Serum concentration of immunoglobulin G‐type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

Several studies suggest that infection by Epstein–Barr virus (EBV) might be one of the environmental factors which facilitates the development of autoimmune disorders in genetically susceptible individuals. Recent data indicate that high anti‐Epstein–Barr nuclear antigen 1 (EBNA)‐1 immunoglobulin (Ig)G titre is a strong risk factor for multiple sclerosis (MS) in patients both with and without the main genetic predisposing trait, human leucocyte antigen (HLA)‐DRB1*15:01. Because no similar studies have been published in systemic lupus erythematosus (SLE) patients, we determined the HLA‐DRB1*15:01 carrier state and the serum titres against the whole EBNA‐1 and its small fragments aa35–58 and aa398–404 in 301 SLE patients, 135 MS patients and in 345 healthy controls. The carrier state of the HLA‐DRB1*15:01 allele was deduced from genotyping of a tagSNP (rs3135388) by applying a Taqman‐based assay. The serum concentrations of antibodies to EBNA‐1 and its aa35–58 or aa398–404 fragments were determined using a commercial assay (ETI‐EBNA‐G) and home‐made enzyme‐linked immunosorbent assays, respectively. The serum concentration of anti‐EBNA‐1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA‐DRB1*15:01 carriers and non‐carriers. Furthermore, titres of antibodies against the aa35–58 EBNA‐1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398–404 EBNA‐1 antibodies were elevated significantly only in the SLE patients. These findings indicate that high anti‐EBNA‐1 IgG titres are HLA‐DRB1*15:01‐independent risk factors not only for MS, but also for SLE, while high antibody titres against the aa398–404 fragment are characteristic for SLE.     

A functional and structural basis for TCR cross-reactivity in multiple sclerosis

The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB1*1501, DRB5*0101 and DQB1*0602 are in strong linkage disequilibrium, making it difficult to determine which is the principal MS risk gene. Here we show that together the DRB1 and DRB5 loci may influence susceptibility to MS. We demonstrate that a T cell receptor (TCR) from an MS patient recognized both a DRB1*1501-restricted myelin basic protein (MBP) and DRB5*0101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB5*0101-EBV peptide complex revealed a marked degree of structural equivalence to the DRB1*1501-MBP peptide complex at the surface presented for TCR recognition. This provides structural evidence for molecular mimicry involving HLA molecules. The structural details suggest an explanation for the preponderance of MHC class II associations in HLA-associated diseases.     

Evidence for novel DRB1*15 allele association among clinically definite multiple sclerosis patients from Mumbai,India

Multiple sclerosis (MS) is a clinically heterogeneous demylinating disease and an important cause of acquired neurologic disability. MS has been reported from different regions of India and its infrequency has been attributed to have genetic implications. Further, a high incidence of MS and its human leukocyte antigen B12 (HLA-B12) associations have been reported among highly inbred Parsi population from Mumbai. However, consistent HLA associations have not been reported from India. We analyzed the HLA-B, -Cw, and -DRB1 allele associations among 23 clinically definite Western Indian non-Parsi MS patients and compared them with 146 ethnically matched clinically normal individuals. HLA serologic (A, B, and Cw) as well as molecular (DRB1) typing methodology was followed. The study revealed a significant increase of HLA-A11 (24% vs. 13%; OR = 2.6; EF = 0.14; 95%CI = 1.1-3.05), B16 (4.3% vs 0.3%; OR = 13.8; EF = 0.03; 95% CI = 1.19-134.44), Cw7 (15.2% vs 3.7%; OR = 5.46; EF = 0.12; 95% CI = 0.944-17.86), and DRB1*15 (21.7% vs 2.2%; OR = 16.15; EF = 0.19; 95% CI = 1.33-68.64). Further molecular subtyping of HLA-DRB1*15 among the patients revealed two novel alleles, DRB1*1506 (20%) and DRB1*1508 (30%), along with the commonly reported DRB1*1501 (50%) for the first time in MS patients that were hitherto unidentified from other parts of India and world as well. This study reveals that there is a complexity of the genetic susceptibility to MS in different populations studied and reported.     

Race-specific type 1 diabetes risk of HLA-DR7 haplotypes

The aim of this study was to test the hypothesis that closely related human leukocyte antigen (HLA) haplotypes containing the DRB1*07:01 gene ['DR7' (DRB1*07:01-DQA1*02:01-DQB1*02:01g or DRB1*07:01-DQA1*03:01-DQB1*02:01g) haplotypes] derived from European and African populations differ in their genetic susceptibility for type 1 diabetes (T1D) depending on the DQ-α molecule present. A combined total of 98 African American T1D patients from the Type 1 Diabetes Genetics Consortium and from Children's Hospital and Research Center Oakland were genotyped for the HLA class II loci DRB1, DQA1, and DQB1. DNA samples extracted from newborn blood spot cards from African Americans born in California (n = 947) were used as a population-based control group. Among African American cases, the European-derived DRB1*07:01-DQA1*02:01-DQB1*02:01g haplotype was protective for T1D risk (odds ratio (OR) = 0.34; 95% confidence interval (CI) 0.14-0.78; P < 0.011), but the African-derived DRB1*07:01-DQA1*03:01-DQB1*02:01g haplotype increased T1D risk (OR = 3.96; 95% CI 1.94-8.08; P < 5.5E-05). The effect of DRB1*07:01-DQB1*02:01g on T1D susceptibility depends on the DQA1 allele. DRB1*07:01-DQA1*02:01-DQB1*02:01g is protective for T1D; however, the presence of DQA1*03:01 on the DRB1*07:01-DQB1*02:01g haplotype not only renders the DR7 haplotype not protective but also creates a haplotype with significant T1D risk. These data underscore the importance of assessing genetic effects within ethnic context.     

HLA alleles and risk of cervical intraepithelial neoplasia among southwestern American Indian women

An increase in cervical intraepithelial neoplasia (CIN) has been described in American Indian women in New Mexico. Differences in human leukocyte antigen (HLA) alleles have been reported in cervical intraepithelial neoplasia (CIN) compared with controls in other populations. We investigated HLA alleles and CIN in Southwest American Indian women. The case control study included 89 women with biopsy-proven CIN II/III (diagnosed November 1994 through October 1997) and 271 similar women with normal cervical epithelium from the same clinics. DRB1, DQB1, and DPB1 alleles were determined using DNA typing techniques. DQA1 and HLA-A allele typing was included for some subjects (randomly chosen n = 37 and n = 163 cases and controls, respectively). We found a decreased risk of CIN with DRB1*1402 (OR 0.5, 95% CI 0.3-0.9) and an increased risk with DRB1*1501 (OR 2.7, 95% CI 0.9-7.3). Additionally, DQA1*0102 was associated with increased risk (OR 4.5, 95% CI 1.3-5.3) and HLA-A*02 with decreased risk (OR 0.4, CI 0.2-0.9). Our findings are discussed along with studies in other populations.     

The HLA-DRB1 gene and Graves disease in Taiwanese children: a case-control and family-based study

Graves disease (GD) is an autoimmune thyroid disease with a female preponderance and a wide range of ages at onset, and human leukocyte antigen (HLA) gene plays a primary role in the susceptibility to GD. We aim to investigate the associations between HLA-DRB1 alleles and Taiwanese children with GD by both case-control and family-based studies. A total of 241 unrelated children with GD, 539 healthy controls, 115 trios of affected patients and their parents, and 121 trios of unaffected siblings and their parents were recruited. HLA-DRB1 genotyping was performed by polymerase chain reaction and sequence-based typing assays. We found that DRB1*09:01 (OR?=?2.60, 95% CI 2.02-3.35, P(c) =?6.55 × 10(-13) ) was associated with GD risk, while DRB1*12:02 (OR?=?0.32, 95% CI 0.20-0.53, P(c) =?4.55 × 10(-5) ) was protective against GD. Transmission/disequilibrium test further confirmed an overtransmission of the DRB1*09:01 (OR 3.37, 95% CI 2.13-6.22, P(c) =?1.0 × 10(-5) ) and an undertransmission of the DRB1*12:02 (OR 0.21, 95% CI 0.05-0.42, P(c) =?1.7 × 10(-3) ). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-DRB1*09:01 confers susceptibility to GD and DRB1*12:02 exerts protection against GD development in Taiwanese children.     

Human leukocyte antigen class II and type 1 diabetes in Latin America: a combined meta-analysis of association and family-based studies

Conclusions from association studies could be spurious because of population stratification; therefore we combined association with family studies seeking to confirm which human leukocyte antigen (HLA) class II alleles/haplotypes were associated with type 1 diabetes (T1D) in the admixed Latin America. By calculating the effect summary odds ratios (OR) and their 95% confidence intervals (95% CI), data up to June 2010 showed that risk associations were observed with DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR]: 7.51; 95% confidence interval [CI]: 3.69-15.25) and DQB1*0302 in presence of DRB1*0405 (OR: 11.64; 95% CI: 3.15-43.01) or DRB1*0401 (OR: 5.85; 95% CI: 3.07-11.14). In contrast, DRB1*0404-DQB1*0302 had a nonsignificant TID risk (OR: 2.23; 95% CI: 0.91-5.43). T1D protective associations were observed with DRB1*11-DQA1*0501-DQB1*0301 (OR: 0.24; 95% CI: 0.1-0.56) and DRB1*15-DQA1*0102-DQB1*0602 (OR: 0.35; 95% CI: 0.17-0.73). These results were similar to those observed in Caucasian and other populations, thus highlighting the primary role of class II HLA in T1D regardless of ethnicity. A DRB1*04 risk hierarchy was confirmed with the DRB1*0405 being in the top. A binding prediction analysis disclosed possible receptor-ligand interactions in the HLA-antigenic peptide complex.     

Multi-locus HLA class I and II allele and haplotype associations with follicular lymphoma

Follicular lymphoma (FL) is an indolent, sometimes, fatal disease characterized by recurrence at progressively shorter intervals and is frequently refractive to therapy. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region on chromosome 6p21.32-33 that are statistically significantly associated with FL risk. Low to medium resolution typing of single or multiple HLA genes has provided an incomplete picture of the total genetic risk imparted by this highly variable region. To gain further insight into the role of HLA alleles in lymphomagenesis and to investigate the independence of validated SNPs and HLA alleles with FL risk, high-resolution HLA typing was conducted using next-generation sequencing in 222 non-Hispanic White FL cases and 220 matched controls from a larger San Francisco Bay Area population-based case-control study of lymphoma. A novel protective association was found between the DPB1*03:01 allele and FL risk [odds ratio (OR) = 0.39, 95% confidence interval (CI) = 0.21-0.68]. Extended haplotypes DRB1*01:01-DQA1*01:01-DQB1*05:01 (OR = 2.01, 95% CI = 1.22-3.38) and DRB1*15-DQA1*01-DQB1*06 (OR = 0.55, 95% CI = 0.36-0.82) also influenced FL risk. Moreover, DRB1*15-DQA1*01-DQB1*06 was highly correlated with an established FL risk locus, rs2647012. These results provide further insight into the critical roles of HLA alleles and SNPs in FL pathogenesis that involve multi-locus effects across the HLA region.     

Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis

Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.     

The influence of the HLA-DRB1 and HLA-DQB1 allele heterogeneity on disease risk and severity in Iranian patients with multiple sclerosis

Multiple sclerosis (MS) is a common autoimmune disorder of the central nervous system. Recent studies have shown that the HLA‐DRB1 and DQB1 alleles are associated with MS susceptibility and severity. However, this is controversial in different population studies. In the present study, the roles of HLA‐DRB1 and DQB1 alleles and the amino acids were investigated on disease risk and severity in 120 Iranian patients with MS and 120 controls. Our findings indicate that the DRB1*1501 allele (OR = 3.203 P = 0.001), the DRB1*1501‐DQB1*0602 haplotype (OR = 7.792 P = 0.003) and the DRB1*1501/0701‐ genotype (OR = 3.320 P = 0.006) and amino acid Leu26 (OR = 1.645 P = 0.005) and Phe9 (OR = 1.893 P = 0.009) on the DQβ1 chain are significantly associated with MS susceptibility. DRB1*1001 was the only allele that had a protective effect against MS (P = 0.0004). We also found that the DQB1*0303 allele was significantly associated with disease severity (mean Multiple Sclerosis Severity Score difference = 1.979, P = 0.002). However, protective effect of the DRB1*1001 against MS and also association of DQB1*0303 allele with MS severity need to be confirmed by larger sample size.     

HLA-class II alleles in Egyptian patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is linked to environmental, dietary, and life style factors. Its incidence and distribution vary widely among ethnic groups, sex, and geographic regions. HBV and HCV Infection, liver cirrhosis, male gender, and old age are important risk factors of HCC. Variability in outcome following exposure, and the clustering of HCC within families raise the possibility that genetic factors are also involved in susceptibility to HCC. The Major Histocompatibility Complex (MHC) plays a key role in anti-virus and tumor defense. HLA polymorphism is implicated in conferring genetic susceptibility to a large number of immune-mediated diseases, including some cancers. The association between HLA class II antigen and HCC in different ethnic populations that has been reported is controversial. Therefore, the aim of this work was to study the association between HLA class II-DRB1 and DQB1 polymorphism and HCC in Egyptian patients and to investigate their role as risk factors for the development of HCC. Methods: HLA-class II (DRB1 and DQB1) typing was done by SSP for 100 subjects; 50 patients suffering from HCC (45 males and 5 females) with age range 40-64 years (51.16 years (y) +/- 6.16); and 50 normal healthy control subjects. Results: 1. A significantly increased frequency of DRB1*04, and DQB1 *02 in HCC patients versus control group (p = 0.016, and 0.032, respectively) was found; 2. A significantly decreased frequency of DQB1*06 (p = 0.032) was found; 3. A significantly increased frequency of DRB1*07 (odds ratio (OR) = 4.929) was found; and 4. A significantly decreased frequency of DRB1*15 (OR = 0.316) was seen. In conclusion, while some alleles are significantly associated with HCC (DRB1*04, DQB1*02) and others are not associated (DQB1*06); therefore, it can be concluded that the DRB1*04 and DQB1*02 alleles might be risk factors for the occurrence of HCC (OR = 4.373 and 3.807, respectively), and DQB1*06 may be a protective allele (OR = 0.259).     

HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations

Ulcerative colitis (UC) and Crohn's disease (CD) are the clinical entities comprising idiopathic inflammatory bowel disease (IBD). Previous studies on the association of IBD and human leukocyte antigen (HLA) class II genes suggested a role for HLA in this disease. Here we present HLA class II (DRB1, DQB1, DQA1, DPB1) allele and haplotype distributions determined using the polymerase chain reaction and sequence-specific oligonucleotide probe methods. A total of 578 UC and CD Caucasian patients and controls from Jewish (Ashkenazi) and non-Jewish populations was examined. Our previously reported association of DR1-DQ5 with CD was attributable to DRB1*0103. A dramatic association with IBD and the highly unusual DRB1*0103-DQA1*0501-DQB1*0301 haplotype (OR = 6.6, p = 0.036) was found. The more common DR1 haplotype, DRB1*0103-DQA1*0101-DQB1*0501, was also associated with IBD (OR = 3.1, p = 0.014), a result suggesting that interaction between DR and DQ may determine the extent of disease risk. Our previously reported association of DR2 with UC was attributable to DRB1*1502 (OR = 2.6, p = 0.006). At the DPB1 locus, a significant association of DPB1*0401 with CD was observed for the combined populations (OR = 1.85, p = 0.007). These observations indicate that some class II alleles and haplotypes confer susceptibility to both UC and CD, implying common immunogenetic mechanisms of pathogenesis, while others confer risk to only one of these diseases, and illustrate the value of DNA HLA typing in disease susceptibility analyses.     

Heat-shock protein 70-1 and HLA class II gene polymorphisms associated with celiac disease susceptibility in Navarra (Spain)

Heat shock proteins (HSP) are thought to play a role in the immune response making probable their contribution to celiac disease (CD). We studied the polymorphisms in the 5' regulatory region of the HSP70-1 gene and performed genomic HLA-DQ and -DR typing in 128 CD patients and 94 healthy controls from Navarra (Spain). The frequency of the C allele of the HSP70-1, characterized by the intermediate electrophoretic mobility of DNA, was significantly increased among CD patients (64.5% vs 37.2%. p <1 x 10(-7)). When subjects were stratified by the HLA II genotype, differences were statistically significant between DR3-negative or DR3-DQB1*02-negative CD patients and matched controls. Homozygosity for the DQB1*02 allele was present in 48.4% of CD patients and 12.8% of controls (OR = 6.4; CI:3.1 to 13.8; p <1 x 10(-7)). Similar increased risk was observed for DQB1*02/*02, DRB1*03/-, or DRB1*03/07 patients. Furthermore, those individuals expressing the classical HLA alleles in CD (DQB1*02/*02, DRB1*03/*07) who also carried the HSP70-1 CC genotype were twelve times more likely to develop the disease than the matched controls. We therefore conclude that although HSP70-1 gene does not seem to be primarily associated with CD, it might be a component of the high risk haplotype, playing a role as an additional predisposing gene for the disease.     

Sensitivity to bee and wasp venoms: association with specific IgE responses to the bee and wasp venom and HLA DRB1 and DPB1

Background Stings from bees and wasps can cause systemic reactions which can be fatal in some individuals. In these venom-sensitive patients, specific IgE to the venom is produced and is considered to participate in the adverse reactions. This immune response requires antigen presentation by human leucocyte antigens (HLA) class II molecules, which includes DR and DP, which are present on antigen presenting cells. Objective To test for associations between HLA class II DRB1 and DPB1 alleles and life- threatening sensitivity to both bee and wasp venoms. To establish further whether any associations are independent of the atopy phenotype. Methods A total of 33 bee- and 44 wasp-venom-sensitive patients was studied. DRB1 genotypes were determined by single stranded oligonucleotide (SSO) probing of PCR products, and DPB1 genotypes by amplified fragment length polymorphism (AFLP) analysis. Total and specific IgE were measured using the Pharmacia Immunocap, FEIA. Patients with specific IgE to the venom antigens only were termed monosensitive and those with additional specific IgE to HDM and/or GP were termed polysensitive. Results Allele frequencies were compared to an unrelated control population. The 33 bee- sensitive patients had a greater prevalence of DRB 1*07 alleles than the control subjects, 26% vs 14%, with an odds ratio (OR) of 2.1 (95%CI, 1.2–3.7, P= 0.015, corrected for multiple comparisons, p_c > = ns). This association was confined to the 15 monosensitive bee patients, who had a 43% DRB 1*07 allele frequency when compared with 11% in the 18 polysensitive bee patients, OR 6.1 (95%CI, 1.73–22, P= 0.004, p_c= 0.05), and when compared with a control group of non-venom subjects, 43% vs 16%, OR 3.9 (95% CI, 1.72–9.0, P= 0.002, p_c= 0.02). The 44 wasp-sensitive patients had an increase in the DRB1*11 allele when compared with the control subjects, 13% vs 6%, with an OR 2.2 (95%CI, 1.0–4.6, P= 0.04, p_c= NS), and a decreased prevalence of DRB 1*04 alleles, 10% vs 19%, with an OR 0.33 (95%CI, 0.24–0.99, P= 0.04, p_c= NS), but these were not significant when multiple comparisons were taken into account. The DPB1 alleles were not significantly different between the venom sensitive patients and the controls. Conclusion Patients monosensitive to bee venom had a significantly greater prevalence of DRB 1 *07 alleles than the non-venom, control population suggesting that IgE responses in these patients may, in part be controlled by immune response HLA class II genes. These results are also suggestive of wasp-sensitive patients having a higher prevalence of DRB1*11 and a lower prevalence of DRB 1*04 than the control population.     

Multiple sclerosis risk markers in HLA-DRA, HLA-C, and IFNG genes are associated with sex-specific childhood leukemia risk

Previous epidemiologic studies showed four times increased risk of acute lymphoblastic leukemia (ALL) in children of women with multiple sclerosis (MS). MS shows a risk association with Human leukocyte antigens (HLA)-DRA single nucleotide polymorphism (SNP) rs3135388, which is a proxy marker for DRB1*1501. We examined the relevance of rs3135388 in childhood ALL risk along with two other HLA-DRA SNPs in two case-control groups: 114 cases and 388 controls from South Wales (UK) and 100 Mexican Mestizo cases and 253 controls. We first confirmed the correlation between rs3135388 and DRB1*1501 in HLA-typed reference cell lines. We noted a female-specific risk association in childhood ALL (pooled odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.5-4.5, Mantel-Haenszel P = 0.0009) similar to the stronger association of DRB1*1501 in females with MS. Examination of an HLA-C 5' flanking region SNP rs9264942, known to correlate with HLA-C expression, showed a protective association in girls (OR = 0.4, 95% CI = 0.2-0.7, Mantel-Haenszel P = 0.0003) similar to the protective HLA-Cw*05 association in MS. In a reference cell line panel, HLA-Cw5 homozygous samples (n = 8) were also homozygous for the minor allele of the SNP. Likewise, the male-specific protective association of interferon-gamma (IFNG) SNP rs2069727 in MS was replicated with the same sex specificity in childhood ALL (OR = 0.6, 95% CI = 0.4-1.0, Mantel-Haenszel P = 0.03). Two other SNPs in superkiller viralicidic activity 2-like and tenascin XB that are markers for systemic lupus erythematosus susceptibility showed female-specific associations but due to linkage disequilibrium with HLA-DRB1*15. Our observations supported the epidemiologic link between MS and childhood ALL and added the sex effect to this connection. It appears that only girls born to mothers with MS may have an increased risk of ALL. Investigating the mechanism of these sex-specific associations may help understand the pathogenesis of MS and ALL.     

HLA‐DRB1 genotyping in patients with juvenile idiopathic arthritis in Taiwan

The object of this study was to investigate whether there is an association between HLA‐DRB1 alleles and the development of juvenile idiopathic arthritis (JIA) in Taiwan. HLA‐DRB1 alleles were studied in 60 patients with JIA and 200 healthy controls using polymerase chain reaction (PCR)/sequence‐specific oligonucleotide probes (SSO). The frequency of HLA‐DRB1*0405 in patients with JIA was found to be significantly higher than that in healthy controls [odds ratio (OR) 2.64, 95% confidence interval (CI) 1.01–6.91]. The DRB1*0405 allele was significantly associated with the development of both polyarthritis (OR 4.30, 95% CI 1.34–13.80) and oligoarthritis (OR 3.27, 95% CI 1.01–10.58). The frequency of HLA‐DRB1*1502 was higher in Taiwanese JIA patients with systemic arthritis than in controls (OR 18.09, 95% CI 2.25–145.73). We conclude that, in Taiwan, HLA‐DRB1*0405 is associated with the development of polyarthritis and oligoarthritis in children, and HLA‐DRB1*1502 is associated with the development of systemic arthritis.     

MCP-1 promoter polymorphism in Spanish patients with rheumatoid arthritis

To investigate the possible role of the polymorphism located in the regulatory region of monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to rheumatoid arthritis (RA), a total of 141 Spanish RA patients and 194 controls, previously typed for human leukocyte antigen DRB1* (HLA-DRB1*), were genotyped for -2518 (A/G) MCP-1 gene polymorphism using polymerase chain reaction-restriction fragment length polymorphism. No association between -2518 (A/G) MCP-1 polymorphism and susceptibility to RA was found. Nevertheless, when patients and controls were stratified according to their HLA shared epitope (SE) status, a significant increase in the frequency of genotype GG was found among SE negative (SE-) patients with respect to both SE positive (SE+) patients and SE- controls (16% versus 4% in SE+ patients, pFisher=0.04, odds ratio [OR]=4.4, 95% confidence interval [95%CI]=1.03-21.48; and 4% in SE- controls, pFisher=0.02, OR=4.13, 95%CI=1.10-15.72). In conclusion, MCP-1 polymorphism is slightly associated with the susceptibility to RA in patients lacking the HLA SE.     

The impact of HLA class I and EBV latency‐II antigen‐specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

In 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency‐II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV⁺cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA‐A*02 is protective in EBV⁺cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA‐A*02^– versus HLA‐A*02⁺ EBV⁺cHL patients, suggesting that LMP2A‐specific CD8⁺ T cell anti‐tumoral immunity may be relatively ineffective in HLA‐A*02^– EBV⁺cHL. To ascertain the impact of HLA class I on EBV latency antigen‐specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV⁺cHL, the magnitude of ex‐vivo LMP1/2A‐specific CD8⁺ T cell responses was elevated in HLA‐A*02⁺ patients. Furthermore, in a controlled in‐vitro assay, LMP2A‐specific CD8⁺ T cells from healthy HLA‐A*02 heterozygotes expanded to a greater extent with HLA‐A*02‐restricted compared to non‐HLA‐A*02‐restricted cell lines. In an extensive analysis of HLA class I‐restricted immunity, immunodominant EBNA3A/3B/3C‐specific CD8⁺ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A‐specific responses were confined largely to HLA‐A*02. Our results demonstrate that HLA‐A*02 mediates a modest, but none the less stronger, EBV‐specific CD8⁺ T cell response than non‐HLA‐A*02 alleles, an effect confined to EBV latency‐II antigens. Thus, the protective effect of HLA‐A*02 against EBV⁺cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency‐II antigen‐specific CD8⁺ T cell hierarchies.     

Serum antibody response to lytic and latent Epstein-Barr virus antigens in undifferentiated nasopharyngeal carcinoma patients from an area of nonendemicity

Epstein-Barr virus (EBV)-associated undifferentiated carcinoma of the nasopharyngeal type (UCNT) is highly prevalent in southeast China, where immunoglobulin A (IgA) antibodies to viral capsid antigen and early antigen (EA) represent important markers, routinely used to assist in diagnosing this malignancy. Our study aimed at determining the EBV serological profiles of 78 UCNT patients from Italy, an area of nonendemicity for this tumor, using different assays specific for both lytic and latent EBV antigens. Serum IgA against both EA and EBNA1 and IgG and IgA to the latent membrane protein 1 (LMP1), to EA, and to the EBV transactivator ZEBRA protein were assessed. These serological responses were then evaluated according to the clinicopathologic parameters at diagnosis. The sensitivities of the IgG assays were 37.7% for LMP1, 73.6% for EA, and 61.0% for ZEBRA. EA/EBNA1 IgA reactivity was 84.4%, and a high association (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7 to 4.0) with UCNT was observed. When EBV serological reactivities were analyzed according to the tumor, node, and metastasis staging system (TNM), a statistically significant association was found between N stage and IgG antibody rates for EA (OR, 3.6; 95% CI, 1.2 to 10.9) and ZEBRA (OR, 2.6; 95% CI, 1.2 to 5.5) and between M stage and IgG antibody rates for ZEBRA (OR, 7.1; 95% CI, 3.2 to 16.0) and LMP1 (OR, 14.0; 95% CI, 1.8 to 110.9). Our results show that no single serological marker allows the detection of all UCNT cases. EA/EBNA1 IgA represents a reliable marker for diagnosis, with a high predictive value also in areas where UCNT is not endemic, such as Italy. The analysis of serological results according to TNM classification is consistent with a progressive impairment of humoral immune response to EBV as the disease advances and may be used to improve the accuracy of diagnosis.     

HLA-Class II Alleles in Egyptian Patients with Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is linked to environmental, dietary, and life style factors. Its incidence and distribution vary widely among ethnic groups, sex, and geographic regions. HBV and HCV Infection, liver cirrhosis, male gender, and old age are important risk factors of HCC. Variability in outcome following exposure, and the clustering of HCC within families raise the possibility that genetic factors are also involved in susceptibility to HCC. The Major Histocompatibility Complex (MHC) plays a key role in anti-virus and tumor defense. HLA polymorphism is implicated in conferring genetic susceptibility to a large number of immune-mediated diseases, including some cancers. The association between HLA class II antigen and HCC in different ethnic populations that has been reported is controversial. Therefore, the aim of this work was to study the association between HLA class II-DRB1 and DQB1 polymorphism and HCC in Egyptian patients and to investigate their role as risk factors for the development of HCC. Methods: HLA-class II (DRB1 and DQB1) typing was done by SSP for 100 subjects; 50 patients suffering from HCC (45 males and 5 females) with age range 40–64 years (51.16 years (y)?±?6.16); and 50 normal healthy control subjects. Results: 1. A significantly increased frequency of DRB1*04, and DQB1 *02 in HCC patients versus control group (p?=?0.016, and 0.032, respectively) was found; 2. A significantly decreased frequency of DQB1*06 (p?=?0.032) was found; 3. A significantly increased frequency of DRB1*07 (odds ratio (OR)?=?4.929) was found; and 4. A significantly decreased frequency of DRB1*15 (OR?=?0.316) was seen. In conclusion, while some alleles are significantly associated with HCC (DRB1*04, DQB1*02) and others are not associated (DQB1*06); therefore, it can be concluded that the DRB1*04 and DQB1*02 alleles might be risk factors for the occurrence of HCC (OR?=?4.373 and 3.807, respectively), and DQB1*06 may be a protective allele (OR?=?0.259).