Distribution of HLA epitope frequencies in Turkish population

Objectives The antibodies interact with the “Human Leukocyte Antigen (HLA) antigens” at specific epitopes. “Epitopes” are present on a single HLA or shared by multiple antigens. In this study, we aim to determine the frequency of prevalent epitopes common in the Turkish population. Methods Non-related 644 healthy volunteers were recruited, and The “HLA-A, -B, -C, -DR -DQ’s” were typed using the “Next Generation Sequencing”. The provisional and confirmed epitopes were identified using the “HLA Epitope Registry databases, HLA Epitopia Maps and Immucor Epitope databases” dated 07.02.2018. Epitope frequencies were calculated by counting the shared epitopes in the total number of shared HLA Class epitopes in our sample database. Results Class I HLA’s had 298 epitopes that repeated a total of 158,117 times with frequencies ranging between 0.0006 and 2.03%, and the most frequent epitope was 170RY found on 119 different alleles. Class II HLA’s had 193 epitopes that repeated a total of 93,082 times with frequencies ranging between 0.002 and 1.36%, and the most frequent epitope was 108P found on 42 different alleles. Conclusions Our findings summarize both the provisional, and confirmed epitope frequencies in the Turkish population and may help clinicians and immunogeneticists develop a better understanding of HLA epitope mismatches.

Impact of transfusion of blood components on the recipient immune system

Transfusions of blood provide essential therapeutic measures in a number of pathological conditions. However, when carrying out blood component therapy, it is important to consider probability of post-transfusion complications. Most of them are immune-mediated side effects. The unfavorable consequences of blood transfusions can manifest at long-range time periods, and pathogenesis of these phenomena may be associated not only with the presence of alloantibodies. They may be caused by alloimmunization to HLA antigens, leukocyte factors, including cytokines, products of leukocyte degranulation, as well as storage-related erythrocyte damage («storage lesion»), immunomodulatory properties of extracellular vesicles or microparticles derived from blood components, and other factors. Despite significant number of publications on this issue, a lot of unresolved issues still remain, concerning transfusion-related effects of blood components on the immune system of recipients. The review article provides the results of current studies in this area. We present and discuss the results of current studies and the features of transfusion-mediated immunomodulation (TRIM) revealed over recent years, when transfusing different blood components. The role of plasma factors, microparticles, platelets and erythrocytes, HLA sensitization and microchimerism in the development of TRIM is highlighted, the data on occurrence and clinical features of TRIM in perioperative period are presented. A separate section of the review provides information about recent clinical studies, devoted to the issues of TRIM in different clinical cohorts, including newborns, patients with malignant neoplasms, immunocompromised patients after heart and vascular surgery. The data on TRIM incidence in the patients with exhausted immune system due to previous disease or treatment, severe comorbidity, extensive surgical thoracic/abdominal intervention and artificial circulation are also in scope. As based on the studies performed, the role of distinct measures, e.g., washing of erythrocyte concentrates, leukodepletion, and gamma irradiation are discussed in view of potential TRIM prevention. The results of published research do not allow us to draw definite conclusions about the effects of blood component transfusion on the immune system of recipients with respect to differences between the studied groups of patients, characteristics of the studied disorders and clinical situations, diversity of hemocomponents, as well as varying standards of transfusion therapy adopted in different countries. However, the systematic literature review may provide some guidance in transfusion-mediated immune modulation.

The HLA Ligandome Comprises a Limited Repertoire of O-GlcNAcylated Antigens Preferentially Associated With HLA-B*07:02

Mass-spectrometry based immunopeptidomics has provided unprecedented insights into antigen presentation, not only charting an enormous ligandome of self-antigens, but also cancer neoantigens and peptide antigens harbouring post-translational modifications. Here we concentrate on the latter, focusing on the small subset of HLA Class I peptides (less than 1%) that has been observed to be post-translationally modified (PTM) by a O-linked N-acetylglucosamine (GlcNAc). Just like neoantigens these modified antigens may have specific immunomodulatory functions. Here we compiled from literature, and a new dataset originating from the JY B cell lymphoblastoid cell line, a concise albeit comprehensive list of O-GlcNAcylated HLA class I peptides. This cumulative list of O-GlcNAcylated HLA peptides were derived from normal and cancerous origin, as well as tissue specimen. Remarkably, the overlap in detected O-GlcNAcylated HLA peptides as well as their source proteins is strikingly high. Most of the O-GlcNAcylated HLA peptides originate from nuclear proteins, notably transcription factors. From this list, we extract that O-GlcNAcylated HLA Class I peptides are preferentially presented by the HLA-B*07:02 allele. This allele loads peptides with a Proline residue anchor at position 2, and features a binding groove that can accommodate well the recently proposed consensus sequence for O-GlcNAcylation, P(V/A/T/S)g(S/T), essentially explaining why HLA-B*07:02 is a favoured binding allele. The observations drawn from the compiled list, may assist in the prediction of novel O-GlcNAcylated HLA antigens, which will be best presented by patients harbouring HLA-B*07:02 or related alleles that use Proline as anchoring residue.

HLA AND CANCER

This review provides updated information on HLA class I and II antigens in cancer. The expression of HLA antigens in normal and tumor tissues, the physiological organization of the components of HLA antigen-processing machinery, the expression patterns of HLA antigens associated with the molecular and regulatory defects identified to date, as well as their functional and clinical significance, are described. This review summarizes clinical and experimental data on the complexity of immune escape mechanisms used by tumour cells to avoid T and natural killer cell responses. The variety of class I HLA phenotypes that can be produced by tumor cells during this process is presented. We also discuss here the potential capacity of metastatic lesions to recover MHC/HLA class I expression after immunotherapy, which depends on the reversible/ soft or irreversible/hard nature of the molecular mechanism responsible for the altered HLA class I phenotypes, and which determines the progression or regression of metastatic lesions in response to treatment. HLA сlass II genes play key roles in connecting innate and adaptive immunity in tumor rejection and when the escape route via HLA-I is already established. Antigens сlass II HLA expression in tumor cells and gives tumor cells the ability to present antigens, becoming less aggressive, and improves prognosis. Malignant tumors, as a genetic disease, are caused by structural alterations of the genome which can give rise to the expression of tumor-associated antigens in the form of either structurally altered molecules or of overexpressed normal molecules. Tumor associated antigens recognized by the immune system and induce a T-cell-mediated immune response. Outgrowing cancers use different strategies to evade destruction by the immune system. Immune evasion mechanisms affecting the expression and/or function of HLA-antigens are of special interest to tumor immunologists, since these molecules play a crucial role in the interaction of malignant cells with immune cells. This review describes the potential role of immunity control points in immunosuppression and therapeutic strategies for restoring the cytotoxicity of immune cells.

The Role of HLA Antigens and Steroid Dose on the Course of COVID-19 of Patients After Kidney Transplantation

Background: Kidney transplant recipients appear to be at higher risk for critical COVID-19. Our analysis aimed to identify the possible risk factors for a severe course of the COVID-19 disease and to determine the influence of selected human leukocyte antigens (HLAs) on the course of the disease.Methods: This is a retrospective, multicenter analysis that included patients that were confirmed to be severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive after kidney transplantation (KT). The group of patients was divided into two subgroups according to the course of the infection, as follows: non-hospitalized and hospitalized.Results: A total of 186 patients (men, 69.4%) with confirmed SARS-CoV-2 positivity were included in the group. The following independent risk factors for the outcome of hospitalization were identified: the age at the time of infection [odds ratio (OR) = 1.19, P < 0.0001], a body mass index (BMI) >29.9 kg/m2 (OR = 7.21, P < 0.0001), <7.5-mg prednisone dose/day (OR = 2.29, P = 0.0008), and HLA-DQ2 with a protective nature (OR = 0.05, P = 0.0034).Conclusions: Higher doses of corticosteroids (>7.5 mg/kg) in standard immunosuppressive regimes and HLA-DQ2 appear to be protective factors in our analysis.

Comparison of haploidentical and umbilical cord blood transplantation after myeloablative conditioning

Haploidentical hematopoietic stem cell transplantation (haplo HSCT) has emerged as an important treatment modality. Most reports comparing haplo HSCT with post-transplant cyclophosphamide (PTCy) and other donor sources have focused on outcomes in older adults treated with reduced intensity conditioning. Therefore, in the current study, we evaluated outcomes in patients with hematological malignancy treated with myeloablative conditioning prior to haplo (n=375) or umbilical cord blood (UCB, n=333) HSCT. All haplo recipients received a 4 of 8 HLA matched graft while recipients of UCB were matched at 6-8/8 (n=145) or ≤5/8 (n=188) HLA antigens. Recipients of 6-8/8 UCB transplants were younger (14 years vs. 21 and 29 years) and more likely to have lower co-morbidity scores compared to recipients of ≤5/8 UCB and haplo HSCT (81% vs. 69% and 63%, respectively). UCB recipients were more likely to have acute lymphoblastic leukemia and transplanted in second complete remission (CR) whereas haplo HSCT recipients were more likely to have acute myeloid leukemia in first CR. Other characteristics, including cytogenetic risk were similar. Survival at 3 years was similar for the donor sources (66% haplo and 61% after ≤5/8 and 58% after 6-8/8 UCB). Notably, relapse at 3 years was lower in recipients of ≤5/8 UCB (21%, p=0.03) compared to haplo (36%) and 6-8/8 UCB (30%). However, non-relapse mortality was higher in ≤5/8 UCB (21%) compared to other groups (p<0.0001). These data suggest that haplo HSCT with PTCy after myeloablative conditioning provides an overall survival outcome comparable to that after UCB regardless HLA match group.

Current Desensitization Strategies in Heart Transplantation

Heart transplant candidates sensitized to HLA antigens wait longer for transplant, are at increased risk of dying while waiting, and may not be listed at all. The increasing prevalence of HLA sensitization and limitations of current desensitization strategies underscore the urgent need for a more effective approach. In addition to pregnancy, prior transplant, and transfusions, patients with end-stage heart failure are burdened with unique factors placing them at risk for HLA sensitization. These include homograft material used for congenital heart disease repair and left ventricular assist devices (LVADs). Moreover, these risks are often stacked, forming a seemingly insurmountable barrier in some cases. While desensitization protocols are typically implemented uniformly, irrespective of the mode of sensitization, the heterogeneity in success and post-transplant outcomes argues for a more tailored approach. Achieving this will require progress in our understanding of the immunobiology underlying the innate and adaptive immune response to these varied allosensitizing exposures. Further attention to B cell activation, memory, and plasma cell differentiation is required to establish methods that durably abrogate the anti-HLA antibody response before and after transplant. The contribution of non-HLA antibodies to the net state of sensitization and the potential implications for graft longevity also remain to be comprehensively defined. The aim of this review is to first bring forth select issues unique to the sensitized heart transplant candidate. The current literature on desensitization in heart transplantation will then be summarized providing context within the immune response. Building on this, newer approaches with therapeutic potential will be discussed emphasizing the importance of not only addressing the short-term pathogenic consequences of circulating HLA antibodies, but also the need to modulate alloimmune memory.

Set Up for Failure: Pre-Existing Autoantibodies in Lung Transplant

Lung transplant patients have the lowest long-term survival rates compared to other solid organ transplants. The complications after lung transplantation such as primary graft dysfunction (PGD) and ultimately chronic lung allograft dysfunction (CLAD) are the main reasons for this limited survival. In recent years, lung-specific autoantibodies that recognize non-HLA antigens have been hypothesized to contribute to graft injury and have been correlated with PGD, CLAD, and survival. Mounting evidence suggests that autoantibodies can develop during pulmonary disease progression before lung transplant, termed pre-existing autoantibodies, and may participate in allograft injury after transplantation. In this review, we summarize what is known about pulmonary disease autoantibodies, the relationship between pre-existing autoantibodies and lung transplantation, and potential mechanisms through which pre-existing autoantibodies contribute to graft injury and rejection.

Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches

Highly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for highly sensitized patients is transplantation with a crossmatch negative donor without any additional therapeutic intervention. The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago with the intention to increase the chance for highly sensitized patients to be transplanted with such a compatible donor. The AM program allows for enhanced transplantation to this difficult to transplant patient group by allocating deceased donor kidneys on the basis of a match with the recipient’s own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing. By using this extended HLA phenotype for allocation and giving priority whenever a compatible donor organ becomes available, organ offers are made for roughly 80% of patients in this program. Up till now, more than 1700 highly sensitized patients have been transplanted through the AM program. Recent studies have shown that the concept of acceptable mismatches being truly immunologically acceptable holds true for both rejection rates and long-term graft survival. Patients that were transplanted through the AM program had a similar rejection incidence and long-term graft survival rates identical to non-sensitized patients transplanted through regular allocation. However, a subset of patients included in the AM program does not receive an organ offer within a reasonable time frame. As these are often patients with a rare HLA phenotype in comparison to the Eurotransplant donor population, extension of the donor pool for these specific patients through further European collaboration would significantly increase their chances of being transplanted. For those patients that will not benefit from such strategy, desensitization is the ultimate solution.

Maternal-Fetal HLA Compatibility in Uncomplicated and Preeclamptic Naturally Conceived Pregnancies

IntroductionIn pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance.MethodsGenotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309).ResultsIn uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies.ConclusionThe data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy.