Regulatory Variants on the Leukocyte Immunoglobulin-Like Receptor Gene Cluster are Associated with Crohn's Disease and Interact with Regulatory Variants for TAP2.

BACKGROUND AND AIMS: Crohn's disease [CD] has a complex polygenic aetiology with high heritability. There is ongoing effort to identify novel variants associated with susceptibility to CD through a genome-wide association study [GWAS] in large Korean populations. METHODS: Genome-wide variant data from 902 Korean patients with CD and 72 179 controls were used to assess the genetic associations in a meta-analysis with previous Korean GWAS results from 1621 patients with CD and 4419 controls. Epistatic interactions between CD-risk variants of interest were tested using a multivariate logistic regression model with an interaction term. RESULTS: We identified two novel genetic associations with the risk of CD near ZBTB38 and within the leukocyte immunoglobulin-like receptor [LILR] gene cluster [p < 5 × 10-8], with highly consistent effect sizes between the two independent Korean cohorts. CD-risk variants in the LILR locus are known quantitative trait loci [QTL] for multiple LILR genes, of which LILRB2 directly interacts with various ligands including MHC class I molecules. The LILR lead variant exhibited a significant epistatic interaction with CD-associated regulatory variants for TAP2 involved in the antigen presentation of MHC class I molecules [p = 4.11 × 10-4], showing higher CD-risk effects of the TAP2 variant in individuals carrying more risk alleles of the LILR lead variant (odds ratio [OR] = 0.941, p = 0.686 in non-carriers; OR = 1.45, p = 2.51 × 10-4 in single-copy carriers; OR = 2.38, p = 2.76 × 10-6 in two-copy carriers). CONCLUSIONS: This study demonstrated that genetic variants at two novel susceptibility loci and the epistatic interaction between variants in LILR and TAP2 loci confer a risk of CD.

Delayed Diagnosis of Chronic Necrotizing Granulomatous Skin Lesions due to TAP2 Deficiency.

Major histocompatibility complex class I (MHC-I) deficiency, also known as bare lymphocyte syndrome type 1 (BLS-1), is a rare autosomal recessively inherited immunodeficiency disorder with remarkable clinical and biological heterogeneity. Transporter associated with antigen processing (TAP) is a member of the ATP-binding cassette superfamily of transporters and consists of two subunits, TAP1 or TAP2. Any defect resulting from a mutation or deletion of these two subunits may adversely affect the peptide translocation in the endoplasmic reticulum, which is an important process for properly assembling MHC-I molecules. To date, only 12 TAP2-deficient patients were reported in the literature. Herein, we described two Iranian cases with 2 and 3 decades of delayed diagnosis of chronic necrotizing granulomatous skin lesions due to TAP2 deficiency without pulmonary involvement. Segregation analysis in family members identified 3 additional homozygous asymptomatic carriers. In both asymptomatic and symptomatic carriers, HLA-I expression was only 4-15% of the one observed in healthy controls. We performed the first deep immunophenotyping in TAP2-deficient patients. While total CD8 T cell counts were normal as previously reported, the patients showed strongly impaired naïve CD8 T cell counts. Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cell counts were increased.

Association study of TAP and HLA-I gene combination with chronic hepatitis C virus infection in a Han population in China.

Host immune system genes play key roles in the progression of chronic hepatitis C virus (HCV) infection. Transporters associated with antigen processing (TAP) play an important role in the loading of viral peptides onto MHC class I molecules. This study aimed to investigate the association between TAP gene polymorphisms and chronic HCV in a Chinese Han population. A total of 232 chronic hepatitis C (CHC) patients and 362 healthy individuals were recruited from the Han population in Yunnan province in southwest China, and a TaqMan SNP genotyping assay was used to detect six single nucleotide polymorphisms (SNPs) of TAP1 and three SNPs of TAP2 genes. The association of the TAP gene with CHC was analysed at the allele, genotype, and haplotype levels. There were no significant differences in the allele and genotype frequencies of these SNPs in the TAP gene between CHC patients and controls after Bonferroni correction. A novel TAP1 allele (TAP1*unknown_1: rs41555220-rs41549617-rs1057141-rs1135216-rs1057149-rs41551515: G-G-A-G-G-G) was only present in the CHC group, and this allele significantly increased susceptibility to CHC (p = .005, odds ratio [OR] = 11.105. 95% confidence interval [CI]: 1.362-90.558). Homozygous TAP1*03:01/TAP1*03:01 was observed only in the CHC group that exhibited an obvious risk for CHC (p = .002, OR = 9.637, 95% CI: 1.153-80.574). And the haplotype TAP1*unknown_1-TAP2*01:01 was only present in the CHC group and indicated a significant risk for CHC (p = .002, OR = 9.498, 95% CI: 1.140-79.149). We observed significant interactions among HLA-A, -B,C, TAP1, and TAP2 alleles, and combination analysis revealed that the combination of TAP1*01:01-TAP2*01:01-HLA-B*35:01 was only present in the control group (2.2%) and resulted in significantly increased resistance to CHC (p = .002, OR = 0.096, 95% CI: 0.012-0.759). Whereas, the combination of TAP1*01:01-TAP2*01:01-HLA-C*07:02 and TAP1*03:01-TAP2*01:01-HLA-C*01:02 increased the susceptibility to CHC significantly (p = .001, OR = 2.016, 95% CI: 1.309-3.106 and p = .002, OR = 8.070, 95% CI: 1.018-63.997, respectively). Our results indicated that TAP and HLA-I may exert a combined effect on CHC susceptibility in the Chinese Han population.

Spotlight on TAP and its vital role in antigen presentation and cross-presentation.

In the late 1980s and early 1990s, the hunt for a transporter molecule ostensibly responsible for the translocation of peptides across the endoplasmic reticulum (ER) membrane yielded the successful discovery of transporter associated with antigen processing (TAP) protein. TAP is a heterodimer complex comprised of TAP1 and TAP2, which utilizes ATP to transport cytosolic peptides into the ER across its membrane. In the ER, together with other components it forms the peptide loading complex (PLC), which directs loading of high affinity peptides onto nascent major histocompatibility complex class I (MHC-I) molecules that are then transported to the cell surface for presentation to CD8+ T cells. TAP also plays a crucial role in transporting peptides into phagosomes and endosomes during cross-presentation in dendritic cells (DCs). Because of the critical role that TAP plays in both classical MHC-I presentation and cross-presentation, its expression and function are often compromised by numerous types of cancers and viruses to evade recognition by cytotoxic CD8 T cells. Here we review the discovery and function of TAP with a major focus on its role in cross-presentation in DCs. We discuss a recently described emergency route of noncanonical cross-presentation that is mobilized in DCs upon TAP blockade to restore CD8 T cell cross-priming. We also discuss the various strategies employed by cancer cells and viruses to target TAP expression or function to evade immunosurveillance - along with some strategies by which the repertoire of peptides presented by cells which downregulate TAP can be targeted as a therapeutic strategy to mobilize a TAP-independent CD8 T cell response. Lastly, we discuss TAP polymorphisms and the role of TAP in inherited disorders.

The association of TAP polymorphisms with non-small-cell lung cancer in the Han Chinese population.

The host immune system plays a crucial role in multiple types of cancer, including non-small-cell lung cancer (NSCLC). Transporter associated with antigen processing (TAP) protein heterodimer complexes might promote intracellular antigen peptide binding with class I major histocompatibility complex (MHC-I) molecules, and in recent years, TAP1 and TAP2 have been reported to be associated with multiple cancer risks. In the current study, we investigated the association of single-nucleotide polymorphisms (SNPs) in TAP1 and TAP2 with NSCLC in a Han Chinese population. Six and seven TAP1 and TAP2 SNPs, respectively, were genotyped and analysed in healthy controls and NSCLC patients. Based on our data, none of the six SNPs in TAP1 is associated with NSCLC risk (P > 0.0038). However, rs2228396 alleles in TAP2 were significantly different between NSCLC patients and healthy controls, and the A allele might be associated with an increased risk of this cancer (P = 0.001, OR = 1.65, 95%CI: 1.23 ∼ 2.21). Moreover, the genotype frequencies of rs2228396 were significantly different between patients and healthy controls (P = 7 × 10-4). Additionally, TAP2 rs241441 alleles exhibited a trend of difference between NSCLC patients and healthy controls, with the C allele possibly being associated with increased risk of NSCLC (P = 0.013; OR = 1.30, 95%CI: 1.06 ∼ 1.60). Moreover, the genotypes of rs241441 in TAP2 showed a significant difference between NSCLC patients and healthy controls (P = 1 × 10-4). In haplotype analysis, the TAP2 SNP haplotype (CAC, TAP2*0102) was significantly associated with increased NSCLC risk in the Han Chinese population (P = 0.003; OR = 1.57, 95%CI: 1.17 ∼ 2.10). Our results indicate that TAP2 SNPs (rs2228396 and rs241441) have a potential role in NSCLC pathogenesis.

Stem cell transplantation as treatment for major histocompatibility class I deficiency.

Major histocompatibility class I deficiency, due to genetic lesions in TAP1, TAP2, TAPBP, or B2M, manifests with recurrent sinopulmonary infections and granulomatous skin ulceration, and is predominately treated with antimicrobial prophylaxis and chest physiotherapy. One previous report of hematopoietic stem cell transplantation has been described in the literature, demonstrating cure of the immune defect without significant graft-versus-host disease. In this report, we expand the literature on HSCT in MHC-I deficiency with follow-up of the original patient, demonstrating maintained resolution of normal immune function and regression of the granulomatous rash 15 years post-transplant, and describe a further patient with mycobacterial disease whose transplant course was complicated by severe graft-versus-host disease.

Polymorphisms in transporter associated with antigen presenting are associated with cervical intraepithelial neoplasia and cervical cancer in a Chinese Han population.

The host immune system plays an important role in infectious diseases and cancers. The heterodimer formed by transporter associated with antigen presenting (TAP)1 and TAP2 is responsible for intracellular peptide loading onto MHC-I molecules. Studies have shown that single-nucleotide polymorphisms (SNPs) in TAP genes might affect the expression and function of TAP and be associated with cancer risk. We aimed to investigate the association of SNPs in the TAP1 and TAP2 genes with cervical intraepithelial neoplasia (CIN) and cervical cancer (CC) in a Chinese Han population. Six SNPs in the TAP1 gene and seven in the TAP2 gene were selected. The 13 SNPs were genotyped in 1255 healthy individuals, 575 patients with CIN and 1034 patients with CC using the SNaPshot assay. The association between these SNPs and CIN and CC risk was analysed. The allelic and genotypic distributions of rs41549617 and rs1135216 showed significant differences between the control and CC groups (P < 0.0038). The T allele of rs41549617 was associated with a decreased risk of CC (OR = 0.476, 95%CI: 0.286-0.791). Moreover, the G allele of rs1135216 appears to be associated with a decreased risk of CC (OR = 0.746; 95%CI: 0.632-0.881). The allele and genotype distribution of rs241441 showed a significant difference between the control and CC groups (P < 0.0038), and the rs241441 G allele was associated with an increased risk of CC (OR = 1.232, 95%CI: 1.092-1.398). In addition, the results of the association between TAP alleles and CC showed that TAP1*020101 and TAP1*0301 have an association with CC (P = 0.001 and P = 0.002, respectively). Our results demonstrate that the TAP1 and TAP2 genes are associated with CC in the Chinese Han population.

Associations of genetic variants at TAP1 and TAP2 with pulmonary tuberculosis risk among the Chinese population.

Tuberculosis (TB) is a common infectious disease, and the present study aims to explore the associations of single nucleotide polymorphisms (SNPs) at rs1135216 and rs1057141 of transporter-associated antigen processing (TAP1) and rs2228396 of TAP2 with pulmonary tuberculosis (PTB) risk. A case-control study including 168 smear-positive PTB cases and 251 controls was conducted. Genotyping of the SNPs at rs1135216, rs1057141 and rs2228396 was performed, and their associations with PTB risk were analysed with SPSS software version 19.0. After conducting stratification for age, a significant association was detected for rs1057141 with increased PTB risk (OR = 0.17, 95% CI 0.04-0.79) among those aged ≥60 years. For those aged <60 years, a marginally significant association was detected between rs1135216 TC/CC and PTB risk (OR = 1.97, 95% CI 0.93-4.19). Haplotype analysis revealed that the haplotype AT at rs1135216 and rs2228396, as well as AAT at rs1057141, rs1135216 and rs2228396, was associated with increased PTB risk, and the ORs were 2.83 (95% CI 1.30-6.14) and 2.89 (95% CI 1.34-6.27), respectively. Rs1057141 is a genetic predictor of reduced PTB risk for those aged ≥60 years, while rs1135216 might be a potential genetic predictor for those aged <60 years. Haplotype AT at rs1135216 and rs2228396, as well as AAT at rs1057141, rs1135216 and rs2228396, is a genetic marker that may predict PTB risk.

Correlations and Influence of TAP2 Genes Polymorphisms and Systemic Lupus Erythematosus Propensity.

OBJECTIVES: The present study was designed to evaluate the association of transporters associated with antigen processing (TAP2) polymorphisms TAP2-379Ile > Val (rs1800454), TAP2-665Thr > Ala (rs241447) and TAP2-565Ala > Thr (rs2228396) as a candidate gene with susceptibility to the Systemic Lupus Erythematosus (SLE). METHODS: To analyze these three polymorphic variants, 88 patients with SLE and 100 healthy controls from northeastern Iran were enrolled from May 2018 to July 2019. Genomic DNA polymorphisms were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. Data were analyzed by SPSS software. RESULTS: In this cross-sectional study, there was a stratification between patients and controls. The distribution of the frequency of Ala73 (41.5%) allele at TAP2/665 and Ile 19 (10.8%) allele at TAP2/379 was higher in patients. Additionally, the Ala/Ala 13(14.8%) and Ala/Thr 49(55.7%) genotypes distributions at 665 positions were higher in SLE patients compared to the controls. Furthermore, frequencies of TAP2*H allele significantly increased in SLE patients 10(5.71%) (P=0.01). Frequency of TAP2*A allele in the control group was 120(60%) (p=0.06) due to the dominant genetic model. This allele has a protective effect against SLE. There was no relationship between TAP2*D, TAP2*E, TAP2*F and TAP2*G alleles with the outbreak of SLE. CONCLUSION: Our data indicated that genetic variants in TAP2 gene may be associated with SLE disease. A correlation between Ala allele at TAP2/665 and Ile allele at TAP2/379 polymorphisms and pathogenesis of SLE was observed.

Transcriptome Analysis Reveals the Neuro-Immune Interactions in Duck Tembusu Virus-Infected Brain.

The duck Tembusu virus (DTMUV) is a mosquito-borne flavivirus. It causes severe symptoms of egg-drop, as well as neurological symptoms and brain damage in ducks. However, the specific molecular mechanisms of DTMUV-induced neurovirulence and host responses in the brain remain obscure. To better understand the host-pathogen and neuro-immune interactions of DTMUV infection, we conducted high-throughput RNA-sequencing to reveal the transcriptome profiles of DTMUV-infected duck brain. Totals of 117, 212, and 150 differentially expressed genes (DEGs) were identified at 12, 24, and 48 h post infection (hpi). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses uncovered genes and pathways related to the nervous system and immune responses in duck brain. Neuro-related genes, including WNT3A, GATA3, and CHRNA6, were found to be significantly downregulated. RIG-I-like receptors (DHX58, IFIH1) and Toll-like receptors (TLR2 and TLR3) were activated, inducing the expression of 22 interferon stimulated genes (ISGs) and antigen-processing and -presenting genes (TAP1 and TAP2) in the brain. Our research provides comprehensive information for the molecular mechanisms of neuro-immune and host-pathogen interactions of DTMUV.

Is the TAP2 single nucleotide polymorphism rs241447 truly associated with psoriasis in Poles?

Psoriasis vulgaris (PsV) is strongly associated with HLA-C*06:02. HLA class I molecules present antigenic peptides to CD8+ T lymphocytes. Peptide transport from cytosol to the endoplasmic reticulum is mediated by a transporter associated with antigen processing (TAP) composed of TAP1 and TAP2 polymorphic proteins. Here, we compared the distribution of three coding single nucleotide polymorphisms (SNPs), rs1057141 in TAP1 and rs1800454 and rs241447 in TAP2 as well as the HLA-C*06:02 allele in 438 patients diagnosed with PsV and 493 control individuals. In patients and controls non-stratified by HLA-C*06:02, TAP2 rs241447 was associated with PsV but other TAP1 and TAP2 SNPs were not. By contrast, stratification according to the Svejgaard and Ryder formula, as well as a logistic regression approach and haplotype analysis demonstrated that the effect of TAP2 rs241447 was entirely related to the presence of HLA-C*06:02. The secondary effect of TAP2 rs241447 in relation to primary effect of HLA-C*06:02 resulted from linkage disequilibrium (albeit not strong) between both markers. We conclude that joint coexistence of HLA-C*06:02 and the TAP2 rs241447C risk allele on the extended haplotype might explain the effect of TAP2 observed by us.

Analysis of transporter associated with antigen presentation (TAP) genes polymorphisms with HIV-1 infection.

Human leukocyte antigen (HLA) class I molecules of the human major histocompatibility complex (MHC) play an important role in modulating immune response. HLA class I molecules present antigenic peptides to CD8+ T cells and thereby play a role in the immune surveillance of cells infected with viruses. TAP1 and TAP2 are MHC-II-encoded genes necessary for the generation of a cellular immune response and polymorphism of these genes can influence the specificity of peptides preferentially presented by the MHC class I molecules and the outcome of the immune response. Several studies implicated genetic variation in TAP genes to various immune-mediated and infectious diseases. To determine the correlation between HIV-1 infection and the TAP1 and TAP2 genes polymorphisms, we performed PCR-RFLP assay of these genes in 500 HIV-1 seropositives and the matched seronegative individuals. Statistical analysis of the data disclosed no correlation between TAP1 (C/T intron 7) gene polymorphism and HIV-1/AIDS disease. However, the current results demonstrated that the heterozygous A/G [OR (95% CI) 1.39 (1.06-1.83), P = 0.0171] and homozygous G/G [OR (95% CI) 3.38(1.56-7.46), P = 0.0010] variants of TAP2 (A/G exon 11) (T665A) gene are positively associated with an increased risk of HIV-1/AIDS infection. This case-control analysis might suggest a possible role of TAP2 (A/G exon 11) (T665A) gene in the susceptibility to HIV-1 infection and disease outcome among North Indian patients.

Quantitative assessment of the association between TAP2 rs241447 polymorphism and cancer risk.

The findings regarding the relation of transporter associated with antigen processing (TAP) to cancer risk have been inconsistent. The aim of this study was to comprehensively evaluate the association between TAP2 rs241447 polymorphism and cancer susceptibility. A meta-analysis of nine investigations with 2800 cases and 1620 controls was conducted to gain a better understanding of the effect of TAP2 rs241447 polymorphism on cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the correlation between TAP2 gene polymorphism and cancer susceptibility. The pooled results from TAP2 rs241447 polymorphism showed a decreased risk of cancer in two dominant genetic models (GG + AG vs AA: OR = 0.86, 95% CI, 0.75-0.99; AG vs AA: OR = 0.85, 95% CI, 0.73-0.99). From the subgroup analysis, decreased cancer susceptibility was found in Caucasians (GG + AG vs AA: OR = 0.82, 95% CI, 0.68-0.99), especially among the subgroup of cervical carcinoma (GG + AG vs AA: OR = 0.82, 95% CI, 0.69-0.96; AG vs AA: OR = 0.83, 95% CI, 0.70-0.99). Overall, the results suggest that TAP2 rs241447 polymorphism contributes to decreased cancer susceptibility.

Chaperones of the class I peptide-loading complex facilitate the constitutive presentation of endogenous antigens on HLA-DP84GGPM87.

Recent work has delineated key differences in the antigen processing and presentation mechanisms underlying HLA-DP alleles encoding glycine at position 84 of the DPß chain (DP84GGPM87). These DPs are unable to associate with the class II-associated Ii peptide (CLIP) region of the invariant chain (Ii) chaperone early in the endocytic pathway, leading to continuous presentation of endogenous antigens. However, little is known about the chaperone support involved in the loading of these endogenous antigens onto DP molecules. Here, we demonstrate the proteasome and TAP dependency of this pathway and reveal the ability of HLA class I to compete with DP84GGPM87 for the presentation of endogenous antigens, suggesting that shared subcellular machinery may exist between the two classes of HLA. We identify physical interactions of prototypical class I-associated chaperones with numerous DP alleles, including TAP2, tapasin, ERp57, calnexin, and calreticulin, using a conventional immunoprecipitation and immunoblot approach and confirm the existence of these interactions in vivo through the use of the BioID2 proximal biotinylation system in human cells. Based on immunological assays, we then demonstrate the ability of each of these chaperones to facilitate the presentation of endogenously derived, but not exogenously derived, antigens on DP molecules. Considering previous genetic and clinical studies linking DP84GGPM87 to disease frequency and severity in autoimmune disease, viral infections, and cancer, we suggest that the above chaperones may form the molecular basis of these observable clinical differences through facilitating the presentation of endogenously derived antigens to CD4+ T cells.

Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008.

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.

An update meta-analysis and systematic review of TAP polymorphisms as potential biomarkers for judging cancer risk.

OBJECTIVE: Transporter associated with antigen processing protein (TAP) is a heterodimer protein consist of TAP1 and TAP2, act a pivotal part in the immune surveillance. In recent days, controversial relationships were reported between TAP polymorphisms and cancer risk, thus, a systematic meta-analysis was performed to resolve this discrepancy. METHODS: We searched the PubMed, EMbase, Web of Science, CNKI and Wanfang databases, the cited references were also manually searched again, covering all the papers published until March 25, 2018. Quality assessment was conducted using the Newcastle-Ottawa Scale. All the meta-analysis was conducted with Stata version 12.0 software to assess the strength of the association. RESULTS: 4719 cases and 4215 controls from 24 case-control studies related to TAP polymorphisms were enrolled. There was no significant association between TAP1-rs1135216, TAP1-rs4148873, TAP2-rs2228396, TAP2-rs241447 and TAP2-rs4148873 and cancer sensibility. Interestingly, a significant positive association was observed between TAP2 rs4148876 C/T polymorphism and increase cancer risk in homozygote and recessive models. Further in-silico results indicated the expression of TAP2 in cancer tissue is higher than that in normal tissue (cervical cancer, TPM = 70.2 vs. 24.0 respectively, P < 0.01; acute myeloid leukemia, TPM = 52.5 vs. 8.8 respectively, P < 0.01), and influence the survival time of acute myeloid leukemia patients (Log-rank P < 0.05). CONCLUSIONS: Our finding suggested that TAP1-rs1135216, TAP1-rs4148873, TAP2-rs2228396, TAP2-rs241447 and TAP2-rs4148873 might not be involved in cancer risk, but the T allele of TAP2-rs4148876 might be a potential biomarker for judging cancer risk, and larger-scale studies are required to confirm our findings.

Distinct mechanisms survey the structural integrity of HLA-B*27:05 intracellularly and at the surface.

HLA-B*27:05 is associated with the development of autoimmune spondyloarthropathies, but the precise causal relationship between the MHC haplotype and disease pathogenesis is yet to be elucidated. Studies focusing on the structure and cellular trafficking of HLA-B*27:05 implicate several links between the onset of inflammation and the unusual conformations of the molecule inside and at the surface of antigen presenting cells. Several lines of evidence emphasize the emergence of those unnatural protein conformations under conditions where peptide loading onto B*27:05 is impaired. To understand how cellular factors distinguish between poorly loaded molecules from the optimally loaded ones, we have investigated the intracellular transport, folding, and cell surface expression of this particular B27 subtype. Our findings show that B*27:05 is structurally unstable in the absence of peptide, and that an artificially introduced disulfide bond between residues 84 and 139 conferred enhanced conformational stability to the suboptimally loaded molecules. Empty or suboptimally loaded B*27:05 can escape intracellular retention and arrive at the cell surface leading to the appearance of increased number of ß2m-free heavy chains. Our study reveals a general mechanism found in the early secretory pathways of murine and human cells that apply to the quality control of MHC class I molecules, and it highlights the allotype-specific structural features of HLA-B*27:05 that can be associated with aberrant antigen presentation and that might contribute to the etiology of disease.

The influence of TAP1 and TAP2 gene polymorphisms on TAP function and its inhibition by viral immune evasion proteins.

Herpesviruses encode numerous immune evasion molecules that interfere with the immune system, particularly with certain stages in the MHC class I antigen presentation pathway. In this pathway, the transporter associated with antigen processing (TAP) is a frequent target of viral immune evasion strategies. This ER-resident transporter is composed of the proteins TAP1 and TAP2, and plays a crucial role in the loading of viral peptides onto MHC class I molecules. Several variants of TAP1 and TAP2 occur in the human population, some of which are linked to autoimmune disorders and susceptibility to infections. Here, we assessed the influence of naturally occurring TAP variants on peptide transport and MHC class I expression. In addition, we tested the inhibitory capacity of three viral immune evasion proteins, the TAP inhibitors US6 from human cytomegalovirus, ICP47 from herpes simplex virus type 1 and BNLF2a from Epstein-Barr virus, for a series of TAP1 and TAP2 variants. Our results suggest that these TAP polymorphisms have no or limited effect on peptide transport or MHC class I expression. Furthermore, our study indicates that the herpesvirus-encoded TAP inhibitors target a broad spectrum of TAP variants; inhibition of TAP is not affected by the naturally occurring polymorphisms of TAP tested in this study. Our findings suggest that the long-term coevolution of herpesviruses and their host did not result in selection of inhibitor-resistant TAP variants in the human population.

Association Study and Fine-Mapping Major Histocompatibility Complex Analysis of Pemphigus Vulgaris in a Han Chinese Population.

To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10-8, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10-6, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.

Sld5 Ensures Centrosomal Resistance to Congression Forces by Preserving Centriolar Satellites.

The migration of chromosomes during mitosis is mediated primarily by kinesins that bind to the chromosomes and move along the microtubules, exerting pulling and pushing forces on the centrosomes. We report that a DNA replication protein, Sld5, localizes to the centrosomes, resisting the microtubular pulling forces experienced during chromosome congression. In the absence of Sld5, centriolar satellites, which normally cluster around the centrosomes, are dissipated throughout the cytoplasm, resulting in the loss of their known function of recruiting the centrosomal protein, pericentrin. We observed that Sld5-deficient centrosomes lacking pericentrin were unable to endure the CENP-E- and Kid-mediated microtubular forces that converge on the centrosomes during chromosome congression, resulting in monocentriolar and acentriolar spindle poles. The minus-end-directed kinesin-14 motor protein, HSET, sustains the traction forces that mediate centrosomal fragmentation in Sld5-depleted cells. Thus, we report that a DNA replication protein has an as yet unknown function of ensuring spindle pole resistance to traction forces exerted during chromosome congression.