updated tables of alleles including those assigned since the publication of the last full report in 2002 (1). There are required conditions for acceptance of new sequences for official names. Where a sequence is obtained from cDNA, or where polymerase chain reaction products are subcloned prior to sequencing, several clones should have been sequenced.

Presents an interim report of the World Health Organization Nomenclature Committee for Factors of the HLA System which lists updated tables of alleles. Naming of additional alleles; Serological specificities associated with alleles; Extension of HLA allele names; IMGT/HLA Sequence Database.

In order to determine highly immunogenic severe acute respiratory syndrome coronavirus (SARS-CoV) epitope peptides capable of inducing long-lasting immunity, we first screened immunoglobulin-G (IgG) antibodies reactive to 197 different overlapping 15-mers from the SARS-CoV proteins in the sera of three infected patients. Forty-two peptides among them were reactive to the sera from all three patients. Consequently, we tested for the reactivity of these 42 peptides to patients' sera (n = 45) at 6-month post-infection. The significantly higher levels of IgG antibodies specific to three (S791, M207 and N161) of 42 peptides were detectable in the post-infection sera from 23 (51%), 27 (60%) and 19 (42%) of 45 patients, respectively. These three peptides, recognized by their long-lasting immunity, may provide a better understanding of the immunogenicity of SARS-CoV. [ABSTRACT FROM AUTHOR]

Provides the nomenclature for factors of the human leukocyte antigen (HLA) system. Naming of additional genes within the HLA region; Naming of additional alleles; Renaming of alleles and removal of incorrect alleles; Extension of HLA allele names.

Presents information on a study which analyzed the effects of polymorphisms in tumor necrosis factor alfa (TNFA) and TNFR2 on the outcome of unrelated bone marrow transplantation. Insight on graft-versus-host disease as a complication in bone marrow transplant; Materials and methodology of the study; Results and discussion.

Two hundred and four unrelated Japanese patients with rheumatoid arthritis (RA) were typed for HLA by serological typing and DNA typing. The serological typing revealed that frequencies of HLA-A11, DR4, DR53 and DQ4 were increased and those of DR8 and DQ1 were decreased in the patients. The DNA typing has precisely defined the disease-associated HLA class II alleles; DRBl*0405, DQAl*03 and DQBl*0401 showed positive associations, while negative associations were found with DRBl*0803, DQAl*0103 and DQBl*0601. The risk for RA was found to be closely associated with particular amino acid sequences of DR-beta chain, including glycine residue at the 86th position in addition to those between 70 and 74, which are known to confer binding specificity and affinity to antigenic peptides. The observation that the frequency of HLA-A11 was increased in the DRBl*0405-positive patients suggested the interaction of these two alleles in the susceptibility to RA. On the other hand, the frequency of DPB1*0201 was increased in the DRBl*0405-negative patients and the frequency of HLA-A2 was increased in the DPBl*0201-positive patients, especially in the younger onset group. These findings suggested that the combination of HLA-A2 and DPBl*0201 may confer the susceptibility in the DRBl*0405-negative patients. Our results suggested the possibility that the susceptibility to RA is controlled by the interaction of HLA-A and DRBl genes or by that of HLA-A and DPBl genes in different patient subgroups. [ABSTRACT FROM AUTHOR]

The entire protein-coding region was divided into 45 fragments, separately amplified and analyzed for polymorphism by the PCR-SSCP (single-strand conformation polymorphism) method. The effect of polymorphism mismatching on the clinical outcome of unrelated bone marrow transplantation was studied to clarify whether products from mtDNA become minor antigens. Variability in PCR-SSCP pattern combinations of the 45 fragments suggests that each individual has a different polymorphism combination in the protein-coding region if all the coding regions were compared at the nucleotide sequence level. Nonsynonymous polymorphisms were found at relatively high frequency in MTATP8 and MTND3. Both the polymorphisms with and without substitution matched the peptide-binding motifs of HLA-A*0201. The effects of the polymorphism matching were retrospectively analyzed in 340 recipients transplanted with HLA-A, -B, -DRB1 allele-matched bone marrow from unrelated donors. There were no effects of polymorphism matching on the incidence of acute GVHD and cumulative disease-free survival. These results suggest that polymorphisms which generate peptides, with and without substitutions, that bind the same HLA molecule hardly influence GVHD because the difference between the HLA-peptide complexes is minute. Bone Marrow Transplantation (2001) 28, 603–607. [ABSTRACT FROM AUTHOR]

Abstract: In order to understand the forces governing the evolution of the genetic diversity in the HLA-DP molecule, polymerase chain reaction (PCR)-based methods were used to characterize genetic variation at the DPA1 and DPB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including individuals of African, Asian, Amerindian, Indian and European origin. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger, presumably admixed populations. Ten DPA1 and 39 DPB1 alleles were identified and observed on 87 distinct DP haplotypes, 34 of which were found to be in significant positive linkage disequilibrium in at least one population. Some haplotypes were found in all ethnic groups while others were confined to a single ethnic group or population. Strong positive global linkage disequilibrium (Wn) between DPA1 and DPB1 was present in all 15 populations. The African populations displayed the lowest values of Wn whereas the Amerindian populations displayed near absolute disequilibrium. Analysis of the distribution of haplotypes using the normalized deviate of the Ewens-Watterson homozygosity statistic, F, suggests that DP haplotypes encoding the functional heterodimer are subject to much lower degrees of balancing selection than other loci within the HLA region. Finally, neighbor joining tree analyses demonstrate the power of haplotype diversity for inferring the relationships between the different populations. [ABSTRACT FROM AUTHOR]

Abstract It is well known that individuals with low, or lack of, antibody production in response to hepatitis B surface antigen (HBsAg) exist in the human population. We have previously reported that HLA class I and class II genes are both involved in antibody production to HBsAg, and that specific alleles of HLA are associated with low and high antibody production. To elucidate further the mechanisms by which the diversity of antibody production to HBsAg is generated in humans, a total of 146 T-cell clones specific for HBsAg were produced from six healthy vaccinees (three low- and three high-antibody responders) and were examined for cytokine production and HLA restriction. It was found that the majority of the T-cell clones from the low-antibody responders were Th1- or Th0-like T cells (62% or 19%, respectively), whereas the majority of T-cell clones from the high-antibody responders were Th2-like T cells (77%), suggesting predominant expansion of Th1/Th0- and Th2-like T cells specific for HBsAg in the low- and high-antibody responders, respectively. This is the first evidence that the diversity of the response to HBsAg in humans is controlled by the activation of functionally distinct CD4[sup +] T-cell subsets, i.e., Th0, Th1, or Th2 T cells. [ABSTRACT FROM AUTHOR]

Presents a nomenclature for factors of the HLA histocompatibility antigen system, released by the World Health Organization in 2000. Naming of new alleles; Serological specificities associated with alleles; Names for genes in the HLA region.

Abstract: A polymorphism in high-affinity receptor of TNF (TNFR2) gene, Met196Arg, was reported to be associated with systemic lupus ery-thematosus (SLE) in Japanese, whereas the association could not be found in Europeans at all and this represents an apparent discrepancy. The association, then, should be tested in other populations to clarify the possible involvement, if any, of the TNFR2 polymorphism in SLE or other related autoimmune diseases. The purposes of this study were to examine the TNFR2 polymorphism in Japanese patients with SLE and to investigate its association with other autoimmune diseases accompanied by vasculitis, mixed connective tissue disease, Buerger's disease, and Takayasu's arteritis. We found no association at all between the TNFR2 polymorphism and any autoimmune diseases including SLE in Japanese. [ABSTRACT FROM AUTHOR]

Polymorphisms in the 5-flanking region of the tumor necrosis factor (TNF)-α gene were examined to study the genetic background of type 1 diabetes in Japanese. Five different biallelic polymorphisms were examined in 136 type 1 diabetic patients and 300 control subjects. The frequencies of individuals carrying TNF-α-857T allele (designated as TNFP-D allele) or -863A/-1,031C allele (designated as TNFP-B allele) were significantly increased in the patients as compared with the controls. Since these TNF-α alleles are in linkage disequilibria with certain DRB1 and HLA-B alleles, two-locus analyses were carried out. The TNFP-D allele did not increase the risk in either the presence or absence of the DRB1∗0405 or HLA-B54 allele, while the DRB1∗0405 and HLA-B54 alleles per se could confer susceptibility in both the TNFP-D allele-positive and -negative populations. Moreover, an odds ratio was remarkably elevated in the population carrying both DRB1∗0405 and HLA-B54. Similarly, the TNFP-B allele did not show significant association with the disease in either the HLA-B61-positive or -negative population, while the HLA-B61 allele could significantly increase the risk in the TNFP-B allele-positive population. These data suggest that the associations of TNFP-D and -B alleles may be secondary to their linkage disequilibria with the susceptible HLA class I and class II alleles. Because HLA-B and DRB1 genes were independently associated, both of these genes may be contributed primarily to the pathogenesis of type 1 diabetes in Japanese. [ABSTRACT FROM AUTHOR]

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)=1.64, P=0.016) and HLA-A*02:07 (OR=2.31, P=0.0067) and confirmed previously reported positive associations between CD and HLA-Cw*14:02 (OR=2.18, P=0.0021) and HLA-B*51:01 (OR=1.70, P=0.033). We also identified novel negative associations between CD and HLA-A*24:02 (OR=0.60, P=0.0047) and HLA-B*07:02 (OR=0.38, P=0.0041). Although the associations were not significant after full Bonferroni correction, we suggested that HLA class I genes have dual functions, susceptibility and resistance in controlling the development of CD. [ABSTRACT FROM AUTHOR]

The urokinase receptor, overexpressed in invasive colon cancer, promotes tumour cell invasion. Since K-Ras is activated in many colon cancers, we determined if urokinase receptor overexpression is a consequence of this activated oncogene. Accordingly, urokinase receptor expression was compared in HCT 116 colon cancer cells containing either a mutation-activated K-Ras or disrupted for this oncogene (by homologous recombination). HCT 116 cells containing the disrupted K-Ras oncogene expressed between 50 and 85% less urokinase receptor protein compared with the parental HCT 116 cells. Reduced urokinase receptor expression in cells containing the disrupted mutated K-Ras was not due to a physical impairment of the urokinase receptor gene since phorbol ester treatment was inductive for its expression. Constitutive urokinase receptor expression in HCT 116 cells required an intact AP-1 motif in the promoter (at -184) and electrophoretic mobility shifting assays indicated less c-Jun, JunD, c-Fos and Fra-1 bound to this motif in the K-Ras-disrupted cells. Since the urokinase receptor accelerates proteolysis, laminin degradation was compared in cells containing the mutation-activated and disrupted K-Ras oncogene. The latter cells displaying fewer urokinase receptors, degraded 80% less laminin. This is the first study to demonstrate a role for K-Ras as a regulator of the constitutive expression of the urokinase receptor. [ABSTRACT FROM AUTHOR]

In December 1991, the Japan Marrow Donor Program (JMDP) was established with the cooperation of the Japanese Red Cross and Japan Marrow Donor Foundation under the auspices of the Ministry of Health and Welfare in Japan. By December 1998, 122365 HLA-A,B typed volunteer marrow donors and 7207 patients had been cumulatively registered in the JMDP. The results of HLA-matching between donors and patients revealed that 5684 out of 7207 (78.9%) patients could have at least one HLA-A,B,DR serologically matched donor. Among these matched pairs, 1829 unrelated bone marrow transplants (UR-BMT) were performed. The initial 500 UR-BMT transplanted from January 1993 to October 1995 were analyzed as of July 1998. Engraftment was achieved in 95% of cases. Probability of the occurrence of grade III and IV acute GVHD was 18.4%. The rate of disease-free survival (DFS) of the patients who had standard-risk leukemia and did not suffer from grade III or IV acute GVHD (n = 154) was 60–71% and the rate of survival of patients with aplastic anemia was 56%. It can be stated that UR-BMT is a modality of treatment which is as effective as related BMT if the occurrence of grade III or IV acute GVHD is predicted and prevented. [ABSTRACT FROM AUTHOR]

The pathogenesis of histiocytic necrotizing lymphadenitis (HNL), which was reported first by Kikuchi et al. and Fujimoto et al. in 1972, is as yet unknown. HNL is frequently reported in Asian countries including Japan, however it is rare in Europe and North America. To elucidate whether the human leukocyte antigen (HLA) alleles and haplotypes are associated with HNL, we performed DNA typing of HLA class II genes (HLA-DR, -DQ, and -DP) in 86 patients with HNL and 525 unrelated healthy Japanese controls with polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP). In this study, we found DPA1*01 and DPB1*0202 allele frequencies in HLA class II genes are significantly higher in HNL patients than in normal controls. It is known that the frequency of DPB1*0202 alleles is extremely low or absent in Caucasians (e.g., French 0.4%, Italian 0.8%) and Negroid (e.g., South African 0%, Hottentot 0%), but relatively frequent in Asians (e.g., Korean 9.9%, Japanese 4.5%). Previous reports have said the incidence of HNL is frequent in Asians but rare in other races. In light of this background, HLA class II genes of HNL and the incidence of HNL in Asian countries, including Japan, might have a positive relationship to DPA1*01 and DPB1*0202 allele. [ABSTRACT FROM AUTHOR]

Matching of human platelet alloantigen (HPA) systems 2–6 was retrospectively investigated in 715 unrelated bone marrow transplantations. Of the five HPA systems studied, HPA-5 mismatching was found to have a significant effect on the disease-free survival rate of recipients following transplantation in the HLA-A, -B, -C, and -DR allele-matched donor-recipient pairs. The effect of the HPA-5 mismatch was most significant in the recipient group possessing the HLA haplotype A*2402-B*5201, which is a highly frequent haplotype among the Japanese population. However, the probability of development of acute graft-versus-host disease (GVHD) was not increased significantly by the HPA-5 mismatching. These findings suggest that the HPA-5 mismatching decreases the recipient’s survival by a mechanism different from that in the case of mismatching of minor antigens found often in transplant recipients developing GVHD. [ABSTRACT FROM AUTHOR]

Presents a nomenclature for factors of the HLA system submitted by the WHO Nomenclature Committee at the ASHI congress in Vancouver, Canada. Names of the genes; Revision of the naming policy; Serological specificities of the genes.

Presents a nomenclature for factors of the HLA system submitted by the WHO Nomenclature Committee at the ASHI congress in Vancouver, Canada. Names of the genes; Revision of the naming policy; Serological specificities of the genes.

Abstract: The association of various HLA class II loci with Crohn's disease (CD) and ulcerative colitis (UC) has yet to be fully elucidated. To determine whether there is an association of HLA class II genes (DR, DQ and DP alleles) with inflammatory bowel disease (IBD), HLA class II genes for polymorphisms were analyzed at the DNA level in 111 patients with CD, 81 with UC and 525 healthy controls by the polymerase chain reaction-sequence specific oligonucleotide probe method. Allele and haplotype frequencies were compared between these populations. Results were as follows: 1) the presence of DQB1∗0402 (RRequals3.90, P[subc]equals0.0001) was positively associated with CD; 2) the presence of DRB1∗1502 (RRequals4.51, P[subc]<1×10[sup−8]), DRB5∗0102 (RRequals4.70, P[subc]<1time;10[sub−8]), DQA1∗0103 (RRequals3.72, P[subc] equals1×10[sup&minus5] ), DQB1&lowast06011 (RRequals3.78, P[subc] equals1×10[sub&minus5]), DPA1∗0201 (RRequals3.23, P[subc]&equals;0.0001) and DPB1∗0901 (RRequals4.83, P[subc]<1×10[sup−8]) was positively associated and that of DRB4&lowast0101 (RRequals0.20, P[subc]<1%times;10[sup&minus8]) and DQA1&lowast0302 (RRequals0.34, P[subc]equals0.001) negatively associated with UC; 3) haplotype analysis showed a positive association between the presence of DRB1∗0410-DQA1∗0302-DQB1∗0402 and DRB1∗ 0802-DQA1∗0401-DQB1∗0402 with CD, and a negative association between the presence of DRB1∗1502-DQA1∗0103- DQB1&lowast06011 and CD, there was no association of DRB1∗08032- DQA1∗0103-DQB1∗06011 with CD; and 4) in UC, a positive association with the presence of DRB1∗1502-DQA1∗0103- DQB1∗06011 was found, but DRB1∗08032-DQA1∗0103- DQB1∗06011 was not associated with it. In conclusion, in CD in the Japanese population, HLA-linked disease susceptibility... [ABSTRACT FROM AUTHOR]

Previous studies have shown that a transgenic I-Eα gene, the mouse homologue of human DRα gene, prevents the development of insulitis and hence of diabetes in NOD mice. To investigate the mechanism of this prevention, we generated two strains of NOD mice expressing DRαEβ molecule: DRα-24-NOD expressing DRαEβ molecule on thymic epithelial cells (TEC) and bone marrow-derived cells (BDC), and DRα -30-NOD expressing DRα Eβ molecule only on the TEC, and these mice were monitored for disease development. Because the DRαEβ molecule reconstituted I-E controlled immune regulation, it would become clear which cell type, TEC or BDC, was responsible for the I-E-mediated disease protection. To our surprise, however, DRα -24-NOD developed insulitis and diabetes comparably to non-transgenic littermates. This suggested that the difference in structure between DRα and Eα molecules contributed to the difference in preventive effect on the development of insulitis and diabetes between DRα-24-NOD and Eα-NOD. In an analysis of the T cell proliferative responses to glutamic acid decarboxylase (GAD) 65-derived peptides which were known lo be diabetogenic autoantigens, it was shown that DRα-24-NOD and NOD acquired comparable level of T cell response to GAD 509-528 but 5-10-fold higher response was observed in Eα-NOD. This suggested that I-ANOD and EαEβNOD molecules could present GAD 509-528 peptide to T cells, while DRαEβNOD could not. Furthermore, T cells from DRα transgenic mice showed proliferative response to antigen-presenting cells from Eα transgenic mice in primary mixed lymphocyte reaction. This also suggested that the Eα Eβ molecule does differ in structure and peptide binding from the DRαEβ molecule. Present data suggested a possibility that the T cell repertoire selection, or the T cell response to GAD 65 and/or other unknown antigens specifically mediated by I-E molecule, may contribute to the prevention of disease development in Eα-NOD. [ABSTRACT FROM AUTHOR]

Immune responsiveness of 121 patients with post-schistosomal liver cirrhosis to schistosomal antigens was investigated. Out of 78 patients, only five (6.4%) showed low responsiveness to schistosomal adult worm antigen whereas 73 (93.6%) were high responders. Out of 57 healthy individuals with previous schistosomal infection, low responders were found in 17.5%. The frequency of low responders to schistosomal adult worm antigen was significantly decreased in the patients with post-schistosomal liver cirrhosis (P < 005). Out of 121 patients, a significant increase in frequency of HLA-Bw44- DEn haplotype was observed (corrected P < 0.02). On the other hand, HLA- Bw52-Dw 12 haplotype which was reported to be in strong linkage disequilibrium with an immune suppression gene for schistosomal adult worm antigen was significantly decreased (corrected P < 0.005). These observations suggested that an HLA-linked immune suppression gene controlled susceptibility or resistance to post-schistosomal liver cirrhosis through regulation of immune responsiveness of the hosts to schistosomal antigen in man. [ABSTRACT FROM AUTHOR]

Thirty-one Japanese nonresponders to subcutaneous hepatitis B vaccination and 15 medical personnel who were accidentally exposed to specimens positive for hepatitis B e antigen and were given hepatitis B immunoglobulin were intradermally immunized with 5 micrograms of plasma-derived hepatitis B vaccine every 2 weeks until delayed type hypersensitivity skin reaction to hepatitis B surface antigen became positive. Thirty (97%) of the 31 nonresponders developed delayed type hypersensitivity skin reactions to hepatitis B surface antigen after 2.3 +/- 1.2 (mean +/- SD) revaccinations. Twenty-nine (94%) of the 31 nonresponders had anti-hepatitis B surface antigen antibody levels greater than 10 IU/L. The immunoglobulin subclass of the antibody to hepatitis B surface antigen was mainly IgG1. After 1 year, 23 (74%) of the 31 nonresponders continued to have anti-hepatitis B surface antigen antibody levels greater than 10 IU/L. Persons accidentally exposed to specimens positive for hepatitis B e antigen developed delayed type hypersensitivity skin reactions to hepatitis B surface antigen following 3.1 +/- 1.1 revaccinations. None developed clinical hepatitis. There was no production of anti-hepatitis B core antigen antibody 1 year after exposure, indicating that protection was 100%. Intradermal hepatitis B vaccination is useful in reversing nonresponsiveness to hepatitis B surface antigen and for prophylaxis after exposure. [ABSTRACT FROM AUTHOR]

Abstract Susceptibility to a series of autoimmune diseases is strongly associated with particular HLA class II alleles. Identification of T cell clones and antigenic epitopes bound by HLA class II molecules involved in autoimmune diseases is critical to understanding the etiology of these HLA class II-associated diseases. However, establishment of T cell clones in autoimmune diseases is difficult because the antigenic peptides are unknown. Peptide library methods which include all possible peptide sequences offer a potentially powerful tool for the detection of cross-reactive antigenic peptides recognized by T cells. Here, we reduced the number of peptides per mixture by utilizing the known binding motifs of peptides for the HLA-DRB1*0405 molecule and evaluated the effectiveness of this library design. Each library mixture evoked a strong proliferative response in the unprimed peripheral blood lymphocytes (PBL) from HLA-DRB1*0405-positive donors but little or no response in the PBL from HLA-DRB1*0405-negative donors. The library also detected antigenic peptides that activated three antigen-specific T cell lines restricted by HLA-DRB1*0405, with different specificities. The motif-based approach thus presents a powerful method for monitoring T cells in large, heterogeneous T cell populations and is useful for the identification of the mimic peptide epitopes of T cell lines and clones. [ABSTRACT FROM AUTHOR]

The WHO Nomenclature Committee for Factors of the HLA System met during the 15th International Histocompatibility and Immunogenetics Workshop in Buzios, Brazil in September 2008. This update is an extract of the main report that documents the additions and revisions to the nomenclature of human leukocyte antigen (HLA) specificities following the principles established in previous reports. [ABSTRACT FROM AUTHOR]

Presents the table of contents of the volume 62 of the 2003 issue of the 'Tissue Antigens' journal.