OBJECTIVE: The study aimed to estimate the prevalence of HLA-B51 and HLA-B52 in Lebanese patients with spondyloarthritis (SpA) compared to healthy controls (HC). We further aimed to evaluate the impact of HLA-B51 on phenotype and identify the distribution of the alleles in the HLA-B locus.
METHODS: A case-control study enrolled consecutive SpA patients from three rheumatology clinics in Lebanon, including axial (axSpA), peripheral SpA (pSpA), and psoriatic arthritis (PsA) and HC from blood donors. Demographic and disease data were collected through interviews and file reviews, with testing of the entire HLA-B locus using molecular techniques. The prevalence of HLA-B51 and B52 was estimated in SpA patients versus controls. Prevalence comparisons were made, and logistic regression identified factors associated with HLA-B51 in patients.
RESULTS: Data from 120 HC and 86 SpA patients (65 axSpA, 15 pSpA, 6 PsA), mean age 25.6 and 46.4 years, respectively, showed a higher HLA-B51 prevalence in SpA (25.6%), especially axSpA (29.2%) versus HC (12.5%), p = 0.016, and a numerically higher HLA-B52 prevalence (8.1% versus 4.2%, p = 0.230). HLA-B51 correlated with recurrent oral ulcerations (OR 7.99(95%CI 2.14-29.84) and radiographic juxta-articular erosions (OR 7.65(95%CI 1.14-38.03)). HLA-B35 was the most dominant allele in both groups (18.7%), followed by HLA-B27 (15.7%) and HLA-B51 (13.4%) in SpA.
CONCLUSIONS: HLA-B51 was identified more frequently in patients with SpA compared to HC and was associated with recurrent oral ulcerations and juxta-articular radiographic erosions. Longitudinal studies are needed to determine whether this association indicates a disease overlap or might correlate with a specific SpA phenotype.

The effectiveness and safety of allogeneic mesenchymal stem/stromal cells (MSCs) can be affected by patient\'s immune recognition. Thus, MSC immunogenicity and their immunomodulatory properties are crucial aspects for therapy. Immune responses after allogeneic MSC administration have been reported in different species, including equine. Interactions of allogenic MSCs with the recipient\'s immune system can be influenced by factors like matching or mismatching for the major histocompatibility complex (MHC) between donor-recipient, and by the levels of MHC expression in MSCs. The latter can vary upon MSC inflammatory exposure or differentiation, such as chondrogenic induction, making both priming and differentiation interesting therapeutic strategies. This study investigated the systemic in vivo immune cellular response against allogeneic equine MSCs in these situations. Either MSCs in basal conditions (MSC-naïve), pro-inflammatory primed (MSC-primed) or chondrogenically differentiated (MSC-chondro) were repeatedly administered subcutaneously into autologous, MHC-matched or MHC-mismatched allogeneic equine recipients. At different time-points after each administration, lymphocytes were obtained from recipient horses and exposed in vitro to the same type of MSCs to assess the proliferative response of different T cell subsets (cytotoxic, helper, regulatory), B cells, and interferon gamma (IFNγ) secretion. Higher proliferative response of helper and cytotoxic T lymphocytes and IFNγ secretion was observed in response to all types of MHC-mismatched MSCs over MHC-matched ones. MSC-primed produced the highest immune response, followed by MSC-naïve, and MSC-chondro. However, MSC-primed activated Treg and had a mild effect on B cells, and the response after their second administration was similar to the first one. On the other hand, both MSC-chondro and MSC-naïve barely induced Treg response but promoted B lymphocyte activation, and proportionally induced a higher cell response after the second administration. In conclusion, both the type of MSC conditioning and the MHC compatibility influenced systemic immune recognition of equine MSCs after single and repeated administrations, but the response was different. Selecting MHC-matched donors would be particularly recommended for MSC-primed and repeated MSC-naïve administrations. While MHC-mismatching in MSC-chondro would be less critical, B cell response should not be ignored. Comprehensively investigating the in vivo immune response against equine allogeneic MSCs is crucial for advancing veterinary cell therapies.

OBJECTIVE: The precise relationship between molecular mimicry and tissue-specific autoimmunity is unknown. Major histocompatibility complex (MHC) class II antigen presenting cell-CD4+ T-cell receptor complex interactions are necessary for adaptive immunity. This study aimed to determine the role of endoneurial endothelial cell MHC class II in autoimmune polyneuropathy.
METHODS: Cryopreserved Guillain-Barré syndrome (GBS) patient sural nerve biopsies and sciatic nerves from the severe murine experimental autoimmune neuritis (sm-EAN) GBS model were studied. Cultured conditional ready MHC Class II antigen A-alpha chain (H2-Aa) embryonic stem cells were used to generate H2-Aaflox/+ C57BL/6 mice. Mice were backcrossed and intercrossed to the SJL background to generate H2-Aaflox/flox SJL mice, bred with hemizygous Tamoxifen-inducible von Willebrand factor Cre recombinase (vWF-iCre/+) SJL mice to generate H2-Aaflox/flox; vWF-iCre/+ mice to study microvascular endothelial cell adaptive immune responses. Sm-EAN was induced in Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+, H2-Aaflox/flox; +/+, H2-Aa+/+; vWF-iCre/+ and untreated H2-Aaflox/flox; vWF-iCre/+ adult female SJL mice. Neurobehavioral, electrophysiological and histopathological assessments were performed at predefined time points.
RESULTS: Endoneurial endothelial cell MHC class II expression was observed in normal and inflamed human and mouse peripheral nerves. Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+ mice were resistant to sm-EAN despite extensive MHC class II expression in lymphoid and non-lymphoid tissues.
CONCLUSIONS: A conditional MHC class II knockout mouse to study cell- and time-dependent adaptive immune responses in vivo was developed. Initial studies show microvascular endothelial cell MHC class II expression is necessary for peripheral nerve specific autoimmunity, as advocated by human in vitro adaptive immunity and ex vivo transplant rejection studies.

Details on the origin and function of the immune system are beginning to emerge from genomic studies tracing the origin of B and T cells and the major histocompatibility complex. This is being accomplished through identification of DNA sequences of ancestral genes present in the genomes of lineages of vertebrates that have evolved from a common primordial ancestor. Information on the evolution of the composition and function of the immune system is being obtained through development of monoclonal antibodies (mAbs) specific for the MHC class I and II molecules and differentially expressed on leukocytes differentiation molecules (LDM). The mAbs have provided the tools needed to compare the similarities and differences in the phenotype and function of immune systems that have evolved during speciation. The majority of information currently available on evolution of the composition and function of the immune system is derived from study of the immune systems in humans and mice. As described in the present review, further information is beginning to emerge from comparative studies of the immune systems in the extant lineages of species present in the two orders of ungulates, Perissodactyla and Artiodactyla. Methods have been developed to facilitate comparative research across species on pathogens affecting animal and human health.

The major histocompatibility complex (MHC) loci, the most polymorphic regions within the human genome, encode protein complexes responsible for antigen presentation and CD4+ and CD8+ cell activation. In prostate cancer (PCa), the second most diagnosed cancer in the male population, MHC loci undergo significant changes in their expression patterns, which affect the ability of the immune system to attack and eliminate malignant cells. The purpose of this study was to explore the genetic diversity of human leukocyte antigen (HLA)-A and HLA-B in patients with PCa and healthy controls (HCs) by performing HLA genotyping using NGS technology. The analysis highlighted statistically significant differences (p < 0.05) in the prevalence of three alleles (A*11:01, A*24:02, and B*18:01). Among the HCs analyzed, 14.89% had A*11:01, 20.21% had A*24:02, and 30.61% had B*18:01; while 5.21% of patients with PCa presented A*11:01, 9.38% presented A*24:02, 18.08% presented B*18:01. Odds ratio (OR) calculations underlined a negative association between the three alleles and the risk of PCa (OR < 1). The results presented in this study suggest a protective role of A*11:01, A*24:02, and B*18:01 in PCa.

Human leucocyte antigen (HLA) alleles may generate antibodies that are undetectable by routine single-antigen beads (SABs) assays if their unique epitopes are unrepresented. We aimed to describe the prevalence and explore the potential impact of unrepresented HLA alleles in standard SAB kits in our cohort. All individuals who had undergone two-field HLA typing (HLA-A/B/C/DRB1/DQA1/-DQB1/-DPA1/-DPB1) from February 2021 to July 2023 were included. Two-field HLA-DRB3/4/5 typing was imputed. Each unrepresented allele was compared with the most similar represented allele in the standard LABScreen, LABScreen ExPlex (One Lambda) and the LIFECODES (Immucor) SAB kits. Differences in eplet expression (HLA Eplet Registry) were identified. Differences in three-dimensional molecular structures were visualized using generated models (SWISS-MODEL). Two-field HLA typing was performed for 116 individuals. Overall, 16.7% of all HLA alleles, found in 36.2% of individuals, were unrepresented by all SAB test kits. Four eplets, found in 12.9% of individuals, were unrepresented in at least 1 SAB kit. Non-Chinese individuals were more likely to have unrepresented HLA alleles and eplets than Chinese individuals. There were differences in HLA allele and eplet representation amongst the different SAB test kits. Use of supplementary SAB test kits may improve HLA allele and eplet representation. Although some HLA alleles were unrepresented, most epitopes were represented in current SAB kits. However, some unrepresented alleles may contain epitopes which may generate undetectable antibodies. Further studies may be needed to investigate the potential clinical impact of these unrepresented alleles and eplets, especially in certain ethnic populations or at-risk individuals.

Hunner-type interstitial cystitis (HIC) is a rare, chronic inflammatory disease of the urinary bladder with unknown etiology and genetic background. Here, we conduct a genome-wide association study of 144 patients with HIC and 41,516 controls of Japanese ancestry. The genetic variant, rs1794275, in the major histocompatibility complex (MHC) region (chromosome 6p21.3) is associated with HIC risk (odds ratio [OR] = 2.32; p = 3.4 × 10-9). The association is confirmed in a replication set of 26 cases and 1,026 controls (p = 0.014). Fine mapping demonstrates the contribution to the disease risk of a completely linked haplotype of three human leukocyte antigen HLA-DQβ1 amino acid positions, 71, 74, and 75 (OR = 1.94; p = 5 × 10-8) and of HLA-DPβ1 amino acid position 178, which tags HLA-DPB1∗04:02 (OR = 2.35; p = 7.5 × 10-8). The three HLA-DQβ1 amino acid positions are located together at the peptide binding groove, suggesting their functional importance in antigen presentation. Our study reveals genetic contributions to HIC risk that may be associated with class II MHC molecule antigen presentation.

BACKGROUND: Life-long immunosuppressive treatment after liver transplantation (LT) prevents graft rejection but predisposes the LT recipient to infections. Herpesvirus infections are associated with morbidity and mortality among LT recipients. Among those, especially cytomegalovirus (CMV) and varicella-zoster virus (VZV) pose challenges after LT. The aim of this study is to provide an in-depth characterization of the cellular immune response against CMV and VZV infections in LT recipients and identify potential risk factors for infection.
METHODS: The Herpesvirus Infections in Solid Organ Transplant Recipients - Liver Transplant Study (HISTORY) consists of an epidemiological and immunological substudy. The epidemiological substudy is a retrospective observational cohort study that includes all patients who underwent LT in Denmark between 2010 and 2023 (N ≈ 500). Using data from nationwide hospital records and national health registries, the incidence of and clinical risk factors for CMV and VZV infections will be determined. The immunological substudy is an explorative prospective observational cohort study including patients enlisted for LT in Denmark during a 1.5-year period (N > 80). Participants will be followed with scheduled blood samples until 12 months after LT. CMV- and VZV-derived peptides will be predicted for their likelihood to be presented in participants based on their HLA type. Peptide-MHC complexes (pMHC) will be produced to isolate CMV- and VZV-specific T cells from peripheral blood mononuclear cells before and after CMV and VZV infection. Their frequency, T cell receptor sequences, and phenotypic characteristics will be examined, and in a subset of participants, CMV- and VZV-specific T cells will be expanded ex vivo.
CONCLUSIONS: This study will provide novel insight into T cell immunity required for viral control of CMV and VZV and has the potential to develop a prediction model to identify LT recipients at high risk for infection based on a combination of clinical and immunological data. Furthermore, this study has the potential to provide proof-of-concept for adoptive T cell therapy against CMV and VZV. Combined, this study has the potential to reduce the burden and consequence of CMV and VZV infections and improve health and survival in LT recipients.
BACKGROUND: ClinicalTrials.gov (NCT05532540), registered 8 September 2022.

OBJECTIVE: HLA alloimmunization is one of the most troublesome consequence of regular transfusion which is itself a mainstay measure to provide longevity to the thalassemia patients. Febrile non-hemolytic transfusion reaction (FNHTR) is one of the most common complication which might be related to the HLA alloimmunization. Here, we studied the HLA antigenic system and alloimmunization rate in the Iranian β-thalassemia patients who suffered from FNHTR compare to the β-thalassemia patients without FNHTR.
METHODS: Total of 60 β-thalassemia patients with FNHTR (case group) and 20 β-thalassemia patients without FNHTR (control group) randomly have been selected and enrolled in the study. All were tested for HLA-A and -B loci by PCR-SSP method and also for the presence of anti-lymphocyte antibodies by LIFT method. Comparisons between two groups were performed by Pearson\'s χ2 test.
RESULTS: Totally, a significant predominance was noted for two HLA alleles, HLA-A*24 (P = 0.029) and B*55 (P = 0.034) which have higher prevalence in control group. Although no significant association was found between the presence of anti-leukocyte antibodies and the development of FNHTR, the HLA-A*32 (P = 0.047) allele was considered as possible genetic markers in the susceptibility to the development of anti-leukocyte antibodies.
CONCLUSIONS: Here some evidences about the possible role of HLA polymorphism in susceptibility to FNHTR are provided. Those results indicated that HLA-A*24 and HLA-B*55 might play protective role on inducing FNHTR in β-thalassemia patients. Further studies which investigate the allele level of HLA-I alongside with specific reactivity of HLA-I antibodies might reveal more deep data about these phenomena.

UNASSIGNED: Up to 30% of individuals with hemophilia A develop inhibitors to replacement factor VIII (FVIII), rendering the treatment ineffective. The underlying mechanism of inhibitor development remains poorly understood. The My Life, Our Future Research Repository (MLOF RR) has gathered F8 and F9 mutational information, phenotypic data, and biological material from over 11,000 participants with hemophilia A (HA) and B as well as carriers enrolled across US hemophilia treatment centers, including over 5,000 whole-genome sequences. Identifying genes associated with inhibitors may contribute to our understanding of why certain patients develop those neutralizing antibodies.
UNASSIGNED: Here, we performed a genome-wide association study and gene-based analyses to identify genes associated with inhibitors in participants with HA from the MLOF RR.
UNASSIGNED: We identify a genome-wide significant association within the human leukocyte antigen (HLA) locus in participants with HA with F8 intronic inversions. HLA typing revealed independent associations with the HLA alleles major histocompatibility complex, class II, DR beta 1 (HLA DRB1*15:01) and major histocompatibility complex, class II, DQ beta 1 (DQB1*03:03). Variant aggregation tests further identified low-frequency variants within GRID2IP (glutamate receptor, ionotropic, delta 2 [GRID2] interacting protein 1) significantly associated with inhibitors.
UNASSIGNED: Overall, our study confirms the association of DRB1*15:01 with FVIII inhibitors and identifies a novel association of DQB1*03:03 in individuals with HA carrying intronic inversions of F8. In addition, our results implicate GRID2IP, encoding GRID2-interacting protein, with the development of inhibitors, and suggest an unrecognized role of this gene in autoimmunity.