There is significant interest in using modern informatics processes for clinical HLA data, but there are few resources developed for clinical use. To help clinical HLA laboratories make use of best practices in informatics and align with published data standards, we developed immunogenetr for the R programming language. immunogenetr was built with tidyverse functions and principles, and uses Genotype List (GL) string, which encodes complete HLA genotypes, including ambiguities, in a single human- and machine-readable object, as the primary data structure. The package includes functions to easily convert HLA genotyping data to and from GL strings, parse and rebuild GL strings, validate and truncate allele names, search for specific alleles within a GL string, and perform matching and mismatching. The functions are highly customizable, with matching and mismatching functions including options for host-versus-graft, graft-versus-host, and bidirectional comparisons, along with configurable homozygous mismatch counting, aligned with published guidelines. The package is open-source and available on CRAN and GitHub. This manuscript gives an overview of immunogenetr, with examples of how the functions can be used in informatics pipelines. Together, this package enables standardized HLA informatics analyses across clinical and research workflows.

Autoimmune thyroid disease (AITD) is among the most common autoimmune diseases, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), but their pathophysiological mechanism isn't fully understood with multiple involved genetic factors. Programmed cell death-1 (PD-1) boosts the suppression of regulatory T cells. The promoter region polymorphism rs36084323 affected PD-1 gene transcription and activation in many cancer and autoimmune diseases. Genetic correlation between this polymorphism and AITD pathogenesis was evaluated in Egyptian patients & included: Group 1; fifty-five GD patients & forty five HT patients, Group 2; one hundred fifty controls by PCR-RFLP technique. GD patients showed significantly higher AG, AA, and A allele frequencies of the PD-1 rs36084323 gene than the control group with no significant disparities between HT patients and controls for any genotype or allele. When analyzing all AITD patients compared to control group, only the A allele showed higher frequency approaching statistical significance (p = 0.057). AA genotype and elevated free T4 were significant risk factors for GD, while elevated TSH was a significant protective factor for GD and a significant risk factor for HT. PD-1 rs36084323 polymorphism differs between GD and HT and is associated with higher risk of GD in Egyptian patients.

This study investigated the prevalence of BKV subtypes in kidney transplant recipients and evaluates their association with viral load and BKVAN risk. A total of 32 kidney transplant recipients with confirmed BKV infection were included in the study. BKV DNA was extracted from urine and plasma samples and genotyped using phylogenetic analysis and a novel genotyping algorithm. Viral loads were compared between subtypes, and the occurrence of BKVAN was analyzed in relation to genotype distribution All samples belonged to genotype I, with 78.5 % classified as Ib-2 and 21.4 % as Ib-1. No genotype II, III, or IV strains were detected. Although the Ib-1 subtype exhibited higher mean viral loads in both urine and plasma, the differences were not statistically significant (p = 0.055 and p = 0.07, respectively). Two patients developed BKVAN, both infected with the Ib-2 subtype. The genotyping algorithm demonstrated a 98 % concordance rate with phylogenetic analysis, confirming its reliability. The predominance of BKV genotype Ib-2 among kidney transplant recipients aligns with global trends. While no significant association between genotype and viral load was found, all BKVAN cases were linked to the Ib-2 subtype, suggesting a potential role in disease progression.

Eplet mismatch (MM) quantification is a valuable tool for refining histocompatibility in kidney transplantation, especially at HLA-DR/DQ loci. However, zero MM at these loci does not ensure complete immunological safety. We report a 17-year-old male who received a living donor kidney transplant via the kidney paired donation (KPD) program. The donor had 0 eplet MMs at HLA-DR/DQ, with negative crossmatch and no pre-transplant donor-specific antibodies (DSAs). Despite this, the patient developed early mixed rejection-T cell-mediated (TCMR) and antibody-mediated (ABMR), and further analysis revealed DSAs targeting an HLA-C 80 K/77 N eplet. Combined treatment for TCMR and ABMR led to histological and functional improvement. This case illustrates the limitation of relying solely on HLA-DR/DQ eplet matching. Despite achieving 0 MM at these loci, the patient developed significant alloimmune injury. Molecular MM scores are useful predictive biomarkers, but they do not fully capture the complexity of immune responses in transplantation.

Reduction in pre-transplant HLA donor specific antibodies (DSA) is a known phenomenon after liver or simultaneous liver kidney (SLK) transplants. However, kidney after liver transplant may be associated with increased immunologic risk, in highly sensitized patients. There is no consensus in avoidance of antibodies in patients with strong historical anti-HLA antibodies who require a second organ after liver transplant. We present a case series of 4 highly sensitized liver recipients who needed a safety net kidney transplant (snKT). To determine which antigens should be avoided, detailed eplet analysis of pre and post liver transplant antibody showed that the liver had successfully cleared eplet-associated DSA; however, third party eplet antibodies persisted. The liver's role in the clearance of DSA versus third party antibody is inconclusive due to a lack of granular eplet analysis data in the literature. Herein, eplet analysis allowed for more accurate determination of higher risk antibodies for snKT.

Psoriasis (PsO) is a chronic, immune-mediated inflammatory disease with systemic manifestations. Its etiology involves an interaction between genetic, immunologic, and environmental factors. The NLRP3 inflammasome plays a key role in innate immune responses and has been implicated in PsO pathogenesis. However, data regarding NLRP3 gene polymorphisms and their relationship with PsO, particularly in the Brazilian population, remain limited. The aim was to investigate the association between the NLRP3 rs10157379 and rs10754558 gene variants with susceptibility and severity of PsO, as well as the risk of developing psoriatic arthritis (PsA). A case-control study was conducted with 154 individuals with PsO and 154 healthy controls. Clinical and demographic data were collected, and genotyping of the NLRP3 rs10157379 T > C and rs10754558 G > C variants was performed using real-time polymerase chain reaction. No significant association was observed between either variant and PsO susceptibility or severity. However, the rs10754558 CG genotype was associated with a reduced likelihood of PsA [odds ratio (OR): 0.32; 95 % confidence interval (CI): 0.10-0.95, p = 0.041], while the GG genotype conferred a higher likelihood (OR: 3.26; 95 % CI:1.03-10.32, p = 0.044). No associations were identified for the rs10157379 variant. In conclusion, the NLRP3 rs10157379 and rs10754558 variants were not associated with PsO susceptibility or severity. However, the rs10754558 variant may influence the chance of joint involvement in individuals with PsO. These findings underscore the potential role of NLRP3 variants in PsA development and highlight the importance of genetic background in PsO pathophysiology.

Cytomegalovirus (CMV) reactivation is a common complication after allogeneic haematopoietic stem cell transplantation (HSCT). It occurs in over a third of alloHSCT recipients, and is a major source of post-transplant mortality. miRNAs are small non-coding RNA molecules that are important regulators of gene expression. They are often dysregulated during disease, including transplant-related complications. Due to their presence in all body fluids, they can be used as potential biomarkers. In this study, we performed miRNA profiling to find differentially expressed host miRNAs in serum that could be linked to CMV reactivation after HSCT. CMV reactivation was confirmed by detection of CMV DNA in serum. We identified two miRNAs, miR-302d-3p (p < 0.001) and miR-6721-5p (p = 0.018), as differentially expressed between day + 30 and + 90 after HSCT in patients with CMV reactivation. Of these, miR-302d-3p was confirmed as overexpressed on day + 30 in a verification analysis performed on an independent cohort of patients (p = 0.027). Furthermore, we analysed two genetic variants in the gene coding for miR-302d-3p. We found one of them, rs13136737, to be significantly associated with CMV reactivation (p = 0.015). In conclusion, our study showed that miR-302d-3p is dysregulated and that its genetic variant rs13136737 may be important in development of CMV reactivation after HSCT.

Chronic alloimmune-mediated injury in kidney transplantation continues to elude effective treatment and negatively impact outcomes. With increased utilization of simultaneous liver and kidney transplants (SLK), many have observed that these recipients have improved kidney graft survival when compared to kidney alone recipients. This intriguing observation has incited a growing group of studies that aim to elucidate the mechanisms behind the liver allograft's ability to modulate recipient's alloimmune responses against the kidney allograft. In this article, we will provide a brief overview of donor specific antibodies (DSA)-mediated injury of kidney allograft, the impact of SLK on recipients with pre-existing DSA, and current theorized pathways through which the liver allograft confers immune tolerance.

Reliable and reproducible testing of Donor Specific HLA-Antibodies (DSA) is essential for clinical decisions in organ transplantation. In this prospective multicentre study from the Italian Transplant Network, we assessed reproducibility and possible bias of Mean Fluorescence Intensity (MFI) values of Luminex-Single Antigen Bead (SAB) assays across 20 laboratories using the 2 commercially available platforms (Vendor 1 and Vendor 2). Both Vendors showed inter-laboratory median MFI coefficient of variation below 20 %. We evaluated the possible MFI bias between Vendors. In the clinically significant 1000-10000 MFI range, a strong MFI bias was observed for class I SAB, with Vendor 1 MFI being approximately one third of Vendor 2 (Vendor 1 MFI = 0.36 Vendor 2 MFI). For class II, the MFI bias was lower, approximately three quarters of Vendor 2 (Vendor 1 MFI = 0.74 Vendor 2 MFI), with several discrepant results for DQ alleles. Ultimately, we defined the best fitting cutoff values for positive and permissive DSA (1000 and 3000, respectively) in use in the current Italian National Kidney Allocation System. These were 500/1000 and 500/2000 for class I and class II for Vendor 1 compared to 1000/3000 for both classes in Vendor 2. Overall, we developed a tool to compare MFI values between different platforms for consistent DSA assignment across laboratories and enable the most appropriate clinical decisions in organ transplantation.

The placenta serves as a vital interface between mother and fetus, facilitating nutrient exchange and immune regulation. Although generally effective in preventing pathogen transmission, some viruses such as CMV and Zika can cross this barrier. The mechanism of vertical transmission of SARS-CoV-2 remains unclear.

Pseudomonas aeruginosa, a notorious pathogen, frequently presents in hospitals and poses numerous health issues due to its drug resistance, making treatment challenging. The rise of multidrug-resistant microorganisms emphasizes the crucial need for novel therapeutic approaches, such as vaccines. This work employed immunoinformatics and subtractive proteomics to find possible universal vaccine candidates. After analyzing the proteome of P. aeruginosa (PAO1 strain), three pathogenic or antigenic proteins were identified as potential targets for vaccines. T and B cell epitopes were predicted from vaccine candidate proteins using various immunoinformatics techniques. A vaccine was developed using specific epitopes (three Helper T lymphocyte (HTL), four Linear B lymphocyte (LBL), and seven Cytotoxic T lymphocyte (CTL) epitopes) and linkers, and a Cholera toxin subunit B adjuvant was added to enhance the immune response. The vaccine binds to and interacts with MHC molecules and TLR4 using molecular dynamics simulations and docking studies. After cloning, we reverse-translated the vaccine in E. coli to optimize protein production. Our approach offers a promising strategy for developing effective, long-lasting vaccines against Pseudomonas aeruginosa infections, which could help address the growing problems of antibiotic resistance in this bacterium.

The pathogenesis of autoimmune diseases such as spondyloarthritis (SpA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) involves genetic factors and gut microbiota dysbiosis, which have been widely reported in patients and animal models. Although genetic factors are known to reshape the gut microbiota, the mechanistic role of the host gene-reshaped gut microbiota in mediating inflammatory diseases remains poorly characterized. This study focused on HLA-B27 to investigate its impact on the gut microbial composition and its association with HLA-B27 related autoimmune inflammatory diseases. The expression of HLA-B27/β2M significantly altered the diversity of the gut microbiota in mice, leading to changes in bacterial species and their functions. Concurrently, HLA-B27/β2M profoundly modified the gut metabolic profile, resulting in increased levels of multiple prostaglandins and decreased levels of anti-inflammatory metabolites. Multi-omics integrated analysis demonstrated that HLA-B27/β2M promoted the synthesis of Gram-negative bacteria while suppressing Gram-positive bacteria, findings validated in both omics datasets. Further validation confirmed that these HLA-B27/β2M-driven alterations in the gut microbial composition caused a shift toward a proinflammatory microbial community. These findings first revealed that genetic factors significantly reshaped the gut microbiota composition and further drove the microbial ecosystem toward a proinflammatory state. This study provides a foundation for identifying gut microbial signature targets in HLA-B27 associated diseases.

Animals have been considered potential sources of organs and complex tissues for clinical transplantation, and occasional cross-species transplants have been performed (when human sources were scarce or unavailable) over the past 120 years. However, no clinical xenotransplant has been deemed successful. Today, after extensive efforts to understand the immunological and biological barriers to xenotransplantation and with the application of genetic engineering and other technologies to overcome these barriers, enthusiasm for xenotransplantation has grown again. A small number of clinical xenotransplants have recently been performed, with formal clinical trials either planned or underway. Therefore, it is important to consider whether and how clinical xenotransplantation might move forward. The key to advancing xenotransplantation from research to clinical practice depends on the experience gained-specifically, whether large clinical trials are necessary to prove feasibility and usefulness, or if such proof must be established before initiating large trials. This question prompted the development and publication of a collection of papers in Human Immunology in 2023. With the outcomes of a few clinical xenografts now known, the question is even more relevant. Consequently, an updated commentary and the contents of the collected papers follow.

The virtual crossmatch (VXM) is a widely implemented tool for assessing immunological risk using donor HLA typing and a recipient's antibody profile. Several studies have documented the efficacy and advantages of the VXM. Most studies validate the accuracy of the VXM by showing correlation with flow crossmatch (FXM) results. However, true utility lies in correlation with transplant outcome and humoral immune response. In this study, we compared the VXM assessment, reported as VXM acceptable or unacceptable, to post-transplant outcome, donor-specific antibody development or resurgence, and FXM results. Overall, a VXM that was deemed acceptable correlated with fewer post-transplant adverse events compared to a VXMunacceptable. Kidney recipients with VXM unacceptable were significantly more likely to demonstrate memory HLA-DSA (p = 0.019), develop antibody-mediated rejection (AMR, p = 0.020), and develop AMR associated with HLA-DSA (p = 0.006) compared to kidney recipients with acceptable VXMs. Heart recipients showed similar trends although the results were not statistically significant due to small size. 94.4 % of VXM acceptable were also negative on FXM, and only 1.1 % of patients with acceptable VXMs benefited from a retrospective FXM. Our findings support the VXM as a reliable alternative to the FXM in most cases and identify situations where the FXM remains beneficial.

A 31-year-old male undergoing evaluation for an allogeneic stem cell transplant exhibited a complete mismatch at the MICA locus compared to his biological mother. The recipient was homozygous MICA*008:04, while the mother was homozygous MICA*002:01. Sample mix-up was ruled out and we sought an alternative explanation. Upon investigation of MICA and HLA-B allele linkage, multiple studies reported an association of a MICA deletion (MICAdel) with HLA-B*48. Interestingly, the patient and his mother both typed as HLA-B*48:02. Furthermore, the patient and his mother each typed as MICB*09:01N. Copy number analysis confirmed a single copy of MICA in both samples, thus providing supporting evidence of a MICAdel in both subjects, and consistent with previously published data on the association of a MICAdel with HLA-B*48. What initially appeared to be a maternal exclusion based on a MICA mismatch was instead attributable to a hemizygous loss of MICA. This case highlights two important considerations: 1) evaluating other loci, not generally considered in most clinical matching algorithms can uncover interesting genetic anomalies usually described only in research settings, 2) The appreciation of such findings can lead to studies that explore the clinical impact of such an evolutionary change.

Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells for treating life-threatening haematological disorders. India's vast population, known for its cultural, linguistic, and genetic diversity, requires a significant need for HLA-matched donors. We analyzed HLA-A, -B, -C, -DRB1, and -DQB1 allele and haplotype diversity in 30,027 UCB units. Samples were categorized into six broad regional populations and further sub-clustered into nine groups based on the predominant language spoken. The most frequent haplotypes identified were A*33:03 ∼ B*44:03 ∼ C*07:06 ∼ DRB1*07:01 ∼ DQB1*02:02 (2.6 %), A*01:01 ∼ B*57:01 ∼ C*06:02 ∼ DRB1*07:01 ∼ DQB1*03:03 (2.4 %), and A*01:01 ∼ B*37:01 ∼ C*06:02 ∼ DRB1*10:01 ∼ DQB1*05:01 (1.4 %), showing significant inter-regional differences. We observed distinct allele distributions and high haplotype diversity, with the India South UCBB population displaying the highest number of unique haplotypes (63 %). Genetic distance analysis and multidimensional scaling revealed genetic relatedness between the regional and sub-regional populations. These findings offer key insights into Indian HLA diversity, inform donor recruitment strategies, enhance understanding of genetic relatedness to neighbouring populations, and highlight the need for population-specific repositories.

Tetanus prevention is effectively managed in infants and young children, yet there remains a need for enhanced measures to improve tetanus prevention among adults.

The role of anti-HLA antibodies in solid organ transplantation has long been recognized, particularly with respect to graft rejection and patient survival. This study aimed to evaluate the impact of de novo donor-specific antibodies (DSA) on graft failure and mortality in Polish lung transplant recipients. The study included 112 patients who had a well-defined immune status prior to transplantation. The presence and specificity of anti-HLA antibodies were assessed using the Luminex platform. We identified 26 patients (23%) as having increased immunological risk. Pre-transplant DSAs were detected in 13 recipients. Post-transplantation, the development of de novo DSAs was evaluated, with a cumulative incidence of 11%. Our findings confirmed that lung transplant recipients with donor-specific immunization frequently develop antibodies targeting antigens at the HLA-DQ locus. Notably, 90% (9 out of 10) of immunized patients exhibited high mean fluorescence intensity (MFI) levels of anti-DQ antibodies. These antibodies were shown to be harmful, with mortality significantly higher in immunized patients: 50% of patients with anti-DQ antibodies died, compared to only 15% in those without DSAs. This is the first study of its kind in the Polish population, confirming that strategies to prevent and treat DQ DSAs may improve outcomes for lung transplant recipients.

Influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coinfection have been shown to intensify symptoms and, therefore, could be considered a significant threat to susceptible populations. Although vaccination is an effective and safe strategy to be used against viruses, large amounts of mutations in these two viruses remain an issue for vaccine design, as some strains of the IAV and SARS-CoV-2 are still present worldwide, regardless of the introduction of various vaccines to protect against the viruses.

Autoimmune diseases occur when the immune system mistakenly attacks healthy tissues, leading to chronic inflammation and progressive organ damage. These conditions affect millions worldwide and often result in long-term disability. The underlying reasons for increased vulnerability remain uncertain, particularly regarding the combined influence of genetic variations and lifestyle factors on disease risk. The purpose of this study is to identify key genetic variants associated with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes, and to investigate how these variants interact with environmental exposures to influence risk and age of onset. Publicly available genetic and molecular data were analyzed, including genome-wide association studies (NHGRI-EBI GWAS Catalog, ImmunoBase, and dbGaP), DNA sequencing datasets (1000 Genomes Project, Genomic Data Commons, and SRA), gene expression profiles (GEO and ArrayExpress), and epigenetic marks (ENCODE and RegulomeDB). This study identifies several significant genetic variants associated with autoimmune diseases, including PTPN22, HLA-DRB1, HLA-DQA1, IRF5, IL10, and other immune-regulatory genes. Notably, the PTPN22 rs2476601 variant increased the risk by approximately 1.8 times, while the HLA-DRB1 rs3135388 variant increased the risk by around 2.1 times. Additional variants, such as HLA-DQ, IRF, and IL10, also play significant roles in immune dysregulation and susceptibility to autoimmune diseases, with specific allele associations yet to be fully explored. Pathway analysis revealed that these genes are primarily involved in antigen presentation, cytokine signaling, and T-cell activation-key processes underlying the pathogenesis of autoimmune diseases. Smoking and vitamin D deficiency further elevated risk in genetically susceptible individuals and were linked with earlier disease onset. The findings highlight genetic markers such as IL2RA and TIM-3 as potential tools for early screening and therapeutic targeting. Integrating genetic testing with lifestyle assessment can support personalized prevention, guide drug development, and improve clinical practice. Validation in diverse populations and long-term studies is recommended to confirm clinical usefulness.