Association of human cytomegalovirus viremia with human leukocyte antigens in liver transplantation recipients

Human cytomegalovirus (HCMV) reactivation is a common complication after liver transplantation (LT). Here, we investigated whether human leukocyte antigen (HLA)-matching was related to HCMV infection and subsequent graft failure after LT for hepatitis B virus cirrhosis. This retrospective study reviewed 91 LT recipients. All the patients were grouped according to HLA-A, HLA-B, and HLA-DR locus matching. Clinical data were collected, including complete HLA-typing, HCMV viremia, graft failure, and the time of HCMV viremia. HLA typing was performed using a sequence-specific primer-polymerase chain reaction kit. HCMV was detected by pp65 antigenemia using a commercial kit. The incidence of HCMV infection post-LT was 81.32%. Graft failure was observed in 16 of 91 (17.6%) patients during the 4-year study. The incidence of HCMV viremia was 100% (5/5), 91.4% (32/35), and 72.5% (37/51) in HLA-A two locus, one locus, and zero locus compatibility, respectively. Nevertheless, the degree of the HLA-A, HLA-B, or HLA-DR match did not influence the time of HCMV viremia, graft failure, or the time of graft failure after a diagnosis of HCMV viremia (all P > 0.05). An interesting discovery was that the risk of HCMV viremia tended to be higher in patients with better HLA-A compatibility. Graft failure, time of HCMV viremia, and graft failure after a diagnosis of HCMV viremia appear to be independent of HLA allele compatibility.     

Enhanced reactivation of ultraviolet-irradiated human cytomegalovirus in normal host cells

Enhanced survival of UV-irradiated human cytomegalovirus (HCMV) is demonstrated in normal human cells exposed to UV light prior to infection. The UV fluence that gave rise to maximum UV reactivation falls in the range of 15 J/m2. A large number of temperature-sensitive HCMV mutants were found under the peak of reactivation. These results confirm the existence of inducible SOS functions in human cells.     

Induction of polymorphonuclear leukocyte response by human cytomegalovirus

Neutrophils are important in the defense against bacterial infections, by ingesting and killing invading microorganisms. Because of the higher incidence of bacterial infections in patients with active human cytomegalovirus (HCMV) infections, we hypothesized that HCMV-infected neutrophils were inefficient in eliminating the bacteria. Therefore, we mock infected or infected neutrophils with HCMV by contact with HCMV-infected human pulmonary artery endothelial cells. We found that HCMV infection without N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation increased the surface expression of CD11b to the same extent as fMLP stimulation of mock infected cells. Also, HCMV-infected neutrophils became more efficient in phagocytosing serum opsonized yeast particles than mock infected cells. Furthermore, we observed an increase in intracellular free calcium and chemiluminescence in HCMV-infected cells, in response to fMLP compared to fMLP-treated mock cells. We also found that apoptosis was significantly inhibited in HCMV-infected neutrophils. In conclusion, our results suggest that neutrophils become more effective in performing their effector functions when infected with HCMV. Thus, the higher incidence of bacterial infections in HCMV patients might not be due directly to a dysfunction in the neutrophils. Instead, the fact that apoptosis is inhibited may cause over-reactive neutrophils to remain in the tissues, where they will start leaking their contents, damaging the tissues and contributing to inflammatory processes.     

Association of human leukocyte antigen DQ1 and dengue fever in a white Southern Brazilian population

Dengue is an infectious disease of viral etiology transmitted by the mosquitoes Aedes aegypti, A. albopictus, and A. scutellaris. It can develop either as a benign form or as a severe hemorrhagic form. Previous work showed an association of the hemorrhagic form with human leukocyte antigens (HLA), suggesting a role of genetic factors in disease susceptibility. Nevertheless, data on HLA association with the classical form of the disease is scarce in literature. Sixty-four patients and 667 normal individuals, living in the state of Parana, Southern Brazil, were used as test and control group, respectively. The patients developed the disease during a virus 1 dengue outbreak either in Maringa city in 1995 (47) or in Paranavai city in 1999 (17). The diagnostic was confirmed through serology and/or viral culture. HLA class I and II typing was performed by the classical microlynfocitotoxicity test using monoclonal antisera and fluorobeads. Qui-square statistical analysis confirmed a positive association with HLA-DQ1 (76.6% vs 57.7%; p = 0.005243; pc = 0.026215). HLA-DR1 also presented an increased frequency in the test group, not statistically significant after p correction though (32.8% vs 15.9%; p = 0.005729; pc = 0.080206). In conclusion, genetic factors may play a role on the susceptibility to the classical dengue, virus 1, in the Brazilian population. Further independent studies should be performed in the Brazilian population to confirm these preliminary data.     

Association of HLA-te22 antigen with anti-nuclear antibodies in Chinese patients with erosive oral lichen planus

The purpose of this study was to determine the frequencies of the presence of serum anti-nuclear antibodies (ANA) and smooth muscle antibodies (SMA) in 76 patients with oral lichen planus (OLP), in 77 patients with other oral mucosal diseases, and in 41 healthy control subjects. HLA phenotypes in some of the patients with OLP and recurrent aphthous ulcers (RAU) were determined to show whether there was an association of HLA antigens with the presence of autoantibodies. Indirect immunofluorescence techniques with mouse liver or stomach as the substrate were used to detect the serum ANA or SMA, respectively. The B lymphocytes isolated from peripheral blood were used for HLA typing by means of a standard microcytotoxicity assay. We found that the positive rate of serum ANA in patients with OLP (29%, p < 0.01), especially in patients with erosive OLP (34%, p < 0.001), was significantly higher than that in the normal control subjects (5%). The frequency of serum SMA in patients with OLP (20%, p < 0.01), in patients with RAU (17%, p < 0.01), or in patients with oral squamous cell carcinomas (41%, p < 0.001) was also significantly higher than that in normal control individuals (0%). In the erosive OLP group, the HLA-Te22 antigen occurred more frequently in patients with positive ANA (75%, p < 0.05) than in those with negative ANA (25%). We conclude that there is an association of HLA-Te22 antigen with ANA in Chinese patients with erosive OLP.     

A mathematical analysis of human leukocyte antigen serology

This paper presents and explores a comprehensive mathematical model for human leukocyte antigen serology, based on a mathematical formalization of the concept of specificity. This model is general enough to take into account such factors as absorption, elution, cross-reactivity, and incomplete immunization. The paper includes a presentation of the relevant immunological background and a short discussion of the underlying computational difficulty of the basic problems. Upper and lower bounds are derived for the minimal number of specificities required to explain a given set of HLA reactions, and it is shown that the numbers of antibodies and antigens involved must be no less then this minimal number of specificities. Other techniques and theorems are also presented to aid in reducing and analyzing HLA reaction matrices.     

Expression of human leukocyte antigen G is associated with prognosis in nasopharyngeal carcinoma

Human leukocyte antigen G (HLA-G) has multiple immune regulatory functions including the induction of immune tolerance in malignancies. The roles of HLA-G have not been investigated in nasopharyngeal carcinoma (NPC). This study is aimed to evaluate the role of HLA-G as prognostic factor for NPC patients as well as its role in the immune regulation. Western assays showed high HLA-G expression in NPC cell lines, but low in the immortalized nasopharyngeal epithelial cell line NP69. HLA-G protein was further detected in 79.2% of 552 NPC specimens with immunohistochemistry (IHC), but not in normal nasopharyngeal epithelium tissue. Moreover, high expression of HLA-G predicted poor survival of NPC patients and positively correlated with tumor N classification and recurrence or metastasis. Multivariate analysis indicated that HLA-G was an independent and unfavorable prognostic factor. Furthermore, the presence of CD68+ macrophages and IL-10 were also examined, which are two prognostic markers of NPC and important factors for regulating immune surveillance. The correlations of HLA-G with these two immune factors were revealed in NPC tissues. Taken together, our results suggest that HLA-G is an independent biomarker for NPC prognosis, and HLA-G might contribute to NPC progression, which might jointly regulate immune surveillance in NPC together with macrophages and IL-10.     

Consensus classification of human leukocyte antigen class II proteins

Class II human leukocyte antigens (HLA II) are proteins involved in the human immunological adaptive response by binding and exposing some pre-processed, non-self peptides in the extracellular domain in order to make them recognizable by the CD4+ T lymphocytes. However, the understanding of HLA–peptide binding interaction is a crucial step for designing a peptide-based vaccine because the high rate of polymorphisms in HLA class II molecules creates a big challenge, even though the HLA II proteins can be grouped into supertypes, where members of different class bind a similar pool of peptides. Hence, first we performed the supertype classification of 27 HLA II proteins using their binding affinities and structural-based linear motifs to create a stable group of supertypes. For this purpose, a well-known clustering method was used, and then, a consensus was built to find the stable groups and to show the functional and structural correlation of HLA II proteins. Thus, the overlap of the binding events was measured, confirming a large promiscuity within the HLA II–peptide interactions. Moreover, a very low rate of locus-specific binding events was observed for the HLA-DP genetic locus, suggesting a different binding selectivity of these proteins with respect to HLA-DR and HLA-DQ proteins. Secondly, a predictor based on a support vector machine (SVM) classifier was designed to recognize HLA II-binding peptides. The efficiency of prediction was estimated using precision, recall (sensitivity), specificity, accuracy, F-measure, and area under the ROC curve values of random subsampled dataset in comparison with other supervised classifiers. Also the leave-one-out cross-validation was performed to establish the efficiency of the predictor. The availability of HLA II–peptide interaction dataset, HLA II-binding motifs, high-quality amino acid indices, peptide dataset for SVM training, and MATLAB code of the predictor is available at http://sysbio.icm.edu.pl/HLA.     

Association of cytomegalovirus with infantile hepatitis

Infantile hepatitis is occasionally seen in apparently healthy children. In most cases, the etiology of the infection is uncertain. However, cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human parvovirus B19, and TT virus (TTV) are considered to be associated with hepatitis in children. The objective of this study was to investigate the correlations between these viruses and infantile hepatitis. Twenty-six children from 1 to 24 months old (median age, 7 months) who had liver dysfunction of unknown etiology were enrolled in this study. Plasma samples were examined by a real-time PCR assay for CMV, EBV, HHV-6, HHV-7, parvovirus B19, and TTV DNA. The DNA of CMV was detected in the plasma of four patients (15.4%) and was detected significantly more often in the patient group than in the control group. The CMV-infected patients were 1 to 3 months old, which was significantly younger than the remaining patients. The serological findings did not always correlate with the results of the real-time PCR assay. The DNA of TTV was detected in four patients (15.4%), while human parvovirus B19 DNA was detected in three (11.5%). However, the detection frequencies of these viral DNAs were not significantly different from those in the control groups, and some of these patients had co-infections. These results indicate that CMV might be one of the major pathogens responsible for infantile hepatitis; however, serological tests have limited utility for the diagnosis of CMV infection in young children.     

Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population

Recent data suggest that brain‐derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD‐I) or type II (BPD‐II) and 386 matched health controls were enrolled, and TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ² = 6.18, df = 2, P = 0.046; allele: χ² = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64–0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD‐I and BPD‐II separately. For BPD‐I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = ?2.27, df = 144, P = 0.025); for BPD‐II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD‐II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD‐I and BPD‐II.     

Recombination in human leukocyte antigen region in two Asian Indian families

BACKGROUND:

Recombination (crossing over) may generate novel haplotypes that can be beneficial to a population against recently introduced pathogens. It may lead to the generation of new alleles.

SETTINGS AND DESIGN:

A prospective study at a tertiary care centre.

AIM:

To report two rare cases of crossing over in HLA region.

MATERIALS AND METHODS:

Tissue-typing was done by sequence specific primers (SSP) for DR locus and by both SSP and serology for Class I which was reconfirmed on fresh samples.

RESULTS:

In one patient crossing over had taken place in the region of A locus resulting in inheritance of A*01 instead of expected A*11. In second family crossing over had taken place in region of DRB1 locus and the sibling inherited DRB1*08 instead of DRB1*10.

CONCLUSIONS:

Possibility of recombination must be considered when interpreting implausible tissue-typing results of families worked up for BMT.     

Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus

Human leukocyte antigen (HLA) class I and class II alleles are implicated as genetic risk factors for many autoimmune diseases. However, the role of the HLA loci in human systemic lupus erythematosus (SLE) remains unclear. Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, we identified three distinct haplotypes that encompassed the class II region and exhibited transmission distortion. DRB1 and DQB1 typing of founders showed that the three haplotypes contained DRB1*1501/ DQB1*0602, DRB1*0801/ DQB1*0402, and DRB1*0301/DQB1*0201 alleles, respectively. By visualizing ancestral recombinants, we narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to an approximately 500-kb region. We conclude that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.