DR Alleles Research Articles

Clinical Phenotype of HLA B*44 Patients in a Rheumatology Outpatient Clinic Favors Peripheral Arthropathies.

Objective: The genetic background of HLA-B*27 in spondyloarthritis is known, and the search for another gene with similar role is ongoing. We wanted to investigate clinical presentations of HLA-B*44 patients in rheumatology practice. Methods: A cross-sectional retrospective study of 303 HLA-B*44 adult patients from the outpatient rheumatology clinic from 5/2018-5/2024. Clinical phenotype, confirmed or excluded rheumatic diagnosis, therapy used, and data on HLA A, B, and DR alleles inherited with B*44 were analyzed. Results: A female predominance of 2.79:1 was noted. A total of 150 [49.5%] patients were referred due to peripheral joint pain, 77 [25.4%] due to combined spine and peripheral joint pain or spine alone (57 [18.8%]). A total of 19 [6.3%] patients had no symptoms of the musculoskeletal system. Statistically significant peripheral joint affection was proved in females but not in males (p = 0.04). A total of 121 [40%] patients from B*44 group had established rheumatic disease, with the rest being excluded or under observation. The most common working diagnoses were polyarthritis (32 [10.5%]) and mono-oligoarthritis (14 [4.6%]). A second allele in addition to HLA B*44 showed a similar frequency to the general population. Patients with HLA B*44/44 and B*27/44 genotypes were at the most risk for having definitive rheumatic disease (>60%). Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) were used in 38.6% of patients, non-steroidal anti-inflammatory drugs were used in 31.6% of patients, biologic DMARDs were used in 8.9% of patients, and corticosteroids were used in 7.3% of patients. Conclusions: The most common presentation in HLA-B*44 patients is peripheral joint affection. Most patients with HLA-B*27/44 and B*44/44 genotypes had definitive rheumatic disease. B*44 homozygosity or B*27/44 might be risk factors for arthritis development.

Ophthalmological and Neurological Findings in Patients with Idiopathic Uveitis Associated with Retinal Vasculitis and the Relation with the HLA DR15 Allele

ABSTRACT Purpose In 15 patients with idiopathic uveitis associated with retinal vasculitis, HLA DRB1 gene testing was performed to detect a possible association. 11 patients tested positive and 4 negative for the HLA DRB1 × 15 allele. The presence of the HLA DRB1 × 15 haplotype might be associated with a higher susceptibility to develop Multiple Sclerosis (MS). Methods In this case series, we describe the ophthalmological and neurological findings in 10 HLA DR15-positive patients and 4 HLA DR15-negative patients that had neurological workup, including Magnetic Resonance Imaging (MRI) of the brain. Results All patients had granulomatous ocular inflammation with either panuveitis or intermediate uveitis. MRI of the brain showed white matter lesions in 13 patients (9/10 and 4/4 respectively) of which 4 patients were eventually diagnosed with MS (3/10 and 1/4 respectively). Conclusion Although the majority of tested patients was carrying at least one HLA DRB1–15 allele, there was no difference in ophthalmological and neurological findings in both groups.

MHCII-peptide presentation: an assessment of the state-of-the-art prediction methods.

Major histocompatibility complex Class II (MHCII) proteins initiate and regulate immune responses by presentation of antigenic peptides to CD4+ T-cells and self-restriction. The interactions between MHCII and peptides determine the specificity of the immune response and are crucial in immunotherapy and cancer vaccine design. With the ever-increasing amount of MHCII-peptide binding data available, many computational approaches have been developed for MHCII-peptide interaction prediction over the last decade. There is thus an urgent need to provide an up-to-date overview and assessment of these newly developed computational methods. To benchmark the prediction performance of these methods, we constructed an independent dataset containing binding and non-binding peptides to 20 human MHCII protein allotypes from the Immune Epitope Database, covering DP, DR and DQ alleles. After collecting 11 known predictors up to January 2022, we evaluated those available through a webserver or standalone packages on this independent dataset. The benchmarking results show that MixMHC2pred and NetMHCIIpan-4.1 achieve the best performance among all predictors. In general, newly developed methods perform better than older ones due to the rapid expansion of data on which they are trained and the development of deep learning algorithms. Our manuscript not only draws a full picture of the state-of-art of MHCII-peptide binding prediction, but also guides researchers in the choice among the different predictors. More importantly, it will inspire biomedical researchers in both academia and industry for the future developments in this field.

Assessing the immunogenicity risk of salmon calcitonin peptide impurities using in silico and in vitro methods.

Advances in synthetic peptide synthesis have enabled rapid and cost-effective peptide drug manufacturing. For this reason, peptide drugs that were first produced using recombinant DNA (rDNA) technology are now being produced using solid- and liquid-phase peptide synthesis. While peptide synthesis has some advantages over rDNA expression methods, new peptide-related impurities that differ from the active pharmaceutical ingredient (API) may be generated during synthesis. These impurity byproducts of the original peptide sequence feature amino acid insertions, deletions, and side-chain modifications that may alter the immunogenicity risk profile of the drug product. Impurities resulting from synthesis have become the special focus of regulatory review and approval for human use, as outlined in the FDA's Center for Drug Evaluation and Research guidance document, "ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin," published in 2021. This case study illustrates how in silico and in vitro methods can be applied to assess the immunogenicity risk of impurities that may be present in synthetic generic versions of the salmon calcitonin (SCT) drug product. Sponsors of generic drug abbreviated new drug applications (ANDAs) should consider careful control of these impurities (for example, keeping the concentration of the immunogenic impurities below the cut-off recommended by FDA regulators). Twenty example SCT impurities were analyzed using in silico tools and assessed as having slightly more or less immunogenic risk potential relative to the SCT API peptide. Class II human leukocyte antigen (HLA)-binding assays provided independent confirmation that a 9-mer sequence present in the C-terminus of SCT binds promiscuously to multiple HLA DR alleles, while T-cell assays confirmed the expected T-cell responses to SCT and selected impurities. In silico analysis combined with in vitro assays that directly compare the API to each individual impurity peptide may be a useful approach for assessing the potential immunogenic risk posed by peptide impurities that are present in generic drug products.

Presence of HLA-DQ2 and HLA-DQ8 /DR4 celiac disease predisposing alleles in tested group of patients in Bosnia and Herzegovina

Celiac disease (CD) is an autoimmune disease characterized by gluten intolerance. The main cause of this immune - mediated enteropathy is gluten, a protein mainly present in wheat, rye, barley and spelt. The predisposition to celiac disease is determined by HLA class II genes encoding MHC II heterodimer molecules, more specifically HLA-DQ2 and HLA-DQ8. Up to date the exact number of people suffering from celiac disease in Bosnia and Herzegovina is still not known because there is no public registry for this disease. The aim of this study was to evaluate the HLA-DQ2 and HLA-DQ8/DR4 presence in tested group of patients (n = 23) referred to Polyclinic Atrijum in Sarajevo in period from August 2022. to August 2023. HLA-DQ2 and DQ8/DR4 allele identification was performed using Real-time PCR technique. According to the obtained results a total of 26% (n=6) of tested patients were positive for HLA-DQ2 and HLA-DQ8/DR4 alleles. Two of the patients were positive for HLA-DQ2 alleles and four patients were positive for HLA-DQ8/DR4 alleles. To our knowledge this is the first study evaluating the presence of HLA-DQ2 and HLA-DQ8 genotypes in tested population in Bosnia and Herzegovina.

P06.09.B TRIAL IN PROGRESS: PHASE 1 DOSE-FINDING STUDY TO EVALUATE SAFETY AND TOLERABILITY OF CVGBM IN PATIENTS WITH NEWLY DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is characterized by a low mutational burden limiting the number of neoantigen targets for cancer vaccines. Vaccination against tumor-associated antigens over-presented via MHC class I and II in GBM is an alternative that has shown promise in previous trials. One cancer vaccine containing peptides presented by HLA-A*02-01 (class I) and some DR alleles (class II), showed evidence of peripheral vaccine-induced immune response against these peptides in patients with GBM. Our study will assess the safety and immunogenicity of the messenger ribonucleic acid (mRNA)-based multiepitope vaccine CV-GBM, an investigational therapeutic mRNA vaccine, encoding eight of these peptides that have demonstrated immunogenicity as peptide vaccines. CV-GBM consists of a mRNA with unmodified nucleotides formulated with lipid nanoparticles. MATERIAL AND METHODS CV-GBLM-001 is a first-in-human, open-label, international, dose-escalation phase 1 trial. HLA-A*02:01-positive patients with newly diagnosed MGMT-unmethylated GBM (CNS WHO Grade 4), including IDH-wildtype astrocytoma with a molecular signature of unmethylated MGMT-GBM who have had a gross total or partial resection and who completed post-surgery radiotherapy with or without chemotherapy, are eligible to receive CVGBM. The trial comprises a dose-escalation part (Part A) followed by a dose-expansion part (Part B). In Part A, the starting dose is 12 µg mRNA, which may be escalated to 25 µg, 50 µg and 100 µg, with 3 to 6 patients per dose level. Dose escalation will be guided by a Bayesian logistic regression model. Patients will receive 7 doses of CVGBM by intramuscular injection on Days 1, 8, 15, 29, 43, 57, and 71, followed by 6 optional doses at 6-week intervals, up to 1 year after the first dose or until disease progression or intolerable toxicity. An independent Data and Safety Monitoring Board will recommend the dose for expansion in Part B in which about 20 patients will be enrolled. Biomarkers and vaccine-induced innate and adaptive immunogenicity, including, but not limited to, systemically induced cytokines and chemokines and antigen-specific CD4+ and CD8+ T cells, will be monitored in the blood, and optionally in vaccine-draining lymph nodes and relapsed tumor. In addition to the primary safety objectives, secondary objectives of efficacy (progression-free survival, overall survival) and patient-reported quality of life outcomes will be assessed. Trial sponsor: CureVac SE, Germany.

The influence of HLA A, B, C, DR alleles and HLA haplotypes on cytomegalovirus-specific cell mediated immunity in seropositive Korean kidney transplant candidates.

We evaluated the effect of specific HLA alleles and haplotypes on cytomegalovirus (CMV)-specific cell mediated immunity (CMI) in kidney transplant (KT) candidates. CMV-specific ELISPOT against pp65 and IE-1 antigens (hereafter referred to as pp65 and IE-1, respectively) was performed in 229 seropositive KT candidates. We analyzed the results related to 44 selected HLA alleles (9 HLA-A, 15 HLA-B, 9 HLA-C, and 11 HLA-DR) and 13 HLA haplotypes commonly found in study participants. The pp65 and IE-1 results in 229 seropositive candidates were 227.5 (114.5-471.5) and 41.0 (8.8-185.8) (median [interquartile range]) spots/2 × 105 PBMCs, respectively. The pp65 and IE-1 results showed significant differences between candidates with different HLA alleles (A*02 vs. A*26 [p = 0.016], A*24 vs. A*30 [p = 0.031], B*07 vs. B*46 [p = 0.005], B*54 vs. B*35 [p = 0.041], B*54 vs. B*44 [p = 0.018], B*54 vs. B*51 [p = 0.025], and C*06 vs. C*14 [p = 0.034]). HLA-A*02 and B*54 were associated with increased pp65 and IE-1 results, respectively (p = 0.005 and p < 0.001, respectively). In contrast, the HLA-A*26 and B*46 alleles were associated with a decreased pp65 response, whereas the A*30 allele was associated with a decreased IE-1 response (p < 0.05). The pp65 results correlated with the HLA-A allele frequencies (R = 0.7546, p = 0.019) and the IE-1 results correlated with the HLA-C allele frequencies of the study participants (R = 0.7882, p = 0.012). Among 13 haplotypes, HLA-A*30 ~ B*13 ~ C*06 ~ DRB1*07 showed decreased CMV-CMIs compared to the other HLA haplotypes, probably due to a combination of HLA alleles associated with lower CMV-CMIs. Our results demonstrated that CMV-specific CMIs may be influenced by the HLA allele as well as the HLA haplotype. To better predict CMV reactivation, it is important to estimate risk in the context of HLA allele and haplotype information.

New Insights on DR and DQ Human Leukocyte Antigens in Anti-LGI1 Encephalitis.

To explore the clinical characteristics and HLA associations of patients with anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients. Seventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples. Our cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9 p < 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1 p < 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2 p < 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9 p < 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles. Our cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

HLA‐DQ and ‐DR alleles in patients with SLE: A tertiary hospital‐based case–control study in Bangladesh

AbstractBackgroundSystemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the involvement of multiple organs and autoantibody production. This study aimed to determine the association of human leukocyte antigen (HLA)‐DQ and ‐DR alleles with SLE at a tertiary hospital in Bangladesh.MethodsThis case–control study was conducted in the Department of Rheumatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. The patients who fulfilled the 1997 revised American College of Rheumatology classification criteria for SLE were considered cases (n = 41). The controls (n = 32) were selected from the hospital staff of BSMMU, including doctors and nurses who did not suffer from any known rheumatic diseases, and there was no such disease in their first‐degree relatives. Polymerase chain reaction using a sequence‐specific primer (PCR‐SSP) in a low‐resolution typing method was carried out on blood samples collected for HLA‐DQ and ‐DR allele typing.ResultsThe cases and controls had comparable mean ages (31 vs. 32 years), and most cases were female (95.1% vs. 34.4%). The most frequent clinical manifestations were mucocutaneous (85.4%), followed by musculoskeletal (70.7%) and constitutional symptoms (58.5%). The cases had a significantly higher frequency of HLA‐DR2 allele compared with healthy controls (70.7% vs. 43.8%; odds ratio: 3.1; 95% confidence interval: 1.2–8.2). In addition, HLA‐DQ6 allele was found to have a significant association with mucocutaneous manifestations of the cases (88.9%, P = 0.03).ConclusionsBangladeshi adults having HLA‐DR2 may be more susceptible to SLE. HLA‐DQ6 allele might be associated with mucocutaneous manifestations of SLE.

Role of the autoantibodies and IL-1 cytokine in the pathogenesis diabetes mellitus

Diabetes mellitus is a complex multifactorial and heterogeneous syndrome characterized by hyperglycemia resulting from inadequate insulin secretion and/or insulin action. T lymphocytes and macrophages appear to play an important role in mediating ß-cell damage and causing Type 1 diabetes.A case-control study is done during the period from Feb., 2011, through the end of Feb. 2012. The study enrolled 90 diabetic patients divided into three groups Type 1, Type2 and LADA ( 30 patients in each group) who attended in Al Zahraa Teaching Hospital in Al-Kut city &amp; 25 non diabetic as a control to determine the prevalence of islet cell autoantibodies, glutamic acid decarboxylase autoantibodies (ICAs&amp; GADAs) and measured (IL-1Α α , IL-4, IL17, TNF α, IFN γ) as well as the frequency of HLA DR was measured in diabetic patients and non-diabetic control with no family history of diabetes. Serological tests for GADA &amp; ICA (by using ELISA) have been done for all sera of the study groups. Dual set ELISA technique is used for estimating the cytokines levels in the sera of all study groups while DNA extracted from whole blood from all study groups and these DNA were used to detected the HLA DR allele by using HISTO SPOT SSO system.According to the results of this study, Type 1 diabetic patients had higher frequency of GADA 65 autoantibodies compared with other study groups, as eighteen of them (60%) showed GADA positive in comparison to 6.6 % in type 2 DM, 56.7% in LADA and 0% in control group. Furthermore, twenty of type 1 diabetic patients which represent (66.7%) were ICA positive in comparison to 33.33% in type 2 DM, 70% in LADA and 4% in control group. Statistical analysis showed highly significant difference.Analysis of the serum sample showed that IL-1 α levels has been elevated significantly in the sera of Type 1(635.8± 685 pg./ml), type 2 (625.5± 55.86 pg./ml) and LADA (383.2± 533.5 pg./ml) diabetics patients positive autoantibodies in comparison with other groups type 1, type 2 and LADA diabetics patients negative autoantibodies and healthy control (60±35.21 pg. /ml)

Association of HLA-A, HLA-B, and HLA-DR alleles in oral squamous cell carcinomas and its correlation with clinical staging

Background: Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial neoplasm affecting the oral cavity. It is the third-most common cancer in India. Several human leukocyte antigen (HLA) types are associated with an increased risk of various immunologically mediated diseases. There is also evidence that the HLA gene complex may mediate susceptibility to or protection from malignancies. Various studies have been conducted worldwide, but there is a paucity of literature in India regarding the association of HLA alleles in oral squamous cell carcinoma patients. In our study, HLA class I (HLA-A and HLA-B) alleles and class II (HLA-DR) alleles were determined in 100 patients with OSCC and an equal number of healthy controls (100) were taken for comparison. DNA was extracted with Innotrain kit, and HLA typing was performed with Fluogene. Data were analyzed using SPSS software version 21.0. Aims: To study the association of HLA-A, HLA-B AND HLA-DR alleles in oral squamous cell carcinomas and its correlation with clinical staging. Objectives: 1. To compare the HLA-A, HLA-B and HLA-DR alleles in oral squamous cell carcinoma patients with healthy controls. 2. To correlate HLA-A, HLA-B, HLA-DR aleles with clinical staging of oral squamous cell carcinoma. Materials and Methods: The study was a cross sectional study conducted in the Department of Pathology and Department of Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi. Blood samples of 100 histologically diagnosed cases of oral squamous cell carcinoma and 100 random healthy age and sex matched controls were chosen. Results: All the cases were compared with the healthy controls, and the data were correlated with the clinical stage of the oral squamous cell carcinoma. HLA-A * 02, HLA-A * 24, HLA-B * 15, HLA-B * 40, HLA-B * 52, HLA-DRB1 * 07, and HLA-DRB1 * 15 alleles were found to have a higher frequency than in controls and were frequently found associated with clinical Stage III of these carcinomas. Conclusion: Thus, this study helps us to establish the possible relationship between HLA-A, B, and DR alleles in oral squamous cell carcinomapatients and its correlation with clinical staging, about which there is paucity in the Indian literature to the best of our knowledge.

Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

Treatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)-DR alleles in conferring irAE risk has not been well studied. To evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma. This case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis. Immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma. The association between irAEs and response to therapy, survival, and HLA-DR alleles. Among the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4. These findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment.

Expanding Our Knowledge of the Immunogenetic Characteristics of Anti-LGI1 Encephalitis—A Study of an Israeli Cohort Suggests Additional Significant HLA Associations With DQ Alleles

Objective Exploring the clinical characteristics and HLA associations of patients with anti-leucine–rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel Background Anti-LGI1E is one of the most commonly diagnosed antibody-associated encephalitic syndromes in adults. Recent studies of various populations reveal significant associations with specific Human Leukocyte Antigen (HLA) genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients. Design/Methods Seventeen consecutive anti-LGI1E patients diagnosed at Tel Aviv Sourasky Medical Center between the years 2011-2018 were included. HLA typing was performed using NGS methodology at the tissue typing laboratory of Sheba Medical Center and compared to data from the "Ezer Mizion" Bone Marrow Donor Registry, containing over 1,000,000 samples. Results Our cohort displayed a male predominance and median age of onset in the 7th decade, as previously reported. All patients responded to immunotherapy, though residual damage was not uncommon (23% with MRS &gt;1). HLA analysis revealed overexpression of DRB1*07:01 (OR 13, CI 0.6 p &lt; 1.e-10) and DRB1*04:02 (OR 12, CI-0.6 p &lt; 1.e-10), as previously reported, as well as of the DQ alleles DQB1*02:02 (OR 12, CI 0.6 p &lt; 1.e-10), DQB1*03:03 (OR 27, CI 0.9 p &lt; 1.e-10), previously attributed to linkage disequilibrium (LD) with the mentioned DR alleles. An additional allele overexpressed among our patients was the DQB1*03:02 allele (OR 12, CI 0.6 p &lt; 1.e-10), which appeared in complete LD with DRB1*04:02. Linkage disequilibrium analysis performed on patients and controls suggests these DR-DQ associations are unique to anti-LGI1E patients. In silico predictions performed for the overexpressed DQ alleles reveal them to be strong binders of LGI1 derived peptides, and suggest a correlation between peptide binding sites of paired DR-DQ alleles. Conclusions Our findings shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying the possible relevance of certain DQ alleles as well as DR-DQ interactions.

Pattern of HLA types in renal transplant patients in Sohag Governorate

Objective This study aimed to assess the pattern of HLA types in Egyptian renal transplant patients in the Sohag governorate. Materials and methods A retrospective chart review was conducted on all patients and their donors, who were scheduled to undergo renal transplantation at Sohag University Hospital through the period from January 2010 to December 2019. We retrieved the following data from eligible patients’ files: age of the recipient and donor, gender of the recipient and donor, consanguinity, blood group, cross-matching, HLA classes A and B, and DR alleles. Results Overall, a total of 26 recipients (70.3%) and 25 donors (67.6%) had HLA-A alleles, while 22 recipients (59.5%) and 26 donors (70.3%) had HLA-B alleles. In terms of the pattern of HLA-A distribution among recipients, the most frequent alleles were A*01/02 (8.1%), A*02/23 (5.4%), A*02/32 (5.4%), and A*02 (5.4%). On the other hand, the most frequent HLA-A alleles in the donors’ group were A*01/02 (5.4%), A*02/03 (5.4%), and A*26/68 (5.4%). Regarding HLA-B allele distribution, all recipients had different alleles. While B*41/52 was the most frequent allele in the donors’ group. All recipients, except two patients, had HLA-DR alleles, most commonly DR*11/13 (13.5%) and DR*13/15 (8.1%). Negative cross-matching was present in 59.5% of the cases. Among female recipients, only A*13/15 and B*27/51/53 alleles were detected. Conclusion In conclusion, our findings were very similar to the results from other local and global studies. Different populations and ethnicities are the main dependent variables of the major differences in terms of HLA allele distribution.

Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study.

To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children. Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3-12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models. Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes. Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes.

Dominant epitopes presented by prevalent HLA alleles permit wide use of banked CMVpp65 T cells in adoptive therapy

AbstractWe established and characterized a bank of 138 CMVpp65 peptide-specific T-cell (CMVpp65CTLs) lines from healthy marrow transplant donors who consented to their use for treatment of individuals other than their transplant recipient. CMVpp65CTL lines included 131 containing predominantly CD8+ T cells and 7 CD4+ T cells. CD8+ CMVpp65CTLs were specific for 1 to 3 epitopes each presented by one of only 34 of the 148 class I alleles in the bank. Similarly, the 7 predominantly CD4+ CMVpp65CTL lines were each specific for epitopes presented by 14 of 40 HLA DR alleles in the bank. Although the number of HLA alleles presenting CMV epitopes is low, their prevalence is high, permitting selection of CMVpp65CTLs restricted by an HLA allele shared by transplant recipient and hematopoietic cell transplant donor for >90% of an ethnogeographically diverse population of hematopoietic cell transplant recipients. Within individuals, responses to CMVpp65 peptides presented by different HLA alleles are hierarchical. Furthermore, within groups, epitopes presented by HLA B*07:02 and HLA A*02:01 consistently elicit immunodominant CMVpp65CTLs, irrespective of other HLA alleles inherited. All dominant CMVpp65CTLs exhibited HLA-restricted cytotoxicity against epitope loaded targets and usually cleared CMV infections. However, immunodominant CMVpp65CTLs responding to epitopes presented by certain HLA B*35 alleles were ineffective in lysing CMV-infected cells in vitro or controlling CMV infections post adoptive therapy. Analysis of the hierarchy of T-cell responses to CMVpp65, the HLA alleles presenting immunodominant CMVpp65 epitopes, and the responses they induce may lead to detailed algorithms for optimal choice of third-party CMVpp65CTLs for effective adoptive therapy.

Novel immunological tools to investigate CD4+ T cell activation in the canine species

Abstract Opportunities to identify T cell epitopes in the dog have been thwarted by a lack of immunological tools specific for the species. As a result, antigen-specific triggers in diseases that affect dogs like autoimmune disorders and allergies remain unknown. Our objective was to develop immunological tools such as: IFN-γ enzyme-linked immunosorbent spot (ELISpot) and activation induced marker (AIM) assays, and an MHC class II tetramer to help overcome these hurdles. We collected splenocytes from dogs that underwent a routine splenectomy. We used these splenocytes to develop: an ELISpot assay detecting canine IFN-γ production by stimulated T cells, an AIM assay to assess early activation by CD40L expression on CD4+CD5+ canine splenocytes using a cross-reactive anti-human monoclonal antibody, and finally, we produced the first-ever canine MHC II tetramer specific for a common canine DR allele. We confirmed the efficacy of these tools in the presence of positive and negative controls, Staphylococcus aureus enterotoxin B (SEB) and dimethyl sulfoxide (DMSO), respectively. SEB induces a robust canine IFN-γ ELISpot readout quantifiable in canine splenocytes. Similarly, we discovered that canine CD40L expression peaks at 3 hours post-stimulation with SEB. Finally, we confirmed the development of the first canine pMHCII tetramer through size discriminatory SDS-PAGE analysis and peptide exchange assays. Our novel canine-specific reagents will help identify and characterize antigen-specific T cells and their cognate antigens driving canine MHC class II-restricted disease, thus guiding research towards the advancement of antigen-specific immunotherapies. Supported by a grant from the NIH (K01 OD027058)

Association study between HLA-A, -B, -C, -DRB1 alleles and Psoriatic arthritis in southern France

Psoriatic arthritis (PsA) is a type of inflammatory arthritis associated with psoriasis. HLA association studies performed in northern Europe, comparing patients with control populations, have shown that the highest risk for PsA is carried by HLA-C*06, HLA-B*57 and HLA-B*27 alleles.This retrospective association study compared HLA-A, -B, -C, and -DR alleles of 500 patients from southern France, who fulfilled the CASPAR criteria for Psoriatic Arthritis (PsA), with 2346 controls from healthy blood donors, using the chi-square test.We classified PsA patients into three different subgroups according to disease: purely axial, purely peripheral and combined axial and peripheral. The ‘axial’ subgroup was associated with HLA-B*27 (OR = 16.3, p = 2.7 × 10−28) and its haplotypes: HLA- B*27-C*01 (OR = 12.4, p = 1.7 × 10−12) and HLA-B*27-C*02 (OR = 8.7, p = 10 × 10−9). The ‘axial and peripheral’ and the ‘peripheral’ subgroups were associated with HLA-C*06 (respectively OR = 1.5, p = 3.6 × 10−10 and OR = 2.4, p = 3.6 × 10−12) and its haplotypes HLA-C*06-B*13 (respectively OR = 2.4, p = 1.2 × 10−6 and OR = 2.8, p = 6.4 × 10−11).This association study on a southern French PsA cohort identifies HLA-C*06 as a marker for peripheral PsA and HLA-B*27 as a marker for purely axial PsA.

HLA Polymorphism in Punjabi Population of Pakistan

ABSTRACT High polymorphism of the human leukocyte antigen (HLA) alleles is frequently used to determine the origin and migration of human population. Furthermore, HLA-A, -B and -DR alleles specific frequencies are important to distingush the genetic structure between related enthic groups and is helpful in hematopoietic stem cell, organ transplantation and disease association. The data on HLA-A, B and DRBI* loci at a high-resolution level is limited in Punjab Population, Pakistan, therefore, the present research was designed to explore the genetic profile of patients collected from Punjab, Pakistan using HLA-A, HLA-B and HLA-DRBI* genotypes with sequence specific primers. The allelic frequencies, haplotype distribution and genetic distances were investigated to map a genetic relationship. The most common alleles and haplotypes originating in Punjabi population were HLA-02, HLA-B*40, HLA-DRB1*15, A*2602-B*08-DRB*03, and A*02-B*51-DRB1*13. The bootstrap stats was applied with the phylogenetic analysis suggesting a strong evolutionary relationship with 80 percent validation. This shows that Punjabis have heredity with Sindhis as their personal predecessor. Altogether, these findings would be helpful in the selection of transplantation procedure, planning donor registry and for anthropologic studies.

Association of end-stage renal disease with HLA phenotypes and panel reactive antibodies in patients awaiting renal transplantation in Hunan Province.

ObjectivesTo explore the immune‐related genetic susceptibility of human leukocyte antigen (HLA) alleles and their correlation with panel reactive antibody (PRA) generation during end‐stage renal disease (ESRD) progression.Materials and methodsData of the expression patterns of HLA‐A, ‐B, and ‐DR alleles and PRAs of 347 ESRD patients awaiting renal transplantation in Hunan Province from 2015 to 2019 were retrospectively studied. The polymerase chain reaction with sequence‐specific primers was used for HLA genotyping and the enzyme‐linked immunosorbent assay for PRA detection. SPSS 21.0 software was used for all allele frequency and statistical analyses.ResultsThirteen HLA‐A, 25 HLA‐B, and 13 HLA‐DR alleles were expressed. The allele frequencies of HLA‐A2, ‐B48, ‐B52, and ‐B55 were significantly higher in the case group than in the control group (p < 0.05), whereas that of HLA‐B60 was significantly higher in the control group (p < 0.05). The frequency of HLA alleles in the PRA‐positive group was significantly higher in females than in males (p < 0.05). The allele frequencies of HLA‐A2, ‐B38, and ‐B46 were significantly higher in the PRA‐positive group than in the PRA‐negative one (p < 0.05), whereas that of HLA‐60 was significantly higher in the PRA‐negative group (p < 0.05).ConclusionHLA‐A2, ‐B48, ‐B52, and ‐B55 may be the ESRD susceptibility alleles in Han Chinese patients in Hunan Province, whereas HLA‐B60 may be the protective allele. Patients carrying HLA‐A2, ‐B38, and ‐B46 are more likely to develop PRA positivity, whereas the opposite is true for those with HLA‐B60.