HLA-DRB1 gene distribution in Croatian arthritis patients

Genetic association between particular HLA-DRB1 genes and severity of rheumatoid arthritis (RA) has been documented in various clinical investigations. Susceptible alleles are *0401, *0404, *0405, *0408, *0101, *1001, *1402. According to the Shared epitope hypothesis presence of these alleles were considered as poor prognostic sign. The aim was to investigate HLA-DRB1 distribution in Croatian arthritis patients. Group of 90 patients with non-specific joint arthritis, non-erosive RA and erosive RA were typed for DRB1 alleles by PCR-SSP method. Susceptible alleles were identified in 58 (64.44 %) patients. The most frequent genes were DRB1 *0101 (43.33 %), *0401 (17.77 %), *0404 (10 %). 9 out of 58 DRB1* positive patients had 2 susceptible alleles, and the rest (49 patients) had only one susceptible allele. The patients with non-specific joint arthritis and non-erosive RA will bee closely followed for more destructive disease course in DRB1* positive patients.     

Shared Molecular Eplet Stimulates Acute Antibody-Mediated Rejection in a Kidney Transplant Recipient With Low-Level Donor-Specific Antibodies: A Case Report

HLA antibodies usually recognize epitopes rather than antigens. This case report reveals that acute antibody-mediated rejection (AMR) that occurred in a kidney transplant recipient with low-level donor-specific antibodies (DSAs) could be explained by shared epitope. A 39-year-old woman received a first kidney transplant from a deceased donor (HLA-DRB1*11:06, *12:02, DRB3*02:02, *03:01). She developed acute AMR confirmed by kidney biopsy on day 4 after transplantation. Antibody testing with pretransplant serum showed anti-DR11 DSA below cutoff level (mean fluorescence intensity [MFI], 702; cutoff >1,000). However, high-level DSAs were detected on day 5 after transplantation (anti-DR11 MFI, 8,531; anti-DR12 MFI, 3,146). We hypothesized that the sharp rise in DSA levels was a result of anamnestic response with donor-antigen sensitization that occurred during pregnancy. High-resolution HLA-DR typing of her husband showed HLA-DRB1*03:01, *15:02:01, DRB3*02:02, DRB5*01:02. No sharing between donor HLAs eliciting reactive antibodies and her husband's HLAs was detected. Nevertheless, we speculated that shared epitope, not antigen, was the cause of allosensitization. To identify the shared epitope recognized by patient's antibodies, we used HLAmatchmaker, a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes for analysis. The results showed that 149H, which was the eplet shared by HLA-DRB1*03:01 (from her husband) and DRB1*11:06, DRB1*12:02, DRB3*03:01 (from donor), was the most prevalent eplet on DRB1 reactive alleles in Luminex assay. In conclusion, pretransplant low-level DSAs can induce AMR early after transplantation as a result of shared epitopes with a previous immunizer.     

Next Generation Sequencing Reveals the Association of DRB3*02:02 With Type 1 Diabetes

The primary associations of the HLA class II genes, HLA-DRB1 and HLA-DQB1, and the class I genes, HLA-A and HLA-B, with type 1 diabetes (T1D) are well established. However, the role of polymorphism at the HLA-DRB3, HLA-DRB4, and HLA-DRB5 loci remains unclear. In two separate studies, one of 500 subjects and 500 control subjects and one of 366 DRB1*03:01–positive samples from selected multiplex T1D families, we used Roche 454 sequencing with Conexio Genomics ASSIGN ATF 454 HLA genotyping software analysis to analyze sequence variation at these three HLA-DRB loci. Association analyses were performed on the two HLA-DRB loci haplotypes (DRB1-DRB3, -DRB4, or -DRB5). Three common HLA-DRB3 alleles (*01:01, *02:02, *03:01) were observed. DRB1*03:01 haplotypes carrying DRB3*02:02 conferred a higher T1D risk than did DRB1*03:01 haplotypes carrying DRB3*01:01 in DRB1*03:01/*03:01 homozygotes with two DRB3*01:01 alleles (odds ratio [OR] 3.4 [95% CI 1.46–8.09]), compared with those carrying one or two DRB3*02:02 alleles (OR 25.5 [3.43–189.2]) (P = 0.033). For DRB1*03:01/*04:01 heterozygotes, however, the HLA-DRB3 allele did not significantly modify the T1D risk of the DRB1*03:01 haplotype (OR 7.7 for *02:02; 6.8 for *01:01). These observations were confirmed by sequence analysis of HLA-DRB3 exon 2 in a targeted replication study of 281 informative T1D family members and 86 affected family-based association control (AFBAC) haplotypes. The frequency of DRB3*02:02 was 42.9% in the DRB1*03:01/*03:01 patients and 27.6% in the DRB1*03:01/*04 (P = 0.005) compared with 22.6% in AFBAC DRB1*03:01 chromosomes (P = 0.001). Analysis of T1D-associated alleles at other HLA loci (HLA-A, HLA-B, and HLA-DPB1) on DRB1*03:01 haplotypes suggests that DRB3*02:02 on the DRB1*03:01 haplotype can contribute to T1D risk.The Type 1 Diabetes Genetics Consortium (T1DGC) (1) is an international collaboration that has collected thousands of multiplex family samples, as well as case and control samples, and has carried out linkage and association analysis for genome-wide single nucleotide polymorphisms (SNPs), candidate gene SNPs, and major histocompatibility complex (MHC) SNPs, as well as for alleles and haplotypes at the highly polymorphic HLA class I and class II genes (2–7). More than 40 different loci have been associated with T1D (3); however, linkage and association analyses have identified the HLA region as the major genetic determinant of T1D risk. The most strongly T1D-associated MHC markers are defined by the HLA-DRB1, -DQA1, and -DQB1 haplotypes (4), although alleles at other HLA loci, notably HLA-A and HLA-B, as well as HLA DPB1 (5–11) and other non-HLA loci across the genome, also contribute to T1D risk (3).Although the association of HLA-DRB1 alleles with T1D is well established, the role of polymorphism at the HLA-DRB3, HLA-DRB4, and HLA-DRB5 loci has been studied less frequently, partly due to technical issues in genotyping. Most high-resolution genotyping strategies for HLA-DRB1 depend on DRB1-specific PCR primers to minimize confounding signals from coamplified secondary DRB loci. All copies of chromosome 6 have a DRB1 locus, and most, but not all, have a functional second DRB locus. This second DRB locus is DRB3 for DRB1*03, *11, *12, *13, and *14 haplotypes, DRB4 for DRB1*04, *07, and *09 haplotypes, and DRB5 for DRB1*15 and *16 haplotypes. DRB1*01, DRB1*08, and DRB1*10 haplotypes do not have a second DRB locus.The clonal sequencing property of next generation sequencing systems, such as the Roche 454 GS FLX and GS Junior Systems, allows the use of generic DRB primers to coamplify and sequence exon 2 from DRB1, DRB3, DRB4, and DRB5 loci (12–14). We have used the Roche 454 amplicon sequencing system with “fusion primers” containing the 454 adaptor (A and B) sequences and 10 base multiplex ID tags (MIDs) to amplify and sequence exon 2 from different individuals (13,14). The genotyping software consolidates these clonal sequence readings, sorts them to individual DRB loci and to individual samples, and compares them to the IMGT/HLA Sequence Database to assign specific genotypes at the HLA-DRB1, HLA-DRB3, HLA-DRB4, and HLA-DRB5 loci.To assess the potential role of these secondary HLA-DRB loci in T1D, association analyses were carried out at the two DRB locus haplotype levels, focusing on the DRB1*03:01 haplotypes bearing DRB3*01:01 or DRB3*02:02. The role of HLA-DRB3 polymorphism in T1D risk was initially evaluated in a case/control study and then examined in a targeted replication study of informative patients from multiplex HLA-genotyped families, allowing analysis of HLA haplotypes and the potential role of T1D-associated alleles at other HLA loci.     

Is there MHC Class II restriction of the response to MHC Class I in transplant patients?

BACKGROUND: In this study, we evaluated distinct HLA-DRB1 alleles to determine class II restriction of the production of HLA-A2-specific antibodies in renal transplant patients. METHODS: Data from 217 renal transplant patients who received an HLA-A2-mismatched renal graft were analyzed with regard to HLA-A2 humoral responsiveness. High-resolution DNA typing of class II HLA-DR alleles was performed by polymerase chain reaction-sequence-specific primer. Patients who had one of the following eight HLA-DRB1 alleles were included in the study: -*0101, -*0301, -*0401, -*0701, -*1101, -*1301, -*1401, and -*1501. Serum samples were screened posttransplantation with the standard complement-dependent cytotoxicity procedure. In addition, recombinant HLA-A2 monomers (the "MonoLISA" assay) were used as a target for the detection of HLA-A2 group-specific antibodies. The following HLA-A2 amino acid positions (termed "epitopes") that are responsible for the induction of an antibody response were defined: 74H, 65-66GK, 62G, 114H, 142-145TTKH, and 107W-127K. The definition of the "HLA-DR permittors" of anti-HLA-A2 response was based on a "class II restriction table" designed for this purpose. Prediction of immunogenic and/or nonimmunogenic HLA-A2 peptides was based on an MHC database. RESULTS: The HLA-DRB1-*0101 and -*1401 alleles had a trend toward a positive correlation with the production of HLA class I-specific antibodies against the HLA-A2 shared (public) epitopes 65-66GK and -62G, respectively. Only the DRB1-*1501 allele had higher trend toward a positive correlation with the production of antibodies against the HLA-A2 private (74H) epitope. In 42 patients with the HLA-DRB1-*1501 allele, 11 (26%) patients produced HLA-specific antibodies against the HLA-A2 group of epitope(s). Moreover, in these patients, spreading of the alloreactivity against "other" HLA antigens was detected. Many of these other HLA antigens did not belong to HLA-A2 group but had newly defined shared epitopes with this group. Furthermore, the epitope prediction, based on an MHC database, revealed differences in the ligation strength (score) to the HLA allele (class I and II) for a specific HLA-A2 peptide in the 42 patients (responders and nonresponders). CONCLUSIONS: The data presented in this paper suggest that the HLA class II allele and the type of the bound allopeptide may influence the humoral and cellular response. The immunogenicity of these allopeptides could be predicted with an MHC database (high-scored peptide=activating peptide and low-scored peptide=suppressor peptide). In the future, production of synthetic peptide analogues, on the basis of these predictions, could be used for induction of T-cell anergy and/or tolerance. In the short term, algorithms, on the basis of our approach, could be tested for influence on graft survival and allosensitization in current high-quality data sets.     

HLA alleles and haplotypes in the east Black Sea Turkish population

HLA class I and class II alleles were studied for the first time in 234 unrelated individuals inhabiting the East Black Sea region in Turkey. This region is on the historic silk road and close to Georgia. HLA class I (A* and B*) and class II DRB1* typing was done by the PCR-SSP method. A total of 17 HLA-A* alleles, 34 HLA-B* alleles, and 15 HLA-DRB1* alleles were detected. HLA-A*-B*, A*-DRB1*, and B*-DRB1* two-loci linkage disequilibrium data show that two specific combinations (A2-B35, A2-DRB1*11, and B35-DRB1*13) had the highest frequency (more than three or four times) compared with the other two-loci combinations, possibly reflecting an ancient founder effect. A*24 B*18 DRB1*13 and A*32 B*27 DRB1*11 were the most common haplotypes in the east Black sea Turkish population. HLA-B* showed the highest heterozygosity (94%) among the samples. The observed diversity in the HLA-A* and HLA-DRB1* loci was quite similar, ranging from 79% to 84%. We suggest that the east Black Sea Turkish population is characterized by the features of the Turkish anthropological type with some influence of other groups, such as Caucasians, Asians, and Mediterraneans.     

Association of HLA haplotypes with paroxysmal nocturnal hemoglobinuria

The pathologies of paroxysmal nocturnal hemoglobinuria (PNH) are primarily caused by somatic mutation in the PIG-A gene in hematopoietic stem cells resulting in glycosyl phosphatidylinositol deficiency and accumulation of phosphatidylinositol (PI) in plasma membranes. The mechanism of pathologic clone domination over normal hematopoietic clones in PNH patients is not yet understood. Forty-four PNH patients, including 9 with aplastic anemia traits (AA/PNH), 31 without full aplasia in bone marrow (de novo PNH, or dn/PNH), and 4 with unclassified PNH, and 200 ethnically matched controls were tested for the HLA A, B, C, DRB1, and DQB1 alleles and haplotype associations. The top block association analysis showed the primary association of PNH with 3 haplotype fragments: the class I fragment A*2501-Cw*1203-B*1801 (risk ratio [RR], 6.64; P=.00012), and 2 class II fragments: DRB1*1501-DQB1*0602 (RR, 7.09; P=.0000015) and DRB1*0401-DQB1*0301 (RR, 6.76, P=.0093). The stratified analysis revealed that the A*2501-Cw*1203-B*1801 haplotype associated preferentially with AA/PNH, and its component HLA molecule showed immunodominant antiapoptotic peptides derived from PI-activated phospholipase D; whereas the DRB1*1501-DQB1*0602 haplotype was associated strongly with dn/PNH and presented immunodominant class II-derived autopeptides. We concluded that certain HLA haplotypes were associated with PNH much more strongly than their allelic components. At least 3 HLA haplotype blocks (A*2501-Cw*1203-B*1801, DRB1*1501-DQB1*0602, and DRB1*0401-DQB1*0301) were primarily associated with PNH. Our results supported the hypothesis of the roles in AA/PNH of antiapoptotic and in dn/PNH of autoimmune mechanisms.     

内蒙古地区宫颈癌患者人乳头瘤病毒16感染分型及其人类白细胞抗原-DRB1、人类白细胞抗原-DQB1基因多态性的关系

目的探讨人乳头瘤病毒(HPV)16感染与宿主人类白细胞抗原(HLA)-DRB1、HLA-DQB1等位基因和宫颈癌发生的相关性。方法以聚合酶链反应(PCR)和多重PCR法检测30例宫颈癌、38例正常宫颈组织HPV感染及型别分布;以PCR-SSP法对22例HPV16阳性宫颈癌及35例HPV阴性正常宫颈组织进行HLA-DRB1、HLA-DQB1基因分型。结果HPV16阳性宫颈癌组与HPV阴性正常对照组比较,HLA-DRB1*15、HLA-DQB1*0301/9,10、HLA-DQB1*06基因表型频率显著增加(P<0.05),经统计学校正后,仅HLA-DRB1*15、HLA-DQB1*06等位基因与HPV16阳性宫颈癌之间呈正相关(分别为OR=3.61,95%CI=1.03~13.08;OR=3.63,95%CI=1.03~13.23)。结论HLA-DRB1*15、HLA-DQB1*06等位基因增加了HPV16阳性妇女患宫颈癌的危险性。     

Lung restricted T cell receptor AV2S3+ CD4+ T cell expansions in sarcoidosis patients with a shared HLA-DRbeta chain conformation

BACKGROUND: Sarcoidosis is a systemic disease of unknown aetiology frequently affecting the lungs. CD4+ T cells, in particular, accumulate in the lungs, implicating them in the pathogenesis of the disease. METHODS: T cell receptor (TCR) variable (V) gene expression on bronchoalveolar lavage (BAL) fluid T cells and the HLA DR alleles of 121 Scandinavian patients with sarcoidosis was determined. RESULTS: As expected from our previous results, almost every DRB1*0301 (i.e. DR17) positive patient (67/69) had significantly increased numbers of AV2S3+ CD4+ T cells in the BAL fluid but normal levels in peripheral blood (that is, lung restricted expansions) compared with only six of 52 DRB1*0301 negative patients. Detailed genotypic HLA analysis showed that these six DRB1*0301 negative patients with lung restricted AV2S3+ T cell expansions had another HLA allele in common-the HLA-DRB3*0101 allele (also called DR52a)-which was not found in any other DRB1*0301 negative patient. A new group of sarcoidosis patients was therefore identified, characterised by a strict correlation between a distinct HLA allele and lung accumulated T cells expressing a particular TCR V segment. Furthermore, the HLA-DRB1*0301 and HLA-DRB3*0101 encoded molecules showed similarities, with identical amino acid sequences in regions important for antigen binding which may enable them to bind and present the same or similar antigenic peptides. CONCLUSIONS: HLA-DRB3*0101 as well as DRB1*0301 positive sarcoidosis patients may have the capacity to present specific sarcoidosis associated antigens in such a way that AV2S3+ CD4+ T cells are stimulated preferentially, generating lung restricted AV2S3+ T cell expansions.     

HLA Class II Genotyping of African American Type 1 Diabetic Patients Reveals Associations Unique to African Haplotypes

HLA genotyping was performed in African American type 1 diabetic patients (n = 772) and controls (n = 1,641) in the largest study of African Americans and type 1 diabetes reported to date. Cases were from Children’s Hospital and Research Center Oakland and from existing collections (Type 1 Diabetes Genetics Consortium [T1DGC], Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications [DCCT/EDIC], and Genetics of Kidneys in Diabetes [GoKinD]). Controls were from the T1DGC and from newborn bloodspot cards. The diversity of HLA DRB1-DQA1-DQB1 haplotypes and genotypes is far greater than that found in Europeans and European Americans. Association analyses replicated many type 1 diabetes risk effects of European-derived haplotypes but also revealed novel effects for African-derived haplotypes. Notably, the African-specific “DR3” haplotype DRB1*03:02-DQA1*04:01-DQB1*04:02 is protective for type 1 diabetes, in contrast to the common and highly-susceptible DR3 DRB1*03:01-DQA1*05:01-DQB1*02:01. Both DRB1*07:01 and DRB1*13:03 haplotypes are predisposing when they include DQA1*03:01-DQB1*02:01g but are protective with DQA1*02:01-DQB1*02:01g. The heterozygous DR4/DR9 genotype, containing the African-derived “DR9” haplotype DRB1*09:01-DQA1*03:01-DQB1*02:01g, exhibits extremely high risk (odds ratio = 30.88), approaching that for DR3/DR4 in European populations. Disease risk assessment for African Americans differs greatly from risk assessment in European populations. This has profound implications on risk screening programs and underscores the need for high-resolution genotyping of multiple populations for the rational design of screening programs with tests that will fairly represent the population being screened.Type 1 diabetes is an autoimmune disease characterized by destruction of insulin-producing β-cells. The incidence and prevalence of type 1 diabetes are much higher for populations of European descent than for other ethnic groups (1). In the United States, diabetes mellitus is more common among nonwhite populations, including African Americans, than among non-Hispanic white (European ancestry) populations (2). Because type 2 diabetes is far more prevalent than type 1 diabetes in African American adults, and because the incidence of type 2 diabetes is increasing in African American youth because of the obesity epidemic, the burden of type 1 diabetes in African American youth has been less emphasized in the literature than that of type 2 diabetes (3). However, type 1 diabetes presents a serious burden among African American youth younger than 10 years of age, and African American adolescents are impacted substantially by both type 1 and type 2 diabetes (3). In fact, although type 2 diabetes incidence is increasing, type 1 diabetes is still approximately three-fold more common than type 2 diabetes in the African American pediatric population at Children’s Hospital and Research Center Oakland. Moreover, early disease onset lengthens disease duration and likely leads to complications at relatively young ages. African American individuals with diabetes are at higher risk for the chronic complications of diabetes than are non-Hispanic white (European) Americans, particularly for diabetic nephropathy (4).The incidence of type 1 diabetes varies widely around the world, partly because of ethnic differences in HLA allele and haplotype frequencies across populations. Susceptibility to type 1 diabetes is strongly associated with alleles at the DRB1 locus and at the DQA1 and DQB1 loci, which encode the α-chain and β-chain of the DQ heterodimer. In general, heterodimers that are DQα Arg52–positive and DQβ Asp57–negative represent high genetic risk for type 1 diabetes (5). Because the heterodimeric DQ molecule is encoded by two polymorphic genes, DQA1 and DQB1, individuals heterozygous for DQA1-DQB1 haplotypes have the potential to express up to four different DQ molecules on the cell surface. Heterodimers encoded in trans are postulated to help explain the extremely high risk of the heterozygous “DR3/DR4” genotype, which confers the highest genetic risk known for type 1 diabetes. Data from many reports show that specific combinations of alleles in DRB1-DQA1-DQB1 haplotypes are associated with type 1 diabetes risk.To date, few studies have been reported on HLA association with type 1 diabetes in African Americans, and some early reports may be confounded by the inclusion of type 2 diabetes patients. This study is the largest of its kind reported to date (772 cases, 1,641 controls) and was made possible by combining data from newly collected samples with data from existing collections.     

Association of HLA-DR3 and HLA-DR4 with sinonasal polyposis in Mexican Mestizos.

OBJECTIVE: The pathogenesis of sinonasal polyposis (SNP) is not clear; it has been suggested that it is polygenic and multifactorial. The major histocompatibility complex is a useful tool to predict genetic susceptibility to diseases, especially to autoimmune diseases. Since such susceptibility is influenced by ethnicity, it is necessary to have a wide knowledge of the structure of the population to which the patient belongs. The purpose of the study was to determine the association of HLA-DRB1 alleles with sinonasal polyposis in the Mexican Mestizo population. STUDY DESIGN: We studied the HLA-DR alleles in 34 adult Mexican Mestizo patients with SNP and compared them to those present in 99 healthy controls. METHODS: Genomic DNA from mononuclear cells was obtained by using the "salting out" technique and high-resolution DNA typing of the HLA-DRB1 alleles was performed after PCR amplification. RESULTS: We found a statistically significant increased frequency of the HLA-DRB1*03 allele (P = 0.03, odds ratio [OR] = 2.9, 95% confidence interval [CI]: 1.0-7.8) and of the HLA-DRB1*04 allele (P = 0.009, OR = 2.2, 95% CI: 1.2-4.2) in patients with SNP as compared to controls, and a statistically significant decreased frequency of the HLA-DRB1*08 allele (P = 0.01, OR = 0.2, 95% CI: 0.05-0.8). CONCLUSION: The HLA-DR locus seems to be associated with the genetic susceptibility to develop SNP in Mexicans. EBM rating: B-2b.     

Distribution of HLA class II (DRB1/DQB1) alleles and haplotypes among Bahraini and Lebanese Arabs

The genetic relationship between Bahraini and Lebanese Arabs in terms of HLA class II (DRB1 and DQB1) gene and haplotype frequencies was investigated in a group of 90 Lebanese and 52 Bahraini Arabs. Subjects of both sexes were unrelated and HLA-DRB1 and DQB1 genes were genotyped using the polymerase chain reaction-sequence specific primer (PCR-SSP) technique. Analysis of the HLA-DRB1 alleles showed that the DRB1*040101 and DRB1*110101 alleles were more common among Lebanese, whereas DRB1*030101, DRB1*130701/1327, and DRB1*160101 alleles were more common among Bahrainis. Similarly, of the 7 HLA-DQB1 alleles analyzed, the presence of DQB1*0201 was higher among Bahrainis, whereas DQB1*030101 was higher among Lebanese. The DRB1*160101-DQB1*050101 (23.08%) and DRB1*030101-DQB1*0201 (21.15%) haplotypes were more frequent among Bahrainis, while the DRB1*110101-DQB1*030101 (56.67%), DRB1*040101-DQB1*0302 (28.89%) and DRB1*040101/DQB1*030101 (25.56%) haplotypes were more frequent in Lebanese subjects. Our results underline significant differences between these two populations in HLA class II distribution, and provide basic information for further studies of MHC heterogeneity among Arab-speaking countries, and as a reference for further anthropologic studies.     

Heterozygosity or homozygosity for 2 HLA class II haplotypes predict favorable outcomes for renal cell carcinoma treated with cytokine therapy

PURPOSE: Durable responses to cytokine therapy occur in a small subset of patients with renal cell carcinoma. We determined if a common HLA genotype existed among these patients which might be associated with response and survival. MATERIALS AND METHODS: The study population consisted of 80 patients with metastatic renal cell carcinoma who had received cytokine therapy. DNA obtained from these patients was used for high resolution typing of HLA A, B, C, DRB1, DQA1 and DQB1 alleles. RESULTS: The class II alleles from patients with prolonged disease-free survival were predominantly composed of haplotype DRB1*0301/DQA1*0501/DQB1*0201 and DRB1*1501/DQA1*0102/DQB1*0602. The frequency of heterozygosity or homozygosity for these alleles was significantly greater in the good outcome group of patients than in those whose disease progressed during therapy. Heterozygosity or homozygosity at these loci was also associated with significant prolongation of survival. CONCLUSIONS: We conclude that heterozygosity or homozygosity for the class II haplotypes DRB1*0301/DQA1*0501/DQB1*0201 and DRB1*1501/DQA1*0102/DQB1*0602 is associated with durable response and survival in patients with metastatic renal cell carcinoma treated with cytokine therapy.     

Human leukocyte antigen DRB1*04 is associated with rheumatoid arthritis in Kuwaiti patients

OBJECTIVES: Rheumatoid arthritis (RA) is a common, complex autoimmune disease known to be associated with inheritance of certain human leukocyte antigen (HLA)-DR alleles in different populations. This study investigated the association of DRB1 alleles in Kuwaiti patients with RA. MATERIALS AND METHODS: DRB1 alleles were analyzed in 47 Kuwaiti patients and 70 ethnically matched controls using a DNA-based sequence specific primer (SSP) method. RESULTS: The frequency of DRB1*04 allele was higher in patients compared to the controls (P < 0.012). The association with of HLA-DRB1*04 allele in our patients with RA was accounted for mainly by the seropositive group of patients (P < 0.05). Moreover, five patients were homozygous for DRB1*4 compared to none in the controls. None of the other DRB1 alleles tested was significantly higher in the patients. All patients homozygous for the DRB1*04 allele were females. There was no statistically significant difference in the frequency of DRB1*04 allele in patients classified according to presence of erosive disease or extra-articular manifestations. CONCLUSION: Our results indicate that in Kuwaiti patients, RA is associated with the presence of DRB1*04 allele. The lack of association with severity or the phenotype of RA is not surprising since this is a hospital-based study where patients tend to have a more severe disease.     

人类白细胞抗原等位基因与慢性乙型肝炎聚乙二醇化干扰素疗效的相关性研究

目的 探讨人类白细胞抗原(HLA)-DRB1等位基因与聚乙二醇化干扰素(PEG-IFN)抗HBV应答的相关性.方法 应用聚合酶链反应-序列特异性引物(PCR-SSP)技术对青岛地区46例慢性乙型肝炎患者HLA-DRB1进行等位基因多态性分析.结果 30例有应答者HLA-DRB1*15等位基因频度(46.67%)高于16例无应答者(12.5%),RR=6.125,P=0.021; HLA-DRB1*07的分布则相反(26.67%对75%,RR=0.121,P=0.002).结论 推测HLA-DRB1*15可能与PEG-IFN的高应答有关, HLA-DRB1*07可能与PEG-IFN低应答有关.     

Meta分析HLA-DRB1等位基因多态性对于食管癌发生的影响

目的 采用系统评价的方法探究HLA-DRB1等位基因多态性与食管癌发生的相关性.方法 计算机检索Medline、EMbase、Cochrane Library、Web of Science、CBM、CNKI、VIP、万方等数据库查找相关文献.中文检索关键词:食管癌、HLA-DRB1;英文关键词:esophageal neoplasm、HLA-DRB1.按照纳入和排除标准筛选后提取数据,采用Stata12.0软件进行Meta分析.结果 最终纳入5篇文献,共包含1630例患者.Meta分析结果显示,食管癌组HLA-DRB1*0901基因易感率明显高于正常人,两组基因易感率差异有统计学意义[OR=1.70,95％ CI(1.31,2.20),P＜0.001];食管癌患者HLA-DRB1* 1501基因易感率明显高于正常人,两组基因易感率差异有统计学意义[OR=3.02,95％ CI(1.65,5.51),P＜0.001];食管癌组HLA-DRB1* 0301基因易感率明显高于正常人,两组基因易感率差异有统计学意义[OR =2.84,95％ CI(0.43,18.96),P＜0.001].结论 食管癌的发生与HLA-DRB1* 0901、HLA-DRB1* 1501与HLA-DRB1* 0301基因有关,但由于目前有关食管癌的发生与HLA-DRB1* 1501和HLA-DRB1* 0301基因之间的关系所研究文献较少,且纳入文献之间存在明显统计学异质性,因此食管癌的发生与它们之间的关系仍有待论证.     

The humoral immune response against an HLA class I allodeterminant correlates with the HLA-DR phenotype of the responder.

BACKGROUND: The genetic basis for control of alloantibody responses against foreign HLA histocompatibility antigens has never been delineated. The most likely postulate would be that HLA class II alloantigens of the host regulate the response through their ability to present processed HLA allopeptide fragments for the cognate interaction between CD4+ T lymphocytes and B lymphocytes that leads to IgG antibody synthesis. METHODS: We have analyzed our allosensitized transplant patient population with regard to humoral responsiveness to a serologically defined public HLA class I epitope, Bw4. Peptides representing the linear sequence of the Bw4 epitope (amino acids 74-86) and the alternative Bw6 epitope were synthesized and assayed for binding to a panel of HLA homozygous lymphoblastoid B cells using a quantitative fluorescence binding assay. RESULTS: We found that 73% of patients who have produced a HLA-Bw4-specific alloantibody express either the HLA-DRB1*01 or HLA-DRB1*03 alloantigen; 19% of the remaining responders expressed HLA-DRB1*04. Analysis of the United Network for Organ Sharing Transplant Registry indicated that the survival of cadaver renal allografts mismatched for Bw4 was significantly compromised in sensitized DRB1*01+ or DRB1*03+ recipients (P<0.01). In vitro, the Bw4 peptide bound strongly to DRB1*01+ and DRB1*03+ lymphoblastoid B cells; no similar binding was observed with Bw6 peptide. These findings were confirmed using murine fibroblast lines transfected with HLA-DR alpha/beta genes and by solid-phase enzyme-linked immunosorbent assay using purified HLA-DR alloantigen. CONCLUSIONS: We conclude that there are at least two human Ir genes, HLA-DRB1*01 and HLA-DRB1*03, that confer a high risk for both humoral allosensitization and renal allograft failure in situations of HLA-Bw4 incompatibility. These findings may be of future benefit in devising new antigen matching strategies for reducing the risk of humoral HLA allosensitization and chronic allograft rejection.     

Susceptibility to vesicoureteral reflux in Japanese is linked to HLA-DR antigen

Objectives. To determine whether vesicoureteral reflux is associated with the human leukocyte antigen (HLA) genes.Methods. We evaluated 40 Japanese patients (27 males and 13 females) with reflux. HLA-DR low-resolution genotyping and high-resolution typing of HLA-DRB1 alleles were performed. The frequencies of the HLAs and alleles were calculated and compared with those previously reported in 493 healthy Japanese.Results. Low-resolution typing showed that the frequency of the HLA-DR11 antigen was significantly higher in the patients with reflux than in the control group. High-resolution typing revealed that the frequencies of HLA-DRB1*1101 and 1502 alleles were significantly higher in the patients with reflux than in the control group. In the patients with and without renal scarring, the frequencies of the HLA-DR11 antigens and HLA-DRB1*1101 alleles were significantly lower in those with renal scarring. In the patients with and without the chief complaint of urinary tract infection symptoms, the frequencies of HLA-DR13 antigens and HLA-DRB1*1302 alleles were significantly lower in those with that chief complaint.Conclusions. The susceptibility to reflux is, in part, controlled by HLA genes themselves or an unknown gene or genes, the locus for which is located close to the DRB1 gene. The lack of a HLA-DRB1*1101 allele and DRB1*1302 allele in patients with reflux might be connected with renal scarring and urinary tract infection, respectively.     

HLA‐DRB1 alleles are associated with the clinical course of disease and steroid dependence in Mexican patients with ulcerative colitis

Aim The aim of this study was to study the association between the HLA‐DRB1 alleles and the clinical course of ulcerative colitis (UC). Method Seventy‐five Mexican patients with UC were studied. High resolution HLA typing was performed using Polymerase Chain Reaction‐Sequence Specific Oligonucleotide PCR‐SSO reverse dot blot and Polymerase Chain Reaction‐single specific primer PCR‐SSP. Molecular typing techniques were applied to define HLA‐DRB1 alleles. Results Seventy‐five patients (36 female patients, 39 male patients) were studied. Significant associations were found between some HLA‐DRB1 alleles and the clinical course of disease: initial active and then inactive and the HLA‐DRB1*14 allele (P = 0.03; OR = 4.63; 95% CI: 1.08–21.23); and HLA‐DRB1*08 allele (P = 0.04; OR = 4.34; 95% CI: 1.9–33.3). On the other hand, the HLA‐DRB1*07 (P = 0.001; OR = 9.76 95% CI: 1.55–65.56) was significantly associated with steroid dependence in UC patients. Conclusions This study suggests that HLA‐DRB1 alleles were associated with the clinical course of disease and steroid dependence in UC patients.     

HLA-DRB1* alleles in Egyptian children with post-streptococcal acute glomerulonephritis

To investigate the association between HLA-DRB1* alleles and post-streptococcal acute glomerulonephritis (PSAGN) in Egyptian children, 32 unrelated patients with PSAGN and 380 healthy individuals from the same locality were typed for DRB1* alleles using the polymerase chain-reverse hybridization technique. Patients with PSAGN had significantly increased frequency of both DRB1* 03011 (46.9 vs. 19.2% in controls, P  = 0.00025) and DRB1* 1105 (31.1 vs. 15.6% in controls, P = 0.0097) alleles. However, after correction of P values, only the difference for DRB1* 03011 allele remained significant (Pc = 0.025). Their relative risks were significantly high (3.71, confidence interval [CI] = 1.8–7.8, and 3.57, CI = 1.4–8.9 respectively). No significant differences in the frequency of the two alleles were observed among patients with different grades of hypertension or proteinuria. In conclusion, DRB1* 03011, and possibly 1105, alleles confer susceptibility to PSAGN. However, the severity of the disease is not determined by these two alleles.     

Genetic similarity in inflammatory and degenerative abdominal aortic aneurysms: a study of human leukocyte antigen class II disease risk genes.

PURPOSE: Clinically, abdominal aortic aneurysms (AAAs) display a spectrum of inflammation that extends from apparently noninflamed (degenerative) AAAs to the classic inflammatory variant. Genes encoded in the human leukocyte antigen (HLA) region are important in the development of both variants of AAA; however, their role in progression to the inflammatory variant is unknown. The purpose of this study was to compare HLA class II genes in patients with degenerative versus classic inflammatory AAAs and to quantify their impact as disease risk factors. METHODS: Genotypes of the 12 major alleles of the HLA-DR B1 locus were determined in patients with degenerative (102) and inflammatory (40) AAAs who were compared with controls (118). Univariate and multivariate logistic regression analyses were used to determine allele distributions and to quantify disease risk. RESULTS: Distribution of the HLA-DR B1 alleles was nonrandom and similar in both degenerative and inflammatory AAA groups compared with controls. The B1*02 and B1*04 alleles were enhanced in both degenerative (39.2% vs. 25.4%, P =.03; and 35.3% vs. 24.6%, P =.08 respectively) and inflammatory (47.5% vs. 25.4%, P =.01; and 32.5% vs. 24.6%, P =.09, respectively) AAAs compared with controls. The B1*02 and B1*04 alleles were associated with risk for both degenerative (odds ratio [OR] 2.2; 95% CI, 1.2-4.0; and OR 2.0; 95% CI, 1.1-3.7, respectively) and inflammatory AAAs (OR 3.7; 95% CI, 1.8-8.6; and OR 2.5; 95% CI, 1.1-6.1). CONCLUSION: This study demonstrates that identical HLA alleles function as genetic risk factors for both inflammatory and degenerative AAAs. These results support the concept of a common, immune-mediated pathogenesis for AAAs that may be modulated by HLA-independent factors.