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.

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.

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.

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)

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.

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.

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.

Reflections on the prevalence of human leukocyte antigen-B27 and human leukocyte antigen-B51 co-occurrence in patients with spondylarthritis

We performed a literature mini-review of the clinical profile of patients with spondylarthritis who are also human leukocyte antigen(HLA)-B51-positive.It seems to us that patients with HLA-B27 and HLA-B51 are more common in men,Asians and between the third and ninth decades of life.They are more likely to develop peripheral joint conditions,with cutaneous manifestations(e.g.,oral ulcers)and uveitis.Therefore,more robust epidemiological studies with more accurate methodology and multicenter locations are needed to better map the role of the interaction between HLA-B51 in patients with spondylarthritis.

Psoriatic arthritis: clinical patterns, rheumatoid factor, anti-cyclic citrullinated peptide and human leukocyte antigen risk alleles

Psoriatic arthritis is an inflammatory arthritis associated with psoriasis.Both rheumatoid factor and anti-cyclic citrullinated peptide antibodies positive psoriatic arthritis patients may be in risk for development of symmetrical polyarthritis pattern.Symmetrical polyarthritis pattern was predominant(42%)among clinical pattern of psoriatic arthritis.Among 10 rheumatoid factor positive patients,8(80%)patients had symmetrical polyarthritis pattern and out of 7 anti-cyclic citrullinated peptide antibody positive patients,7(100%)patients had symmetrical polyarthritis pattern.Association of anti-cyclic citrullinated peptide(P=0.008)and rheumatoid factor(P=0.006)showed statistical significance with symmetrical polyarthritis pattern.Human leukocyte antigen-B*07,*38 and human leukocyte antigen-C*07 were predominantly found in rheumatoid factor and anti-cyclic citrullinated peptide positive psoriatic arthritis patients.Background:Psoriatic arthritis is an inflammatory arthritis associated with psoriasis.It is usually seronegative in nature but a small percentage of patients may be positive for rheumatoid factor and anti-cyclic citrullinated peptide antibodies.Anti-cyclic citrullinated peptide and rheumatoid factor are highly specific for rheumatoid arthritis but their role is not clear in psoriatic arthritis.The prevalence and prognostic value of anti-cyclic citrullinated peptide antibody and rheumatoid factor in psoriatic arthritis patients is not well known.The aim of this study was therefore to investigate the prevalence of anti-cyclic citrullinated peptide antibodies and rheumatoid factor in psoriatic arthritis patients and assess their clinical associations and also to see the distribution of human leukocyte antigen-B and human leukocyte antigen-C locus antigens in anti-cyclic citrullinated peptide antibody and rheumatoid factor positive psoriatic arthritis patients.Methods:Fifty patients with psoriatic arthritis were tested for the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies.Polymerase chain reaction was done with sequence specific primer for detection of human leukocyte antigen-B and human leukocyte antigen-C locus antigens in rheumatoid factor and anti-cyclic citrullinated peptide positive psoriatic arthritis patients.Data on five clinical patterns of rheumatological manifestations of psoriatic arthritis patients were collected prospectively on all patients and statistically compared between anti-cyclic citrullinated peptide,rheumatoid factor positive and negative patients by chi-square test.We also see the distribution of human leukocyte antigen-B and human leukocyte antigen-C locus antigens in anti-cyclic citrullinated peptide antibody and rheumatoid factor positive psoriatic arthritis patients.Results:Among 50 psoriatic arthritis patients,rheumatoid arthritis test was positive in 10(20%)patients and anti-cyclic citrullinated peptide was positive in 7(14%)patients.Symmetrical polyarthritis pattern is predominant among clinical pattern of psoriatic arthritis which was found in 21(42%)patients.Among 7 anti-cyclic citrullinated peptide positive psoriatic arthritis patients,symmetrical polyarthritis pattern is predominant and it was found in 7(100%)patients.Among 10 rheumatoid factor positive psoriatic arthritis patients,symmetrical polyarthritis pattern is predominant and it was found in 8(80%)patients.In this study,symmetrical polyarthritis pattern is statistically associated with anti-cyclic citrullinated peptide positive psoriatic arthritis patients(P=0.008)and rheumatoid factor positive psoriatic arthritis patients(P=0.006).Human leukocyte antigen-B*07,*38 and human leukocyte antigen-C*07 were predominantly found in rheumatoid factor and anti-cyclic citrullinated peptide positive psoriatic arthritis patients.Conclusion:Both rheumatoid factor and anti-cyclic citrullinated peptide positive psoriatic arthritis patients may be in risk for development of symmetrical polyarthritis pattern.Among rheumatoid factor and anti-cyclic citrullinated peptide positive psoriatic arthritis patients,Human leukocyte antigen-B*07,*38 and human leukocyte antigen-C*07 alleles were more frequently found alleles.

Soluble Human Leukocyte Antigen-G Expression in Pregnancy Success and Early Pregnancy Loss in Korle-Bu Teaching Hospital

Introduction: Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility complex (MHC) class Ib antigen characterized by a limited polymorphism. The expression of HLA-G at immune privileged sites and its ability to inhibit the effectors functions of immune cells has set HLA-G as a molecule of immune tolerance. This expression pattern is unique among HLA genes and suggests that HLA-G may be involved in interactions that are critical in establishing and/or maintaining pregnancy. Methods: Soluble HLA-G (sHLA-G) levels were measured using a BioVendor sHLA-G ELISA kit following the manufacturer’s protocol. The study participants include women undergoing spontaneous abortion, non-pregnant women, males and an archive sample of women who had normal vaginal deliveries without any complications and any history of malaria infection from gestation to delivery. Results: Soluble HLA-G levels were higher among women undergoing spontaneous abortion as compared to women who had normal vaginal delivery and non-pregnant women. Soluble HLA-G levels were also higher in second trimester as compared to first trimester in both women who had spontaneous abortions and women who had normal delivery. Conclusion: Although sHLA-G levels were higher among women undergoing spontaneous abortion as compared to non-pregnant women and women who had normal delivery, this may be playing a role in the maintenance of maternal immune tolerance to fetal antigen, since plasma sHLA-G levels increased with increasing trimester in both women who had normal delivery and women undergoing spontaneous abortion.

Decreased human leukocyte antigen-D-related expression on CD14^(+)monocytes in patients with out-of-hospital cardiac arrest provided target temperature management therapy:a prospective observational study

Background:Post–cardiac arrest syndrome involves systemic inflammation,which causes subsequent neurological impairments.We investigated the influence of targeted temperature management(TTM)therapy in patients with out-of-hospital cardiac arrest(OHCA)after return of spontaneous circulation(ROSC)by observing the changes in circulating CD14^(+)monocytes and the expression of human leukocyte antigen D–related(HLA-DR)and programmed cell death ligand 1(PD-L1)in CD14^(+)monocytes.Methods:Adult patients admitted to the emergency department of Beijing Chao-Yang Hospital after OHCA between January 2017 and March 2018 were included in this study.Thirty control subjects,10 patients with OHCA,and 37 patients with OHCA who received 72 hours of TTM therapy were enrolled.Peripheral blood samples of patients in the OHCA and TTM groups were collected on Days 1 and 3(D1 and D3)after ROSC and evaluated for HLA-DR and PD-L1 expression on CD14^(+)monocytes using flow cytometry.Results:Compared with control subjects,the percentage of circulating CD14^(+)monocytes,HLA-DR+/CD14^(+)monocyte ratios,and mean fluorescence intensity were significantly decreased in patients with OHCA.After ROSC,HLA-DR expression in CD14^(+)monocytes in the TTM group was lower than that in patients with OHCA.However,there were no significant differences in the percentage of PD-L1+/CD14^(+)monocytes or the mean fluorescence intensity between patients with OHCA and healthy volunteers.Conclusion:After ROSC,circulating CD14^(+)monocytes and HLA-DR+/CD14^(+)monocyte ratios decreased significantly in patients with OHCA.Human leukocyte antigen D–related expression in CD14^(+)monocytes was lower in patients treated with TTM.

Human leukocyte antigen compatibility and incidence of donorspecific antibodies in pediatric liver transplant recipients

BACKGROUND Antibody-mediated rejection following liver transplantation(LT)has been increasingly recognized,particularly with respect to the emergence of de novo donor-specific antibodies(DSAs)and their impact on graft longevity.While substantial evidence for adult populations exists,research focusing on pediatric LT outcomes remains limited.AIM To investigate the prevalence of human leukocyte antigen(HLA)mismatches and DSA and evaluate their association with rejection episodes after pediatric LT.METHODS A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre,Brazil,between December 2013 and December 2023.Only patients who survived for>30 days after LT with at least one DSA analysis were included.DSA classes I and II and cross-matches were analyzed.The presence of de novo DSA(dnDSA)was evaluated at least 3 months after LT using the Luminex®single antigen bead method,with a positive reaction threshold set at 1000 MFI.Rejection episodes were confirmed by liver biopsy.RESULTS Overall,67 transplanted children were analyzed;61 received grafts from living donors,85%of whom were related to recipients.Pre-transplant DSA(class I or II)was detected in 28.3%of patients,and dnDSA was detected in 48.4%.The median time to DSA detection after LT was 19.7[interquartile range(IQR):4.3-35.6]months.Biopsyproven rejection occurred in 13 patients at follow-up,with C4d positivity observed in 5/13 Liver biopsies.The median time to rejection was 7.8(IQR:5.7-12.8)months.The presence of dnDSA was significantly associated with rejection(36%vs 3%,P<0.001).The rejection-free survival rates at 12 and 24 months were 76%vs 100%and 58%vs 95%for patients with dnDSA anti-DQ vs those without,respectively.CONCLUSION Our findings highlight the importance of incorporating DSA assessment into pre-and post-transplantation protocols for pediatric LT recipients.Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.

A novel approach to human leukocyte antigen-mismatched transplantation in patients with malignant hematological disease

Background Many patients requiring allogeneic hematopoietic stem cell transplantation (HSCT) do not have an human loukocyte antigen (HLA) matched donor Alternative donors, such as HLA mismatched family donors, are associated with higher rates of graft rejection and acute graft versus host disease (aGVHD) if T cells are not first depleted We developed a new technique for HLA mismatched allogeneic HSCT using G CSF primed bone marrow plus G CSF mobilized peripheral blood stem cells without ex vivo T cell depletion Methods In this study, 58 patients, including 33 with high risk or advanced leukemia, were transplanted with cells from an HLA haploidentical family donor with 1-3 mismatched loci After conditioning, patients received G CSF primed bone marrow grafts that had not been depleted ex vivo of T cells, in combination with G CSF mobilized peripheral blood stem cells, as well as GVHD prophylaxis Result All patients achieved sustained, full donor type engraftment The incidence of grade Ⅱ Ⅳ aGVHD was 37 9%, including 3 patients with grade Ⅲ Ⅳ aGVHD The development of aGVHD was not associated with the extent of HLA disparity Chronic GVHD was observed in 30 of 51 evaluable patients (65 4%) Fourteen patients died among whom 7 died of recurrent disease and 7 of transplant related complications Forty four of the 58 patients survived, and 42 remained disease free at the time of a median follow up of 12 months (3 5 to 39 5 months) The 2 year probabilities of disease free survival were 74 8% and 69 3% for standard and high risk patients, respectively Conclusion We developed a new method to use bone marrow from haploidentical family donors without ex vivo T cell depletion, in combination with G PBSCs, as a source of stem cells even in cases of HLA mismatched transplantation

Anti-human leukocyte antigens and anti-major histocompatibility complex class I-related chain A antibody expression in kidney transplantation during a four-year follow-up

Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens （HLA） and anti-major histocompatibility complex class I-related chain A （MICA） antibody expression after kidney transplantation. Methods We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine （SCr） levels were evaluated at each follow-up. Patients were divided into 4 groups： HLA（＋） MICA（-）, HLA（-）MICA（＋）, HLA（＋）MICA（＋） and HLA（-）MICA（-）. The impact of post-transplant antibody level on kidney allograft function was evaluated. Results Antibodies were detected in 38.1% （32/84） of the renal allograft recipients. HLA, MICA and HLA＋MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were All, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% （10/84） of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti- MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. Conclusions Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.

Polymorphism of the second exon of human leukocyte antigen-DQA1, -DQB1 gene and genetic susceptibility to idiopathic dilated cardiomyopathy in people of the Han nationality in northern China

Idiopathic dilated cardiomyopathy ( IDC) is characterized by dilation andimpaired contraction of the left ventricle or both, and it is a relevant cause of heart failure anda common indication for heart transplantation. The major pathogenetic hypothesis in IDC involvesautoimmune mediated damage to myocytes. The development of autoimmune inflammatory damage occursonly in patients with a predisposing genetic background. Changes in the immune system concerningcell-mediated and humoral immunity have been detected. The immune system is strictly related tohuman leukocyte antigen (HLA), which is located on the surface of antigen presenting cells. Itsprimary function is to restrict T-cell receptors in the process of recognizing auto- or exteriorantigen, and thus participates in or mediates immunological recognition, immunological response andimmune regulation at various levels. HLA is a genetic marker of susceptibility to autoimmunemyocardial damage. In the present study, the HLA-DQA1 and -DQB1 alleles in IDC patients weredetected with the techniques of polymerase chain reaction-sequence specific primers ( PCR-SSP) toexplore the immunogenetic mechanisms involved in the pathogenesis of IDC.

Impact of Human Leukocyte Antigen Loci and Haplotypes on Intestinal Acute Graft-versus-host Disease after Human Leukocyte Antigen-matched Sibling Peripheral Blood Stem Cell Transplantation

Background： Acute graft-versus-host disease （aGVHD） is a common and severe complication of allogeneic hematopoietic stem cell transplantation （allo-HSCT）. Some studies have found that the presence of certain specific human leukocyte antigen （HLA） loci could affect the occurrence of aGVHD. Meanwhile, the impact of HLA haplotypes on aGVHD has been rarely studied. This study aimed to investigate the effects of HLA loci and haplotypes on intestinal aGVHD. Methods： Totally, 345 consecutive patients undergoing first HLA-matched sibling peripheral blood stem cell transplantation （PBSCT） from February 2004 to June 2013 at Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were enrolled in this study. HLA loci and haplotypes of recipients with frequency over 5% were searched and their effects on intestinal aGVHD were investigated. Other important factors including donor age, recipient age, donor-recipient sex combinations, and conditioning regimens were also evaluated using logistic regression. Pure upper gastrointestinal tract aGVHD without diarrhea was excluded because the histological proof was unavailable. The follow-up end-point was 6 months after HSCT. Results： The cumulative incidence of intestinal aGVH D was 19.4%, with 18.0% of the patients classified as classic aGVH D and 1.4% as persistent, recurrent, or late aGVH D. Multivariate analysis showed that HLA-A31 locus （odds ratio [OR] 2.893, 95% confidence interval [CI] [1.054, 7.935], P = 0.039）, H LA B40-DR 15 （OR 3.133, 95% CI [1.250, 7.857], P = 0.015）, and HLA B46-DR9 haplotypes （OR 2,580, 95% CI l1.070, 6.220], P- 0.035）, fizmale donor for male recipient （OR 2.434, 95% （27 [1.319, 4.493], P = 0.004） were risk factors tbr intestinal aGVHD. Conclusion： The presence of certain HLA loci and haplotypes may influence the occurrence of intestinal aGVHD in PBSCT with HLA-identical sibling donors.

Outcomes of peripheral blood stem cell transplantation in patients from human leukocyte antigen matched or mismatched unrelated donors

Background AIIogeneic peripheral blood stem cell transplantation from unrelated donors （UR-PBSCT） is an alternative treatment for many hematologic diseases due to lack of human leukocyte antigen （HLA）-identical sibling donors. This study aimed to evaluate the impact of the degree of the HLA match on the clinical efficacy of UR-PBSCT. Methods Patients who underwent UR-PBSCT from September 2003 to September 2012 were retrospectively investigated. They were divided into three groups according to high-resolution molecular typing. SPSS version 17.0 was used to analysis and compare the statistics of engraftment, incidence of GVHD, other complications and survival among the groups. Results One hundred and eleven patients received UR-PBSCT, 60 of them with an HLA matched donor （10/10）, 36 of them with a one locus mismatched donor （9/10）, and 15 of them with a two loci mismatched donor （8/10）. Similar basic characteristics were found in the three groups. No differences were found in engraftment of myeloid cells or platelets in the three groups （P〉0.05）. Two-year cumulative incidence of relapse, overall survival （OS） and disease-free survival （DFS） among those three groups were similar （P〉0.05）. The cumulative incidence of 100-day Ill-IV aGVHD in the HLA matched group and the one HLA locus mismatched group were significantly lower than that in the two HLA loci mismatched group （3.3%, 8.6%, and 26.7%, P=0.009）. The occurrence rate of new pulmonary infections in the HLA matched group was lower than in the two HLA mismatched groups （26.67%, 52.78%, and 41.18%, P=0.035）. The cumulative incidence of 100-day and 2-year transplantation related mortality （TRM） in two HLA loci mismatched group was higher than in the HLA matched group and in the one HLA locus mismatched group, （8.4%, 11.8% and 33.3%, P=0.016） and （12.3%, 18.7% and 47.5%, P=0.002）. Conclusions HLA mismatch will not significantly impact the engraftment or 2-year survival after UR-PBSCT, but two mismatched HLA loci may increase the cumulative incidence of severe aGVHD and TRM. Chin Med J 2014;127 （14）： 2612-2617

Role of human leukocyte antigen molecules in selecting potential donors for allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation （alloHSCT） has been used to treat a variety of hematologic malignancies and non-malignant diseases.Hematopoietic stem cell donor selection is based on identical human leukocyte antigen （HLA） related or unrelated donor matching with the recipient.Donor-recipient HLA mismatching has been associated with graft-versus-host disease （GVHD）,increased mortality and decreased disease free survival （DFS）.1 Not all patients are able to find a suitable donor,as no more than 25% of patients have an HLA-identical sibling.Much effort has been devoted to the establishment of bone marrow （BM） registries for HSCT.Keywords：human leukocyte antigen; transplantation; donor; genotyping

Association of human leukocyte antigen-DR-DQ-DP haplotypes with the risk of hepatitis B virus-related hepatocellular carcinoma

Aim:Genetic polymorphisms of human leukocyte antigen(HLA)class II molecules are associated with chronic hepatitis B virus(HBV)infection.We aimed to investigate the impacts of HLA-II haplotypes on viral evolution and the risks of HBV-caused liver diseases.Methods:HLA-DR-DQ-DP haplotypes were estimated in 1210 healthy controls,296 HBV clearance subjects,301 asymptomatic hepatitis B surface antigen carriers,770 chronic hepatitis B patients,443 HBV-related liver cirrhosis(LC)patients,and 1037 HBV-related hepatocellular carcinoma(HCC)patients.HBV mutations were determined by sequencing.The associations of HLA-DR-DQ-DP haplotypes with viral mutations and the risks of liver diseases were assessed by multivariate logistic regression.Results:Compared to HBV-free subjects,the haplotypes CCAACG,CCGACG,TCAATA,and TCGATA were associated with decreased HCC risk,with an odds ratio(OR)[95%confidence interval(CI)]of 0.62(0.40-0.95),0.60(0.39-0.92),0.73(0.54-0.98),and 0.58(0.42-0.78),respectively.CCAACG,CCGACG,and TCAATA were significantly associated with decreased frequencies of the HCC-risk HBV mutations:preS1 deletion,APOBECsignature HBV mutations in the core promoter and preS regions,A51C/T,G104C/T,and G146C/T.TCGATA and TTAACG were associated with increased LC risk,with an OR(95%CI)of 1.54(1.03-2.30)and 2.23(1.50-3.33),respectively.However,TCGATA and TTAACG were not consistently associated with the cirrhosis-risk HBV mutations.Conclusion:CCAACG,CCGACG,and TCAATA are inversely associated with HCC risk,possibly because they are involved in creating an immune microenvironment attenuating the generation of HCC-risk HBV mutations.TCGATA and TTAACG might predispose the polarity of immunity towards Th17 isotype related to LC.

Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.