We investigated the effects of TNF-α, IFN-γ, IL-10 polymorphisms on viral infections (CMV, BKPyV, HHV-6, EBV) after renal transplantation. IFN-γ+874 A > T (lower IFN production) was associated with CMV disease (p = .039) in patients under mycophenolate-based therapy and graft failure (p = .025). This study underscores the role of IFN-γ+874 SNP in CMV infection.
Christopher Byrnes1, Andrew Hastings2, Ira Lacej2, Renuka Palanicawandar2, Eduardo Olavarria2, Arthi Anand1
1Histocompatbility and Immunogenetics, North West London Pathology, London, UK; 2Department of Haematology, Imperial College Healthcare NHS Trust, London, UK
Relapse is a major cause of treatment failure in haploidentical haematopoietic progenitor cell transplant (HPCT) with PTCy. Natural killer cells are the first to reconstitute post HSCT, suppressing graft versus host disease and mediating the graft versus leukaemia effect, driven by killer cell immunoglobulin-like receptors (KIRs). Emerging research suggests that donor KIR genotype may influence outcomes of haploidentical HPCT. Haploidentical donors are readily available, and donor selection could hinge on predicted KIR NK cell alloreactivity. This study investigates whether donors with greater KIR B motifs associate with greater relapse free survival (RFS), overall survival (OS), non-relapse mortality (NRM), acute graft versus host disease (GvHD) and infection.
Following KIR genotyping, seventy-seven haploidentical donor recipient pairs (myeloablative n = 30, RIC n = 47) with various haematological malignancies are categorised into neutral (n = 49) or better and best (n = 28), using KIR B motif content. Kaplan-Meier and Cox Regression survival functions are performed to investigate associations with potential outcomes.
Our results show that the better and best category has significantly reduced RFS (p = .004) (HR 4.13, 95% CI 1.45–11.74: p = .008) and trend towards greater infections (p = .080) (HR 2.09, 95% CI 0.90–4.84: p < .1), decreasing OS (p = .008) (HR2.44, 95% confidence interval [CI] 1.24–4.81: p = .01), without impacting GvHD or NRM.
In our study, neutral donor outcomes are favourable in T cell depleted haplo-HPCT, potentially due to alloresponsive donor NK cells being targeted by immunosuppressive PTCy treatment delaying reconstitution. Further studies focusing on a homogenous pathology and treatment modality would determine the utility of KIR B content calculator in haploidentical donor selection.
Miss Rebecca Cope1,2, Rhea McArdle1,2, Veena Surendrakumar3, Afzal Chaudhry1,4, Vasilis Kosmoliaptsis3, Gavin Pettigrew3, Stephen Pettit5, Peter Riddle5, Sarah Peacock1
1Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 2Faculty of Biology, Medicine and Health, Division of Medical Education, School of Medical Sciences, The University of Manchester, Manchester, UK; 3Department of Surgery, University of Cambridge, Cambridge, UK; 4Department of Medici
Anthony Calvert1, Anthony Poles1, Matthew Hopkins1, Tim Hayes2
1NHS Blood and Transplant, Filton, UK; 2Manchester University NHS Foundation Trust, UK
Heparin induced thrombocytopenia (HIT) is a rare complication of heparin therapy with mild thrombocytopenia but potentially fatal thrombosis. HIT antibodies target the epitope of platelet factor 4 (PF4) and heparin. Laboratory investigations commonly detect antibodies by ELISA. The British Society for Haematology guidelines suggest clinical significant IgG antibodies equate to an OD > 1.0. Studies show an OD ≥ 1.4 corresponds with ≥50% chance of positive serotonin release assay (SRA) (Warkentin et al. J Thromb Haemost 2008; 6(8):1304-12).
Common practice for a HIT positive patient is repeat testing until a negative result indicates the safe use of Heparin, which is then administered pre-procedure and ceased immediately afterwards. Conditioning includes antibody titre reduction by plasmapheresis, multiple sessions are costly and can delay surgery. PF4/heparin antibodies are detected in 5-22% cardiac surgery patients but only 1%–2% have HIT (Pishko et al. Semin Thromb Hemost 2017; 43(7): 691-698).
A HIT positive pre-transplant patient was tested after each plasmapheresis using ELISA (Immucor HAT45G) and a platelet activation assay (IQ Products HITAlert) to compare HIT antibody levels with ability to activate platelets. Results showed an OD > 1.4 associated with positive activation, comparable to Warkentin's observations. The advantage of HITAlert is it detects functional antibodies and measures the expression of activation markers by flow cytometry, not radiolabelled serotonin release. The assay is then suitable for use in the routine laboratory environment, but requires freshly isolated (<2 h) ABO O platelets.
The patient received a successful heart transplant after the first negative activation result, sooner than waiting for negative ELISA results.
Carla Rosser1, Deborah Sage1
1NHS Blood and Transplant, Tooting, UK
The use of antibody-epitope analysis tools can improve the interpretation of in vitro HLA antibody identification assay data, particularly for identification of false positive reactions. HLA antibody-epitope analysis using HLAMatchmaker was performed on 22 crossmatched sera where donor-specific antibody (DSA) had previously been identified by One Lambda LABScreen™ Single Antigen (LABScreen). These sera were retrospectively tested by Immucor LIFECODES LSA (LIFECODES) and BAG Healthcare HISTO SPOT® (HISTO SPOT) assays.
All three HLA antibody identification assays identified DSA in serum that did not cause a positive flow-cytometric crossmatch (FCXM). Antibody-epitope analysis supports the presence of DSA in 12/22 of these sera, indicating a higher sensitivity of the solid ph
Several single nucleotide polymorphisms (SNPs) associated with susceptibility to Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) have been identified. The aim of this study was to identify susceptibility loci for HL and DLBCL in Polish patients. Altogether, DLBCL (n = 218 and HL patients (n = 224) and healthy individuals (n = 1181) were recruited. Lymphoma diagnosis was based on standard criteria. Genome-wide association study (GWAS) was performed using pooled-DNA samples on llumina Infinium Omni2.5 Exome-8 v1.3, and selected loci were replicated by TaqMan SNP genotyping of individuals. GWAS detected thirteen and seven SNPs associated with DLBCL and HL, respectively. In the replication study, six and seven SNPs reached significance after correction for multiple testing in the DLBCL and HL cohorts, respectively. One and four SNPs associated with DLBCL and HL, respectively, were localized within, and two SNPs—near the major histocompatibility complex (MHC) region. In conclusion, the majority of loci associated with HL and DLBCL aetiology in previous studies have potential roles in immune function. Our pooled-DNA GWAS enabled the identification of several susceptibility loci for DLBCL and HL in the Polish population; some of them were mapped within or adjacent to the MHC, and other associated SNPs were located outside the MHC.
We aimed to determine whether the interferon (IFN)-γ +874 T/A polymorphism (rs2430561) is associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A meta-analysis was conducted to assess the association between the IFN-γ +874 T/A polymorphism and SLE or RA using allele contrast, homozygous contrast, recessive, and dominant models. A total of nine studies (six on SLE and three on RA), involving 1839 patients and 2272 controls, were included in the meta-analysis. The meta-analysis revealed a significant association between SLE and the TT genotype of the IFN-γ +874 T/A polymorphism (odds ratio [OR] = 0.751, 95% confidence interval [CI] = 0.634–0.899, p = .001), and stratification by ethnicity indicated an association between the IFN-γ +874 TT genotype and the Asian population. The analysis also revealed a significant association between SLE and the TT + TA genotype of the IFN-γ +874 T/A polymorphism in Arab populations (OR = 1.598, 95% CI = 1.053–2.425, p = .028). However, no association between the IFN-γ +874 T/A polymorphism and RA was found using allele contrast, recessive, dominant or homozygous contrast models in all study subjects and ethnic groups. This meta-analysis demonstrated that the IFN-γ +874 T/A polymorphism is associated with susceptibility to SLE in Asian and Arab populations.
Human neutrophil antigens possess significant clinical implications especially in the fields of transfusion and transplantation medicine. Efforts to estimate the prevalence of genetic variations underpinning the antigenic expression are emerging. However, there lacks a precise capture of the global frequency profiles. Our article emphasizes the potential utility of maintaining an organized online repository of evidence on neutrophil antigen-associated genetic variants from published literature and reports. This, in our opinion, is an emerging area and would significantly benefit from the awareness and understanding of population-level diversities.
Host genetic factors may be correlated with the severity of coronavirus disease 2019 (COVID-19). Angiotensin-converting enzyme 2 (ACE2) plays a vital role in viral cell entrance. The current study aimed to evaluate the association of ACE2 rs2285666 polymorphism and clinical parameters with COVID-19 mortality. The ACE2 rs2285666 polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism in 556 recovered and 522 dead patients. In this study, the frequency of ACE2 rs2285666 CC was significantly higher than TT genotype in dead patients. The multivariate logistic regression analysis results showed that the higher levels of alanine aminotransferase, alkaline phosphatase, creatinine, erythrocyte sedimentation rate, and C-reactive protein and the low levels of uric acid, cholesterol, low density lipoprotein, 25-hydroxyvitamin D, real-time PCR Ct values, and ACE2 rs2285666 CC genotype were associated with increased mortality rates after COVID-19. In conclusion, our findings demonstrated a possible link between COVID-19 mortality, clinical parameters, and ACE2 rs2285666 CC. Further research is required to confirm these results.
The HISTO SPOT®AB ID assay (BAG Diagnostics GmbH) is a novel single antigen HLA Class I & II antibody definition test used with the MR.SPOT® processor. We compared this assay with Luminex®-based assays to assess its potential application in defining unacceptable antigens for transplantation in patients awaiting transplants with cardiothoracic organs. A cohort of 40 sensitized cardiothoracic patients were identified, and one sample was selected from each patient. The required screening was based on the patients’ antibody profiles (Class I, n = 17, Class II, n = 11, Class I & II, n = 12). Samples were screened with LABScreen™ Single Antigen (SAg), LIFECODES® LSA™, HISTO SPOT® AB ID, and an acid modified LABScreen™ SAg test for detecting antibodies against denatured HLA. Results indicated that HISTO SPOT® AB ID had reduced sensitivity (68% for Class I; 69% for Class II). When compared to LABScreen™ and LIFECODES®, HISTO SPOT® AB ID failed to detect Luminex®-defined antibodies with median fluorescence intensity (MFI) ranging from 1114 to 24,489. The HISTO SPOT® AB ID panel used in the study had reduced antigen representation compared with Luminex®-based assays which further compromised its capacity for antibody detection and definition. Further work is needed to evaluate the clinical relevance of these differences between the performance of HISTO SPOT® and Luminex®-based methods.
Multiple sclerosis (MS) is a chronic neurological disease believed to be caused by autoimmune pathogenesis. The aetiology is likely explained by a complex interplay between inherited and environmental factors. Genetic investigations into MS have been conducted for over 50 years, yielding >100 associations to date. Globally, the strongest linkage is with the human leukocyte antigen (HLA) HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype.
Here, high-resolution sequencing of HLA was used to determine the alleles of DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 as well as their extended haplotypes and genotypes in 100 Swedish MS patients. Results were compared to 636 population controls.
The heterogeneity in HLA associations with MS was demonstrated; among 100 patients, 69 extended HLA-DR-DQ genotypes were found. Three extended HLA-DR-DQ genotypes were found to be correlated to MS; HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype together with
(A) HLA-DRB4*01:01:01//DRB4*01:01:01:01-DRB1*07:01:01-DQA1*02:01//02:01:01-DQB1*02:02:01,
(B) HLA-DRBX*null-DRB1*08:01:01-DQA1*04:01:01-DQB1*04:02:01, and
(C) HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01.
At the allelic level, HLA-DRB3*01:01:02 was considered protective against MS. However, when combined with HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01, this extended haplotype was considered a predisposing risk factor. This highlights the limitations as included with investigations of single alleles relative to those of extended haplotypes/genotypes.
In conclusion, with 69 genotypes presented among 100 patients, high-resolution sequencing was conducted to underscore the wide polymorphisms present among MS patients. Additional studies in larger cohorts will be of importance to define MS among the patient group not associated with HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01.
Human leucocyte antigen (HLA) alleles are very diverse and characterized by ethnicity. To date, information about the frequencies and distributions of HLA alleles among the Vietnamese population is still limited. In this study, HLA-DQB1 alleles of 2076 cord blood units from individuals belonging to Vietnam's Kinh ethnic people were genotyped using Luminex-based polymerase chain reaction sequence-specific oligonucleotide. The results of the study demonstrated that there were 23 alleles on the locus HLA-DQB1. Among those, there were six alleles with high frequencies of over 5%, including DQB1*03:01 (35.9%), DQB1*05:01 (12.8%), DQB1*03:03 (12.2%); DQB1*06:01 (7.20%), DQB1*05:02 (6.62%) and DQB1*02:01 (5.30%) and five rare alleles with low frequencies of below 0.1%. More importantly, this study for the first time reported the presence of two new rare alleles including DQB1*01:01 and DQB1*01:02. Conclusively, this study provided significant information about HLA-DQB1 alleles for further investigations and clinical applications.
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