Human Leukocyte Antigen System Research Articles

Pharmacogenomics in Psychiatric Disorders

The broad arsenal of psychotropic medications is characterised by significant interindividual variability in clinical response and adverse effects, stringent monitoring requirements, potential drug-drug interactions, difficult long-term adherence and high costs. Pharmacogenomics investigates the correlation between genetic polymorphisms and responsiveness to drugs and could provide a valuable guide to fulfill the promise of personalized therapy in the context of the genomic medicine era, by tailoring treatment based on the patient’s specific genetic markers. The present paper overviews the current advances in the clinical applications of pharmacogenomics to individualized psychotropic therapy. Material and methods. The relevant recent pharmacogenomics literature is selected and analysed in order to illustrate the impact on the clinical outcomes and quality of life in psychiatric patients of the genetic variants in the neurotransmitter receptors (dopamine and serotonin), metabolic pathways of drugs (cytochrome CYP450 2D6 and 2C19) and the human leukocyte antigen system. The paper focuses on some of the major psychotropic drug classes, such as: antipsychotics, antidepressants and mood stabilizers. Validation of statistically significant pharmacogenomics relationships has enabled the development and market approval of some predictive tests which are already integrated into some psychotropic drugs label. Results and discussions. Predictive pharmacogenomics tests have changed the classical approach of prescription “trial-and error” and “one dose fits all patients” towards personalized therapy. In addition, in new therapeutic candidates’ clinical development, pharmacogenomics practically guides the clinical studies design, by substantially reducing the failure rates, costs and exposure risks of non-responders patients to new drugs. Current translation barriers of predictive pharmacogenomic tests from bench to clinical practice are also discussed. Conclusion. The paper emphasizes the current progress and future prospects in the field of pharmacogenomics as a guide to personalized therapy of psychiatric disorders, by: a) pretreatment selection of the right drug, prescribed in its optimized dose, to the right patient, according to one’s specific genetic biomarkers; b) by improved clinical trials design based on genetic stratification of patients’ population into responders versus non-responders, especially in the costly phases III and IV.

Cribado de enfermedad celiaca en niños y adolescentes con diabetes mellitus tipo 1: ¿qué estrategia utilizar?

IntroductionChildren and adolescents with type1 diabetes mellitus (T1DM) are at high risk for the development of celiac disease (CD) because of the common genetic characteristics of both conditions. The study objectives were to investigate the frequency of the human leukocyte antigen system (HLA) for CD in pediatric T1DM patients and to determine whether HLA testing is suitable for CD screening in that population and is cost-effective as compared to serological screening for CD. Patients and methodsA retrospective, descriptive study was conducted in 296 patients (148 girls; 148 boys) with T1DM aged <18years who attended a hospital in Madrid. Data on the frequency of genotypes DQ2/DQ8 in a subgroup of 92 patients and the additional cost of performing HLA typing for screening CD were collected. Only when the risk HLA haplotype (DQ2/DQ8) is negative no further serological screening for CD is required. ResultsTwenty-three patients with T1DM (7.77%) also had CD. Alleles DQ2 or DQ8 were found in 91.3% of patients in whom the HLA haplotype was studied. Thus, only 8.7% with a negative haplotype would have benefited from HLA testing. The additional cost of HLA typing was €105.2 for each patient with positive DQ2 or DQ8 in our population. ConclusionsHLA typing is not a cost-effective screening method for CD in T1DM because of the frequent association of T1DM with risk genotypes for CD.

The significance of angiotensin II type 1 receptor (AT1 receptor) in renal transplant injury.

Humoral response beyond human leukocyte antigen (HLA) is of great interest in the transplant community. We decided to summarize the data on a new antigenic target called angiotensin II type 1 receptor (AT1 receptor). Non-HLA antibodies can now be detected in routine clinical care of patients after transplantation, but their role is not fully understood. Numerous analyses showed that non-HLA response may exert a higher risk of allograft rejection and allograft loss independently of the HLA system. Non-HLA response may even have a higher rate of antibody-mediated rejection. Information regarding antigen target, as well as the pathophysiology of its antibodies and diagnostic tools, is essential for a better understanding of non-HLA humoral response. Angiotensin II type 1 receptors are the most recognized target for non-HLA antibodies. Anti-AT1R Abs (anti-angiotensin II type 1-receptor-activating antibodies) may identify renal transplant patients at higher risk of graft rejection and loss. The presence of AT1 receptor expression analyzed together with anti-AT1R Abs should be considered for better transplant immunological risk assessment. Further assessment is required for a better understanding and to create appropriate therapeutic strategies.

HLA studies in the context of coronavirus outbreaks.

Little is known at the moment about specific immune mechanisms that would work against SARS-CoV-2, although such knowledge is expected to play a vital role. In this context, a particular focus has to be given to the human leucocyte antigen system that governs our adaptive immunity.

Pervasive functional translation of noncanonical human open reading frames.

Ribosome profiling has revealed pervasive but largely uncharacterized translation outside of canonical coding sequences (CDSs). In this work, we exploit a systematic CRISPR-based screening strategy to identify hundreds of noncanonical CDSs that are essential for cellular growth and whose disruption elicits specific, robust transcriptomic and phenotypic changes in human cells. Functional characterization of the encoded microproteins reveals distinct cellular localizations, specific protein binding partners, and hundreds of microproteins that are presented by the human leukocyte antigen system. We find multiple microproteins encoded in upstream open reading frames, which form stable complexes with the main, canonical protein encoded on the same messenger RNA, thereby revealing the use of functional bicistronic operons in mammals. Together, our results point to a family of functional human microproteins that play critical and diverse cellular roles.

Pleasant body odours, but not genetic similarity, influence trustworthiness in a modified trust game

Identifying trustworthy partners is an important adaptive challenge for establishing mutually cooperative relationships. Previous studies have demonstrated a marked relationship between a person’s attractiveness and his apparent trustworthiness (beauty premium). Kin selection theory, however, suggests that cues to kinship enhance trustworthiness. Here we directly tested predictions of the beauty premium and kin selection theory by using body odours as cues to trustworthiness. Body odours reportedly portray information about an individuals’ genotype at the human leucocyte antigen system (HLA) and thus olfactory cues in body odours serve as a promising means for kin recognition. Ninety men played trust games in which they divided uneven sums of monetary units between two male trustees represented by their body odour and rated each body odour for pleasantness. Half of the odours came from HLA-similar men (suggesting closer kin) and half from HLA dissimilar men (suggesting non-kin). We found that the amount of money the players transferred was not related to HLA-similarity, but to the pleasantness of the trustee’s body odour. By showing that people with more pleasant body odours are trusted more than people with unpleasant body odour we provide evidence for a “beauty-premium” that overrides any putative effect of kin.

Variation in the Human Leukocyte Antigen system and risk for endemic Burkitt lymphoma in northern Uganda.

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma associated with Plasmodium falciparum (Pf) malaria and Epstein-Barr virus (EBV) infections. Variation in the Human Leukocyte Antigen (HLA) system is suspected to play a role, but assessments using less accurate serology-based HLA typing techniques in small studies yielded conflicting results. We studied 200 eBL cases and 400 controls aged 0-15years enrolled in northern Uganda and typed by accurate high-resolution HLA sequencing methods. HLA results were analyzed at one- or two-field resolution. Odds ratios and 95% confidence intervals (aOR, 95% CI) for eBL risk associated with common HLA alleles versus alleles that were rare (<1%)ordiffered by <2% between the cases and controls as the reference category, were estimated using multiple logistic regression adjusting for age, sex, microgeography, region, malaria positivity and treatment history, and genetic variants associated with eBL. Compared to the controls, eBL cases had a lower frequency of HLA-A*02 (aOR=0·59, 95% CI 0·38-0·91), HLA-B*41 (aOR=0·36, 95% CI 0·13-1·00), and HLA-B*58 alleles (aOR=0·59, 95% CI 0·36-0·97). eBL cases had a lower frequency of HLA-DPB1 homozygosity (aOR=0·57, 95% CI 0·40-0·82) but a higher frequency of HLA-DQA1 homozygosity (aOR=2·19, 95% CI 1·42-3·37). Our results suggest that variation in HLA may be associated with eBL risk.

Ibrutinib for Pure Red Cell Aplasia after Allogeneic Hematopoietic Stem Cell Transplant with Major ABO Incompatibility

<h3>Introduction</h3> Since Human leukocyte antigen (HLA) and ABO blood group system are inherited independently and with up to 50% of allogeneic hematopoietic cell transplantations (HCT) are performed with donor-recipient ABO incompatibility, recipients are at increased risk for acute and delayed hemolytic reaction and delayed RBC precursors engraftment; i.e. pure RBC aplasia (PRCA). PRCA is a sever consequence of major and bi-directional ABO mismatch after alloHCT, leading to frequent transfusions, iron overload and secondary complications. Risk factors for PRCA after Major ABO incompatibility include; stem cell source, conditioning intensity, and titer of iso-agglutinins. Treatment is mostly supportive with transfusions and growth factors as well as withdrawing immunosuppressive therapy (IS). Targeting recipient immune system with high-dose steroids, DLI, and rituximab have been reported with variable results. Here we report a case series of a novel method of targeting recipient iso-agglutinins-producing B cells by Ibrutinib. <h3>Methods</h3> We report 3 cases of PRCA refractory to conventional therapy who responded to ibrutinib, a BTK inhibitor targeting recipient B cells to allow engraftment of donor RBCs. Patient, transplant and disease characteristic including prior therapies, time to transfusion independence, and switch of blood group (BG) are summarized in Table 1. First patient's day 30 post-transplant bone marrow biopsy (BMBx) showed complete remission (CR) with full donor chimera, but BG remained O. He developed severe anemia requiring transfusions and Day 100 BMBx showed CR with markedly decreased number of erythroid progenitors. He did not respond to IS withdrawal, prednisone, rituximab or bortezomib. But BMBx 4 weeks after starting ibrutinib showed trilineage hematopoiesis. Second patient remained RBC transfusion dependent post-HCT with Day 100 biopsy showing PRCA and full donor chimera. BG remained O. He developed severe GVHD of skin and eyes after DLI and His PRCA was refractory to multiple lines of therapies but responded to ibrutinib. Third patient underwent HCT for refractory AML with MDS; Anti-A isoagglutinin level pre-HCT was high and patient underwent plasma exchange. Day 30 BMBx showed CR and full donor chimera. Day +73 BMBx showed CR with near absent erythropoiesis. PRCA was refractory to rituximab and responded to ibrutinib. <h3>Conclusion</h3> All three patients with PRCA refractory to multiple lines of therapy responded to ibrutinib with median time to transfusion independence of 4 weeks and median time to BG switch of 6 weeks. All patients tolerated therapy well. Our experience at City of Hope shows that ibrutinib could offer a safe and efficacious treatment option for cases of refractory PRCA. Prospective studies are needed to assess if early therapy with ibrutinib could reduce the morbidity resulting from frequent transfusions, and GVHD complications.

MHCherryPan: a novel pan-specific model for binding affinity prediction of class I HLA-peptide

The Human Leukocyte Antigen (HLA) system or complex plays an irreplaceable role in regulating the humans' immune system. Accurate prediction of peptide binding with HLA can efficiently promote to identify those neoantigens, which potentially make a great change in immune drug development. HLA is one of the most polymorphic genetic systems in humans, and thousands of HLA allelic versions exist (Choo, 2007). Owing the high polymorphism of HLA complex, it is still pretty difficult to accurately predict the binding affinity. In this paper, we proposed a novel algorithm which combined convolutional neural network and long short-term memory to solve this problem. Our model has been tested with the experimental benchmark from IEDB and shows the state-of-the-art performance compared with other currently popular algorithms.

Entropy of human leukocyte antigen and killer-cell immunoglobulin-like receptor systems in immune-mediated disorders: A pilot study on multiple sclerosis.

BackgroundEntropy is a thermodynamic variable statistically correlated with the disorder of a system. The hypothesis that entropy can be used to identify potentially unhealthy conditions was first suggested by Schrödinger, one of the founding fathers of quantum mechanics. Shannon later defined entropy as the quantity of information stored in a system. Shannon’s entropy has the advantage of being adaptable across a variety of disciplines, including genetic studies on complex immunogenetic systems such as the human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) systems.MethodsIn our study, entropy associated to the HLA and KIR systems was compared between a cohort of 619 Sardinian healthy controls and a group of 270 patients affected by multiple sclerosis (MS), the latter stratified into 81 patients with primary progressive multiple sclerosis (PPMS) and 189 patients with relapsing remitting multiple sclerosis (RRMS).ResultsThe entropy associated to HLA four-loci haplotypes (A, B, C, DR) and combinations of two inhibitory KIR genes was significantly higher in patients affected by RRMS than in healthy controls. No significant differences were observed for patients with PPMS. By calculating the total HLA and KIR entropy ratio in each subject, it was possible to determine the individual risk of developing MS, particularly RRMS.ConclusionsIn addition to the standard statistical methods used to evaluate immunogenetic parameters associated to immune-mediated disease, the analysis of entropy measures the global disorder status deriving from these parameters. This innovative approach may represent a useful complementary tool to the risk assessment of immune-mediated disorders. Improved risk assessment is particularly important for family members of patients with MS. However, further investigation is warranted to confirm our findings and to evaluate the validity of the entropy-based method in other types of immune-mediated disorders.

Sequence analysis and 3D molecular structure simulation of a novel HLA allele B*51:159

To identify a novel human leukocyte antigen (HLA) B allele in a Chinese Han individual and construct its three-dimensional structure. The initial HLA genotyping was performed by PCR-sequence-based typing (PCR-SBT). The ambiguous allele was confirmed with single-strand DNA sequencing. The DNA sequence was analyzed to identify the difference between the novel allele and its closest matching allele. Finally, the three-dimensional molecular structure of the novel allele was constructed using a Swiss-Model. One allele of the subject at the HLA-B locus was B*44:03:01, whilst the other was a novel allele which differed from the closest matching allele B*51:01:01:01 by nucleotide (nt) 329 A to C in exon 2, resulting in an amino acid change at codon 86 (p.Asn86Thr). A novel HLA-B allele has been identified and officially named as HLA-B*51:159 by the WHO Nomenclature Committee for Factors of the HLA System. The three-dimensional structure of B*51:159 was simulated.

Human leucocyte antigen diversity: A biological gift to escape infections, no longer a barrier for haploidentical Hemopoietic Stem Cell Transplantation.

Since the beginning of life, every multicellular organism appeared to have a complex innate immune system although the adaptive immune system, centred on lymphocytes bearing antigen receptors generated by somatic recombination, arose in jawed fish approximately 500 million years ago. The major histocompatibility complex MHC, named the Human leucocyte antigen (HLA) system in humans, represents a vital function structure in the organism by presenting pathogen-derived peptides to T cells as the main initial step of the adaptive immune response. The huge level of polymorphism observed in HLA genes definitely reflects selection, favouring heterozygosity at the individual or population level, in a pathogen-rich environment, although many are located in introns or in exons that do not code for the antigen-biding site of the HLA. Over the past three decades, the extent of allelic diversity at HLA loci has been well characterized using high-resolution HLA-DNA typing and the number of new HLA alleles, produced through next-generation sequencing methods, is even more rapidly increasing. The level of the HLA system polymorphism represents an obstacle to the search of potential compatible donors for patients affected by haematological disease proposed for a hematopoietic stem cell transplant (HSCT). Data reported in literature clearly show that antigenic and/or allelic mismatches between related or unrelated donors and patients influences the successful HSCT outcome. However, the recent development of the new transplant strategy based on the choice of haploidentical donors for HSCT is questioning the role of HLA compatibility, since the great HLA disparities present do not worsen the overall clinical outcome. Nowadays, NGS has contributed to define at allelic levels the HLA polymorphism and solve potential ambiguities. However, HLA functions and tissue typing probably need to be further investigated in the next future, to understand the reasons why in haploidentical transplants the presence of a whole mismatch haplotype between donors and recipients, both the survival rate and the incidence of acute GvHD or graft rejection are similar to those reported for unrelated HSCTs.

Human Leucocyte Antigens in blood transfusion

Human Leucocyte Antigen (HLA) genes and molecules have an important role in transplantation, aetiology of many autoimmune, non‐autoimmune and infection diseases. Due to the extremely high polymorphism of HLA genes and their different frequency distributions in various populations, an increasing probability of HLA non‐compatible blood products, tissues or organs usage exists. For that reason, the aim of this paper was to give a concise overview of the role of HLA antigens and antibodies in adverse reactions caused by administration of transfusion products. The HLA system can cause detrimental immune reactions in transfusion therapy (platelet immune refractoriness, febrile transfusion reaction, transfusion‐related acute lung injury and transfusion‐associated graft versus host disease). Anti‐HLA antibodies present in the patient are responsible for some of these reactions, while anti‐HLA antibodies or HLA reactive cells present in the transfused product are accountable for immune‐reactivity in other cases. In order to avoid or reduce the development of these transfusion‐related events, anti‐HLA antibody‐negative or compatible products should be used. This is increasingly facilitated by introduction of more sensitive and specific techniques to determine anti‐HLA antibodies and gene polymorphisms. In conclusion, the most common adverse reactions related to administration of incompatible HLA transfusion products are discussed. Basic information about HLA genes and antibodies as well as methods for their detection is also provided in order to give sufficient data for safe and efficient administration of transfusion products.

Inheritance of HLA-Cw7 Associated With Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is a behaviorally defined disorder that is now thought to affect approximately 1 in 69 children in the United States. In most cases, the etiology is unknown, but several studies point to the interaction of genetic predisposition with environmental factors. The immune system is thought to have a causative role in ASD, and specific studies have implicated T lymphocytes, monocytes, natural killer (NK) cells, and certain cytokines. The human leukocyte antigen (HLA) system is involved in the underlying process for shaping an individual’s immune system, and specific HLA alleles are associated with specific diseases as risk factors. In this study, we determine whether a specific HLA allele was associated with ASD in a large cohort of patients with ASD. Identifying such an association could help in the identification of immune system components which may have a causative role in specific cohorts of patients with ASD who share similar specific clinical features. Specimens from 143 patients with ASD were analyzed with respect to race and ethnicity. Overall, HLA-Cw7 was present in a much greater frequency than expected in individuals with ASD as compared to the general population. Further, the cohort of patients who express HLA-Cw7 shares specific immune system/inflammatory clinical features including being more likely to have allergies, food intolerances, and chronic sinusitis as compared to those with ASD who did not express HLA-Cw7. HLA-Cw7 has a role in stimulating NK cells. Thus, this finding may indicate that chronic over-activation of NK cells may have a role in the manifestation of ASD in a cohort of patients with increased immune system/inflammatory features.

Proteogenomic discovery of cancer antigens: Neoantigens and beyond.

Host T cells infiltrate the cancer lesion and contribute to patient survival. T cells recognize antigen peptides displayed by the cancer cell human leukocyte antigen (HLA) system. Cancer antigens constitute an essential element of T-cell discrimination and play an indispensable role in anti-cancer responses. HLA ligandome analysis directly and comprehensively detects the peptides that are naturally presented by HLA of given cells, leading to discovery of cancer antigens. A proteogenomic approach, which combines conventional proteomics with genomic information, has further deciphered the landscape of the cancer HLA ligandome. Neoantigens that arise from somatic mutations are arguably the major type of peptides patient T cells recognize. Moreover, cancer cells present peptides derived from alleged noncoding regions, which also elicit T-cell responses thereby serving as cancer antigens. The diversity of newly discovered antigen sources implies that T cells are capable of sensing a variety of genomic aberrations in cancer.

Características diferenciales de la hepatitis autoinmune en adultos mayores colombianos: estudio de cohorte

Introducción: en la hepatitis autoinmune (HAI), los ancianos representan una población especial debido a que, según se ha descrito, poseen una predisposición mediada por el antígeno leucocitario humano (Human Leukocyte Antigen, HLA) y padecen un curso indolente y progresivo de la enfermedad. No se conocen datos en la población latinoamericana.&#x0D; Objetivos: Analizar comparativamente las características de los pacientes con HAI mayores y menores de 65 años en cuanto a su presentación clínica, diagnóstico, tratamiento, respuesta al tratamiento y curso de la enfermedad.&#x0D; Métodos: estudio de cohorte retrospectiva de pacientes con HAI evaluados entre enero de 2010 y diciembre de 2016. Se realizó un análisis estadístico utilizando el programa SPSS versión 20.1.&#x0D; Resultados: se incluyeron 214 pacientes. Los pacientes ancianos tuvieron, en su mayoría, hipertensión arterial (34,5 % frente a 15,1 %, p = 0,011), dislipidemia (20,7 % frente a 5,9 %, p = 0,006) y enfermedad cardiovascular (17,2 % frente a 2,7 %, p = 0,001). Además, al momento del diagnóstico, los pacientes ancianos tuvieron una mayor frecuencia de cirrosis evaluada histológica y radiológicamente (55,1 % frente a 33,5 %, p = 0,024). Los pacientes mayores tuvieron una mayor remisión bioquímica con el tratamiento (100 % frente a 83,9 %, p = 0,022). No hubo diferencias en la analítica hepática, autoanticuerpos, tipo de tratamiento farmacológico recibido, recaídas, efectos adversos relacionados con el tratamiento, requerimiento de trasplante hepático y muerte.&#x0D; Conclusión: La HAI afecta a población colombiana adulta de todas las edades y debe ser considerada en el abordaje diagnóstico de los ancianos con enfermedad hepática, debido a que este grupo de pacientes tiene una mayor frecuencia de cirrosis al momento del diagnóstico. Un diagnóstico temprano es importante debido a que el tratamiento es efectivo y bien tolerado

Management of post-transplant lymphoproliferative disorders.

Management of post-transplant lymphoproliferative disorders.

Inflammatory bowel diseases and spondyloarthropathies: From pathogenesis to treatment.

Spondyloarthropathies (SpA) include many different forms of inflammatory arthritis and can affect the spine (axial SpA) and/or peripheral joints (peripheral SpA) with Ankylosing spondylitis (AS) being the prototype of the former. Extra-articular manifestations, like uveitis, psoriasis and inflammatory bowel disease (IBD) are frequently observed in the setting of SpA and are, in fact, part of the SpA classification criteria. Bowel involvement seems to be the most common of these manifestations. Clinically evident IBD is observed in 6%-14% of AS patients, which is significantly more frequent compared to the general population. Besides, it seems that silent microscopic gut inflammation, is evident in around 60% in AS patients. Interestingly, occurrence of IBD has been associated with AS disease activity. For peripheral SpA, two different forms have been proposed with diverse characteristics. Of note, SpA (axial or peripheral) is more commonly observed in Crohn’s disease than in ulcerative colitis. The common pathogenetic mechanisms that explain the link between IBD and SpA are still ill-defined. The role of dysregulated microbiome along with migration of T lymphocytes and other cells from gut to the joint (“gut-joint” axis) has been recognized, in the context of a genetic background including associations with alleles inside or outside the human leukocyte antigen system. Various therapeutic modalities are available with monoclonal antibodies against tumour necrosis factor, interleukin-23 and interleukin-17, being the most effective. Both gastroenterologists and rheumatologists should be alert to identify the co-existence of these conditions and ideally follow-up these patients in combined clinics.

Correlation of alteration of HLA-F expression and clinical characterization in 593 brain glioma samples

BackgroundHuman gliomas are highly fatal tumors with a significant feature of immune suppression. The association of the immune system in gliomas is gradually revealed, and immunotherapy is expected to improve the survival of glioma patients. In-depth understanding of the immune microenvironment of gliomas and their associated immunotherapy was increased exponentially in recent years. Gliomas provide clinical targets for immunotherapy during the search of key regulators of immune response. Our study focused on the human leukocyte antigen (HLA) system that is responsible for regulating the immune system, and discovered the relationship between HLA-F expression and clinical prognosis in gliomas.MethodsA total of 593 patients with gliomas were included in our research. Of these, 325 patients were from the Chinese Glioma Genome Atlas (CGGA) and 268 were from the GSE 16011 set. Kaplan-Meier (KM) analysis was performed to explore the prognostic value of HLA-F. t test analysis was used to find the distribution difference in various groups. R language packages are used for other statistical computations and figure drawing.ResultsHLA-F was negatively correlated with overall survival (OS) in all grades of glioma and glioblastoma (GBM). Moreover, HLA-F was enriched in GBM and isocitrate dehydrogenase 1 wild-type (IDH1 wt) group and considered HLA-F as a mesenchymal subtype marker. Pearson correlation test showed that HLA-F was correlated with other HLA-I molecules.ConclusionHLA-F expression was positively correlated with malignant phenotype and negatively correlated with OS, indicating that HLA-F could predict the immune state of gliomas and might be a clinical target of glioma immunotherapy.

Detecting donor-specific antibodies: the importance of sorting the wheat from the chaff.

Human leukocyte antigen (HLA) compatibility is very important for successful transplantation of solid organs. In this paper, we focused on the humoral arm of immunity in the clinical setting of organ transplantation: how HLA antibodies develop, how they can be detected, and what they can do to injure organ transplants. Specifically, we explore the technical perspectives of detecting donor-specific antibodies (DSA) in HLA laboratories, and use real-life clinical cases to explain the principles. Currently there are many tools in our HLA antibody detection toolbox: conventional cytotoxicity cross match, flow cross match, and solid phase assays using beads conjugated with single or multiple HLA antigens. Single antigen bead (SAB) assay is the most sensitive tool available for detecting HLA antibodies and assessing the immunological risk for organ transplant. However, there are intrinsic limitations to solid-phase assays and they are prone to both false negativity and importantly, false positivity. Denatured antigens on single antigen beads might be the most prominent source of false positive reactivity, and may have been underestimated by many HLA experts. No single assay is perfect and therefore multiple methods, including the less sensitive assays, should be employed to determine the clinical relevance of detected HLA antibodies. Thoughtful process, including knowledge of HLA systems, cross reactivity, epitopes, and the patient's clinical history should be employed to correctly interpret data. The clinical team should work closely with HLA laboratories to ensure accurate interpretation of information and optimal management of patients before and after organ transplantation.