Importance of human leukocyte antigen antibodies and leukocyte antigen/killer-cell immunoglobulin-like receptor genes in liver transplantation

Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance,which is described by eventual imbalances or deregulation in the balance of cytokines,mediators,effectors,and regulatory cells in the complex milieu of the liver.In this section,we will comment on the importance of donorspecific anti-human leukocyte antigen(HLA)antibodies(DSA)as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor(KIR)genotypes in the evolution of liver transplantation.Thus,HLA compatibility,viral infections,and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival.There have been reports of increased risk of acute and chronic rejection with ductopenia,faster graft fibrosis,biliary problems,poorer survival,and even de novo autoimmune hepatitis when DSAs are present in the recipient.Higher mean fluorescence intensity(MFI)values of the DSAs and smaller graft size were associated with poorer patient outcomes,implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods,according to the investigators.Similarly,in a combined kidney-liver transplant,a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment.The renal graft was lost owing to antibody-mediated rejection(AMR).The HLA antigens expressed by the transplanted liver graft influenced antibody elimination.Pathologists are increasingly diagnosing AMR in liver transplants,and desensitization therapy has even been employed in situations of AMR,particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex.In conclusion,after revealing the negative impacts of DSAs with high MFI,pretransplant virtual crossmatch techniques may be appropriate to improve evolution;however,they may extend cold ischemia periods by requiring the donor to be typed.

Prevalence of Human Leukocyte Antigen HLA-B*5701 in HIV-1 Infected Individuals in Brazil

This study was designed to establish the prevalence of HLA-B*5701 at HIV-1 infected individuals in Brazil. A total of 517 consecutive individuals were followed in this study from February 2009 through July 2011. The presence of HLA-B*5701 was determined by Nested-PCR with HLA-B*57 and HLA-B*5701 sequence-specific primers (PCR-SSP). The expression of HLA-B*57 was negative in the 385 (74.5%) and positive in the 103 (19.9%) of infected individuals. Among these, the expression of HLA-B5701 was positive in the 29 (5.6%) of individuals. No demographic or ethnic differences were found between HLA-B*57/HLA-B*5701 HIV-1 negative patients, with a prevalence of Caucasians (57.1%) individuals. During the period of study, 68 patients were submited to an abacavir contain- ing regimen. The HLA-B*5701 allele was observed in 7 (10.3%) patients, with a significant incidence of Hypersensitivity reactions at 4 of them (p < 0.001). Conclusions: Although Brazilian population consists of a mixture of individuals of Caucasian, African and Native American genetic background, prevalence of HLA-B*5701 in this population is similar to the one found in pure Caucasians.

Association of cytomegalovirus infection with human leukocyte antigen genotypes in recipients after allogeneic liver transplantation

BACKGROUND: Cytomegalovirus (CMV) infection is the important cause affecting the survival rate and function of the transplanted organ after transplantation. The occurrence of CMV infection after liver transplantation (LT) is associated with many factors. Lots of studies suggest that genetic mutation between hosts and CMV may play a role in the occurrence and development of CMV infection. CMV exists in an incubative state, affect or destroy the expression of human leukocyte antigen (HLA) molecules in the host cell surface, and interfere antigen's submission. This mechanism is the key of CMV to avoid immune defense mechanism of the host. To detect HLA and CMV antibody (CMV-Ab), CMV antigen (CMV-Ag) of transplantation recipients, we evaluated the association of CMV infection and the particular HLA genotypes in recipients after LT. METHODS: 277 blood samples were collected from 39 LT recipients. CMV antibody and antigen were detected by ELISA or immunohistochemical methods. The HLA types of the recipients were determined by PCR. To analyze the association of HLA alleles and the occurrence of CMV antigenemia in the patients, relative risk degree (RR) was used as the parameter for the Chi-square test. RESULTS: The LT recipients were serum CMV IgG positive (100%), but none of them was CMV IgM positive (0%). Thirty-three LT recipients (84.6%) were CMV antigenic positive with 1-50 positive leukocytes per 50000 leukocytes in extent and 7.2±4.2 positive leukocytes per 50000 leukocytes on average. Thirteen patients developed CMV pneumonia, with CMV antigenic positive (100%) and 17.7±5.5 positive leukocytes per 50000 leukocytes on average. Some HIA alleles were associated with the occurrence and extent of CMV antigenemia. HLA-A2 was the higher frequency allele for patients with antigenemia (P<0.05), and 7 patients carrying HLA-DR11 allele developed antigenemia (P<0.05). In the lower antigenemia group, HLA-A11 was higher in frequency than others (P<0.05). Besides, none of the patients carrying HLA-B16 allele developed clinical symptoms of CMV infection (P<0.05). CONCLUSIONS: The variability of HLA alleles might modulate immune response to CMV infection. HLA examination before transplantation should be made for prevention and treatment of CMV infection aider operation.

Impact of human leukocyte antigen matching on hepatitis B virus recurrence after liver transplantation

BACKGROUND: Liver transplantation (LT) is an effective therapy for end-stage hepatitis B virus (HBV) infection. Recurrence of HBV is one of the frequent complications. In the present study, we investigated whether human leukocyte antigen (HLA) matching influences the incidence of HBV recurrence, and the time point of HBV recurrence after LT. METHODS: One hundred and two recipients of LT with end-stage chronic HBV infection were reviewed. The triple-drug immunosuppression regimen consisted of tacrolimus, mycophenolate, and prednisone. All patients were subjected to prophylaxis with hepatitis B immunoglobulin and lamivudine. HLA typing was performed using a sequence-specific primer-polymerase chain reaction kit. Serology for hepatitis B and HBV DNA was examined using a commercial kit. RESULTS: The incidence of recurrent HBV infection post-LT was 6.86%. The recurrent infection of HBV was independent of the degree of H LA matching (P>0.05). The time point of HBV recurrence, however, was prolonged in HLA-A matched patients compared with matchless patients (P=0.049). The recurrence of HBV infection was independent of H LA compatibility. CONCLUSIONS: This retrospective analysis showed that more HLA-A locus compatibility is associated with a prolonged time of recurrence of HBV in patients after LT for end-stage HBV infection. The incidence of HBV recurrence is independent of HLA compatibility. (Hepatobiliary Pancreat Dis Int 2010; 9: 139-143)

Relationship of human leukocyte antigen class II genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients

AIM: To study the relationship of human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon (IFN) in HBV-infected patients.METHODS: Low-resolution DNA typing kit was used to determine HLA-DR-1 and -DQB1 genes in 72 patients with chronic hepatitis B (CHB) and HLA-DRB1 in 200 healthy people ready to donate their bone marrow in Shanghai.Among CHB patients, 35 were treated with IFNα-1b for 24 wk.RESULTS: The frequencies of HLA-DRB1*06, DRB1*08and DRB1*16 alleles in 72 patients were higher than in 200 healthy people (2.08% vs0%, OR = 3.837, P= 0.018;11.11% vs5.50%, OR = 2.148, P= 0.034; and 6.94% vs 3.00%, OR = 0.625, P = 0.049, respectively); whereas that of DRB1*07 allele was lower (2.78% vs 7.75%,OR = 0.340, P = 0.046). The frequency of HLA-DRB1* 14allele was higher in 11 responders to IFN compared with 24 non-responders (18.18% vs2.08%, OR = 10.444,P = 0.031), whereas that of DQB1*07 allele was inverse (9.09% vs 37.50%, OR = 0.167, P= 0.021).CONCLUSION: The polymorphism of HLA class Ⅱ may influence the susceptibility to HBV infection and the response to IFN in studied CHB patients. Compared with other HLA-DRB1 alleles, HLA-DRB1*06, DRB1*08, and DRB1*16 may be associated with chronicity of HBV infection, HLA-DRB1*07 with protection against HBV infection, and HLA-DRB1*14 allele may be associated with a high rate of the response of CHB patients to IFN treatment.Compared with other HLA-DQB1 alleles, HLA-DQB1*07 may be associated with low response rate to IFN.

Human leukocyte antigen DQ2/8 prevalence in non-celiac patients with gastrointestinal diseases

AIM: To investigate the prevalence of human leukocyte antigen (HLA) DQ2/8 alleles in Southern Italians with liver and gastrointestinal (GI) diseases outside of celiac disease. METHODS: HLA DQ2/8 status was assessed in 443 patients from three ambulatory gastroenterology clinics in Southern Italy (University of Federico Ⅱ, Naples, Loreto Crispi Hospital, Ruggi D'Aragona Hospital, Salerno). Patients were grouped based on disease status [pre-post transplant liver disease, esophageal/gastric organic and functional diseases, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD)] and DQ2/8 alleles, which correspond to a celiac disease genetic risk gradient. Subject allele frequencies were compared to healthy Italian controls. RESULTS: One hundred and ninety-six out of four hundred and forty-three (44.2%) subjects, median age 56 years and 42.6% female, were DQ2/8 positive. When stratifying by disease we found that 86/188 (45.7%) patients with liver disease were HLA DQ2/8 positive, 39/73 (53.4%) with functional upper GI diseases and 19/41 (46.3%) with organic upper GI diseases were positive. Furthermore, 38/105 (36.2%) patients with IBS and 14/36 (38.9%) with IBD were HLA DQ2/8 positive (P = 0.21). Compared to healthy controls those with functional upper GI diseases disorders had a 1.8 times higher odds of DQ2/8 positivity. Those with liver disease had 1.3 times the odds, albeit not statistically significant, ofDQ2/8 positivity. Both those with IBS and IBD had a lower odds of DQ2/8 positivity compared to healthy controls. CONCLUSION: The proportion of individuals HLA DQ2/8 positive is higher in those with liver/upper functional GI disease and lower in IBS/IBD as compared to general population estimates.

Human leukocyte antigen typing and crossmatch:A comprehensive review

Renal transplantation remains the best option for patients suffering from end stage renal disease(ESRD).Given the worldwide shortage of organs and growing population of patients with ESRD,those waitlisted for a transplant is ever expanding.Contemporary crossmatch methods and human leukocyte antigen(HLA) typing play a pivotal role in improving organ allocation and afford better matches to recipients.Understanding crossmatch as well as HLA typing for renal transplantation and applying it in clinical practice is the key step to achieve a successful outcome.Interpretation of crossmatch results can be quite challenging where clinicians have not had formal training in applied transplant immunology.This review aims to provide a worked example using a clinical vignette.Furthermore,each technique is discussed in detail with its pros and cons.The index case is that of a young male with ESRD secondary to Lupus nephritis.He is offered a deceased donor kidney with a 1-0-0 mismatch.His complement dependent cytotoxicity(CDC) crossmatch reported positive for B lymphocyte,but flow cytometry crossmatch(FCXM) was reported negative for both B and T lymphocytes.Luminex-SAB(single antigen bead) did not identify any donor specific antibodies(DSA).He never had a blood transfusion.The positive CDCcrossmatch result is not concordant with DSA status.These implausible results are due to underlying lupus erythematosus,leading to false-positive B-lymphocyte crossmatch as a result of binding immune complexes to Fc-receptors.False positive report of CDC crossmatch can be caused by the underlying autoimmune diseases such as lupus erythematosus,that may lead to inadvertent refusal of adequate kidney grafts.Detailed study of DSA by molecular technique would prevent wrong exclusion of such donors.Based on these investigations this patient is deemed to have "standard immunological risk" for renal transplantation.

Impact of human leukocyte antigen mismatching on outcomes of liver transplantation:A meta-analysis

AIM:To assess the effect of human leukocyte antigen(HLA) mismatching on liver graft outcome and acute rejection from a meta-analysis of available cohort studies.METHODS:Articles in PubMed/MEDLINE,EMBASE and the Cochrane database from January 1970 to June 2009,including non-English literature identified in these databases,were searched.Only studies comparing HLA or sub-phenotype matching with mismatching were extracted.The percentage of graft survival was extracted by "Engauge Digitizer" from survival curves if the raw data were not displayed.A meta-analysis was performed when at least 3 studies provided data.RESULTS:Sixteen studies met the inclusion criteria.A lower number of HLA mismatches(0-2 vs 3-6) did reduce the incidence of acute rejection(relative risk:0.77,P = 0.03).The degree of HLA mismatching(0-2 vs 3-6) had no significant effect on 1-year [hazard ratio(HR):1.04,P = 0.68] and 5-year(HR:1.09,P = 0.38) graft survival.In sub-phenotype analysis,the degree of HLA-A,B and DR mismatching(0 vs 1-2) had no significant effect on 1-year and 5-year graft survival,either.The HRs and P-values were 0.95,0.71(HLA-A,1-year);1.06,0.60(HLA-A,5-year);0.77,0.16(HLA-B,1-year);1.07,0.56(HLA-DR,1-year);1.18,0.23(HLADR,5-year),respectively.CONCLUSION:The results of this systematic review imply that good HLA compatibility can reduce the incidence of acute rejection in spite of having no influence on graft outcomes.To obtain a short recovery time and minimize rejection post transplantation,HLA matching studies should be considered before the operation.

Methodological aspects of anti-human leukocyte antigen antibody analysis in solid organ transplantation

Donor human leukocyte antigen(HLA)-specific antibodies(DSA) play an important role in solid organ transplantation. Preexisting IgG isotype DSA are considered a risk factor for antibody mediated rejection, graft failure or graft loss. The post-transplant development of DSA depends on multiple factors including immunogenicity of mismatched antigens, HLA class Ⅱ typing of the recipient, cytokine gene polymorphisms, and cellular immunoregulatory mechanisms. De novo developed antibodies require special attention because not all DSA have equal clinical significance. Therefore, it is important for transplant clinicians and transplant immunologists to accurately characterize DSA. In this review, the contemporary immunological techniques for detection and characterization of anti-HLA antibodies and their pitfalls are described.

Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation

Antibody-mediated rejection(AMR) caused by donorspecific anti-human leukocyte antigen antibodies(DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This "immune-tolerance" liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant(LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class Ⅱ human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional antirejection therapy, can allow a rational approach to this threat.

Clinicopathological significance of human leukocyte antigen F-associated transcript 10 expression in colorectal cancer

BACKGROUND Colorectal cancer(CRC) is a common malignancy of the gastrointestinal tract. The worldwide mortality rate of CRC is about one half of its morbidity. Ubiquitin is a key regulatory factor in the cell cycle and widely exists in eukaryotes. Human leukocyte antigen F-associated transcript 10(FAT10), known as diubiquitin, is an 18 kDa protein with 29% and 36% homology with the N and C termini of ubiquitin. The function of FAT10 has not been fully elucidated, and some studies have shown that it plays an important role in various cell processes.AIM To examine FAT10 expression and to analyze the relationship between FAT10 expression and the clinicopathological parameters of CRC.METHODS FAT10 expression in 61 cases of CRC and para-cancer colorectal tissues was measured by immunohistochemistry and Western blotting. The relationship between FAT10 expression and clinicopathological parameters of CRC was statistically analyzed.RESULTS Immunohistochemical analysis showed that the positive rate of FAT10 expression in CRC(63.93%) was significantly higher than that in tumor-adjacent tissues(9.84%, P < 0.05) and normal colorectal mucosal tissue(1.64%, P < 0.05). Western blotting also indicated that FAT10 expression was significantly higher in CRC than in tumor-adjacent tissue(P < 0.05). FAT10 expression was closely associated with clinical stage and lymphatic spread of CRC. FAT10 expression also positively correlated with p53 expression.CONCLUSION FAT10 expression is highly upregulated in CRC. FAT10 expression is closely associated with clinical stage and lymphatic spread of CRC.

Association of human leukocyte antigen DQB1 and DRB1 alleles with chronic hepatitis B

AIM: To investigate the effect of human leukocyte antigen(HLA) DRB1 and DQB1 alleles on the inactive and advanced stages of chronic hepatitis B.METHODS: Patient records at a single institution's hepatology clinic were reviewed. Demographic data, laboratory results, endoscopy results, virological parameters, biopsy scores and treatment statuses were recorded. In total, 355 patients were eligible for thestudy, of whom 226(63.7%) were male. Overall, 82(23.1%) were hepatitis B early antigen(HBeAg) positive, 87(24.5%) had cirrhosis, and 66(18.6%) had inactive disease. The presence of DQB1 and DRB1 alleles was determined by polymerase chain reaction with sequence-specific primers. The distribution of the genotyped alleles among patients with cirrhosis and patients with chronic active hepatitis was analyzed.RESULTS: The most frequent HLA DQB1 allele was DQB1*03:01(48.2%), and the most frequent HLA DRB1 allele was DRB1*13/14(51.8%). DQB1*05:01 was more frequent in patients with active disease than in inactive patients(27% vs 9.1%; P = 0.002, Pc = 0.026). DRB1*07 was rare in patients with cirrhosis compared with non-cirrhotics(3.4% vs 16%; P = 0.002, Pc = 0.022). Older age(P < 0.001) and male gender(P = 0.008) were the other factors that affected the presence of cirrhosis. In a multivariate logistic regression analysis, DRB1*07 remained a significant negative predictor of cirrhosis(P = 0.015). A bioinformatics analysis revealed that a polymorphic amino acid sequence in DRB1*07 may alter interaction with the T-cell recognition site.CONCLUSION: This study demonstrates that HLA alleles may influence cirrhosis development and disease activity in Turkish chronic hepatitis B patients.

Association between human leukocyte antigen gene polymorphisms and multiple EPIYA-C repeats in gastrointestinal disorders

BACKGROUND Polymorphisms of human leukocyte antigen(HLA)genes are suggested to increase the risk of gastric cancer(GC).AIM To investigate the HLA allele frequencies of patients with GC relative to a control group in terms of CagA+multiple(≥2)EPIYA-C repeats.METHODS The patient group comprised 94 patients[44 GC and 50 duodenal ulcer(DU)patients],and the control group comprised 86 individuals[(50 non-ulcer dyspepsia patients and 36 people with asymptomatic Helicobacter pylori(H.pylori)].Polymerase chain reaction was performed for the amplification of the H.pylori cagA gene and typing of EPIYA motifs.HLA sequence-specific oligonucleotide(SSO)typing was performed using Lifecodes SSO typing kits(HLA-A,HLA-B HLA-C,HLA-DRB1,and HLA-DQA1-B1 kits).RESULTS The comparison of GC cases in terms of CagA+multiple(≥2)EPIYA-C repeats showed that only the HLA-DQB1*06 allele[odds ratio(OR):0.37,P=0.036]was significantly lower,but significance was lost after correction(Pc=0.1845).The HLA-DQA1*01 allele had a high ratio in GC cases with multiple EPIYA-C repeats,but this was not significant in the univariate analysis.We compared allele frequencies in the DU cases alone and in GC and DU cases together using the same criterion,and none of the HLA alleles were significantly associated with GC or DU.Also,none of the alleles were detected as independent risk factors after the multivariate analysis.On the other hand,in a multivariate logistic regression with no discriminative criterion,HLA-DQA1*01(OR=1.848),HLA-DQB1*06(OR=1.821)and HLA-A*02(OR=1.579)alleles were detected as independent risk factors for GC and DU.CONCLUSION None of the HLA alleles were detected as independent risk factors in terms of CagA+multiple EPIYA-C repeats.However,HLA-DQA1*01,HLA-DQB1*0601,and HLA-A*2 were independent risk factors with no criterion in the multivariate analysis.We suggest that the association of these alleles with gastric malignancies is not specifically related to cagA and multiple EPIYA C repeats.

Human leukocyte antigen class II DQB1*0301, DRB1*1101 alleles and spontaneous clearance of hepatitis C virus infection: A meta-analysis

AIM: To assess the associations of human leukocyte antigen (HLA) class Ⅱ DQB1*0301 and/or DRB1*1101 allele with spontaneous hepatitis C virus (HCV) clearance by meta-analysis of individual dataset from all studies published till date.METHODS: To clarify the impact of HLA class Ⅱ polymorphisms on viral clearance, we performed a metaanalysis of the published data from 11 studies comparing the frequencies of DQB1*0301 and DRB1*1101 alleles in individuals with spontaneous resolution to those with persistent infection. As we identified the heterogeneity between studies, summary statistical data were calculated based on a random-effect model.RESULTS: Meta-analyses yielded summary estimatesodds ratio (OR) of 2.36 [95%CI (1.62, 3.43), P<0.00001]and 2.02 [95%CI (1.56, 2.62), P<0.00001] for the effects of DQB1*0301 and DRB1*1101 alleles on spontaneous clearance of HCV, respectively.CONCLUSION: These results support the hypothesis that specific HLA class Ⅱ alleles might influence the susceptibility or resistance to persistent HCV infection.Both DQB1*0301 and DRB1*1101 are protective alleles and present HCV epitopes more effectively to CD4+T lymphocytes than others, and subjects with these two alleles are at a lower risk of developing chronic HCV infection. Large, multi-ethnic confirmatory and welldesigned studies are needed to determine the host genetic determinants of HCV infection.

Up-regulation of Human Leukocyte Antigen G Expression in Primary Cutaneous Malignant Melanoma Associated with Host-vs-tumor Immune Response

Human leukocyte antigen G （HLA-G） is one of the molecules implicated in immunotolerance. To investigate the role of HLA-G in primary cutaneous malignant melanoma （CMM）, a series of 47 skin melanocytic lesions were immunohistochemically evaluated. The correlation between HLA-G expression and CMM clinicohistopahtological data and Bcl-2 expression was also analyzed. HLA-G expression was detected in a variety of cell types. No significant difference in HLA-G expression was observed between malignant and non-malignant melanocytic lesions. HLA-G expression was significantly correlated with the inflammatory infiltration and Bcl-2 expression, whereas no significant correlation with ulceration, tumor thickness, clinical stage, histopathological subtypes were observed. HLA-G expression may be the result of host immune reaction in tumor microenvironment rather than a malignant feature of CMM.

Key role of human leukocyte antigen in modulating human immunodeficiency virus progression: An overview of the possible applications

Host and viral factors deeply influence the human immunodeficiency virus(HIV) disease progression. Among them human leukocyte antigen(HLA) locus plays a key role at different levels. In fact, genes of the HLA locus have shown the peculiar capability to modulate both innate and adaptive immune responses. In particular, HLA class Ⅰmolecules are recognized by CD8+ T-cells and natural killers(NK) cells towards the interaction with T cell receptor(TCR) and Killer Immunoglobulin Receptor(KIR) 3DL1 respectively. Polymorphisms within the different HLA alleles generate structural changes in HLA classⅠpeptide-binding pockets. Amino acid changes in the peptide-binding pocket lead to the presentation of a different set of peptides to T and NK cells. This review summarizes the role of HLA in HIV progression toward acquired immunodeficiency disease syndrome and its receptors. Recently, many studies have been focused on determining the HLA binding-peptides. The novel use of immune-informatics tools, from the prediction of the HLA-bound peptides to the modification of the HLAreceptor complexes, is considered. A better knowledge of HLA peptide presentation and recognition are allowing new strategies for immune response manipulation to be applied against HIV virus.

Inhibition of host immune response in colorectal cancer:Human leukocyte antigen-G and beyond

Colorectal cancer(CRC)is one of the most diffuse cancers worldwide and is still a clinical burden.Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells.Their type,density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients.The non-classical MHC class?Ⅰ?human leukocyte antigen-G(HLA-G),is a crucial tumor-driven immune escape molecule involved in immune tolerance.HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells,and adaptive immune cells as cytotoxic T and B lymphocytes.HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance.This review highlights the current knowledge on HLA-G contribution in CRC,in related inflammatory dis-eases and in other type of cancers and disorders.HLA-G genetic setting(specific haplotypes,genotypes and alleles frequencies)and association with circulating/soluble profiles was highlighted.HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.

Human leukocyte antigen-DP loci are associated with the persistent infection of hepatitis B virus in Chinese population

A genome-wide association study recently showed that genetic variants in human leukocyte antigen (HLA)-DP loci were strongly associated with a risk of persistent infection of hepatitis B virus (HBV) in Japanese and Thai individuals and variants in interleukin 28B (IL-28B) have been associated with responses to anti-hepatitis C virus (HCV) treatment. The aim of this study was to investigate whether the HLA-DP loci and IL-28B were associated with different outcomes of chronic HBV infection (CHB) in Chinese subjects. The rs9277535 near HLA-DPB1,rs3077 near HLA-DPA1, and rs12979860 near IL-28B were genotyped by direct sequencing in 185 CHB patients and 193 self-limited hepatitis B virus (SLHBV)-infected subjects who recovered from HBV infection. The rs9277535 near HLA-DPB1 was strongly associated with CHB (P=0.000 018 1, OR=1.905). This association was observed independent of HBV e antigen (HBeAg) status and HBV viral loads in HBeAg-positive CHB patients (P=0.000 4, OR=1.956), in HBeAg-negative CHB patients (P=0.000 9, OR=1.857), and in HBeAg-negative CHB individuals without detectable levels of HBV DNA in serum (P=0.001 1, OR=2.05). The rs3077 near HLA-DPA1 was associated with CHB (P=0.020 6, OR=0.686 5) and HBeAg-positive CHB infection status (P=0.014 3, OR=0.604 7). Meanwhile, a genetic variation of insertion-deletion (INDEL) polymorphism (rs361527, -/ATAAATGTTGA) near HLA-DPA1 was found to be associated with CHB (P=0.030 7, OR=0.702 8) and HBeAg-positive CHB infection status (P=0.023 3, OR=0.619). However,the rs12979860 genotype near IL-28B had no correlation with CHB. This study demonstrated that in the Han Chinese populations, HLA-DP loci, but not IL-28B, were associated with persistence of infection in different outcomes of HBV-infected patients; however, the mechanism needs to be further investigated.

Human leukocyte antigen class-Ⅱ DRB1 alleles and Giardia lamblia infection in children: A case-control study

Objective:To compare the genotype frequencies of HLA class-ⅡDRB1 alleles in Giardia(G.)lamblia-infected children.Methods:A total of 490 Egyptian children aged 2-16 years were subjected to microscopic stool examination to detect G.lamblia infection,and to exclude other intestinal pathogens.On the basis of their microscopic findings,a group of 80 children were chosen as giardiasis cases,another 80 children were confirmed as Giardia free control group by immunochromatographic test,and the remaining children were excluded.Both giardiasis and control groups were then subjected to blood examination to identify their genetic type of HLA-DRB1 alleles.Results:HLA class-ⅡDRB1*03:01 and DRB1*13:01 alleles were significantly associated with G.lamblia infection(P<0.001 for each variable).On the other hand,HLA class-ⅡDRB1*04:02,DRB1*10:01,DRB1*14:01 and DRB1*15:01 alleles were significantly demonstrated in Giardia free children.However,other HLA-DRB1 alleles did not show any significant association with giardiasis.Conclusions:HLA class-ⅡDRB1*03,DRB1*13,DRB1*04,DRB1*10,DRB1*14 and DRB1*15 alleles may be involved in the establishment of host immune response to G.lamblia infection.

Occurrence of human leukocyte antigen B51-related ankylosing spondylitis in a family:Two case reports

BACKGROUND Ankylosing spondylitis(AS)is strongly associated with the human leukocyte antigen(HLA)B27 haplotype.In regions where conventional polymerase chain reaction for HLA typing is available for antigens such as HLA B27 or HLA B51,it is common to perform the HLA B27 test for evaluation of AS.While HLA B27-associated clustered occurrences of AS have been reported in families,we report the first case series of HLA B51-related occurrences of AS in a family.CASE SUMMARY A father and his daughters were diagnosed with AS and did not have the HLA B27 haplotype.Although they were positive for HLA B51,they exhibited no signs of Behçet’s disease(BD).Of the five daughters,one had AS,and three,including the daughter with AS,were positive for HLA B51.The two daughters with the HLA B51 haplotype(excluding the daughter with AS)exhibited bilateral grade 1 sacroiliitis,whereas the daughters without the HLA B51 haplotype did not have sacroiliitis.Thus,this Korean family exhibited a strong association with the HLA B51 haplotype and clinical sacroiliitis,irrespective of the symptoms of BD.CONCLUSION It is advisable to check for HLA B51 positivity in patients with AS/spondyloarthropathy who test negative for HLA B27.