Human Immunology[JOURNAL]
Sun
200 papers
The significance of galectin-9 and T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) in patients with chronic lymphocytic leukemia: The role of immune evasion.
Hussein S, Mohamed EM, Ebian HF … +7 more , Waley AB, Alshamy MGM, Aboafya ZI, Elsayed BS, Alsharidah A, Atef N, Sakr MMH
Hum Immunol · 2026 Jul · PMID 42391833 · Publisher ↗
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a hematological malignancy with the accumulation of mature, monoclonal B lymphocytes. CLL cells can escape the host's immune response by inducing T-cell exhaustion. This...
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a hematological malignancy with the accumulation of mature, monoclonal B lymphocytes. CLL cells can escape the host's immune response by inducing T-cell exhaustion. This occurs by upregulation of inhibitory checkpoint receptors, such as T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3). Galectin-9 (Gal-9) is a soluble ligand for TIM-3. Its interaction with TIM-3 can induce T-cell exhaustion in various cancers. Therefore, targeting these inhibitory pathways may be a potential therapy for CLL. SUBJECTS& METHODS: This case-control study included 200 participants, divided into two groups. Group 1 included 100 treatment-naïve patients with newly diagnosed CLL. Group 2 (control group) included 100 age- and sex-matched healthy individuals. Gal-9 expression was estimated by real-time polymerase chain reaction, while flow cytometric %TIM-3 on CD3, CD3CD4, and CD3CD8 T cells was measured. RESULTS: Galectin-9 mRNA expression and flow cytometric %TIM-3 on CD3, CD3CD4, and CD3CD8 T-cells were significantly higher in CLL patients than healthy controls. Both markers were significantly associated with prognostic markers (β2-microglobulin, lactate dehydrogenase (LDH), chromosomal abnormalities, and Rai stage). CONCLUSION: Galectin-9/TIM-3 interaction has a possible role in the development and progression of CLL. Gal-9 mRNA expression and %TIM-3 on CD3, CD3CD4, and CD3CD8 T-cells are potential discriminators between CLL patients and healthy controls. This was demonstrated by high sensitivity and specificity. Additionally, they had significant correlations with prognostic markers, including β2-microglobulin, LDH, chromosomal abnormalities, CD38, and Rai stage.
The functional relevance of human leukocyte antigens in the development of cord blood derived advanced cellular therapies: A new direction of public cord blood banks.
Mallis P, Chatzistamatiou T, Siorenta A … +6 more , Dinou A, Michalopoulos E, Sarri EF, Roumellioti K, Vlachou MS, Giokas CS
Hum Immunol · 2026 Jun · PMID 42364409 · Publisher ↗
CBUs have been applied as alternative source of HSCs transplantation. The increasing preference for haploidentical HSC transplantation has resulted in a reduced application of CBUs worldwide. Banked CBUs in public CBBs h...
CBUs have been applied as alternative source of HSCs transplantation. The increasing preference for haploidentical HSC transplantation has resulted in a reduced application of CBUs worldwide. Banked CBUs in public CBBs have been processed with the highest quality standards, representing a valuable biologic source for potential production of ATMPs. The aim of this study was to characterize the HLA allele and haplotype composition of the HCBB inventory and compare its immunogenetic profile with Greek and selected international populations. Stored CBUs (n = 461) were HLA typed and analyzed in terms of allele and haplotype distribution. Unsupervised machine learning algorithms were utilized to compare the HLA allele and haplotype frequencies with the populations registered in the DKMS. Finally, Greek hematological patients (n = 432) were HLA typed, to descriptively assess similarities in HLA allele and haplotype distributions between the HCBB inventory and a representative Greek patient cohort. The results demonstrated similar HLA allele and haplotype frequency distributions between the HCBB inventory, Greek hematological patients, and several geographically related populations. These findings provide a descriptive characterization of the HCBB inventory and indicate that its HLA profile shares common features with the populations examined.
From educational to graded: redefining proficiency testing in ABO genotyping.
Hod-Dvorai R, Murphey C, Bravo-Egana V … +1 more , Timofeeva O
Hum Immunol · 2026 Jun · PMID 42361447 · Publisher ↗
AIM: ABO genotyping is a valuable tool when serologic typing is inconclusive or not feasible. This study evaluated whether ABO genotyping delivers the same high accuracy and inter-laboratory consistency as serologic meth...
AIM: ABO genotyping is a valuable tool when serologic typing is inconclusive or not feasible. This study evaluated whether ABO genotyping delivers the same high accuracy and inter-laboratory consistency as serologic methods, and whether a graded proficiency testing (PT) program is warranted for ABO genotyping. We also aimed to determine if molecular ABO typing could be considered for routine use in assigning ABO phenotype in the transplantation setting. METHODS: Data including ABO genotype, ABO A subgroup (when applicable), phenotype and method were extracted from participants in the 2023-2025 ABO genotyping PT challenges (n = 55 specimens; 25 ASHI, 30 Southwest Immunodiagnostics). Molecular ABO genotyping was performed in parallel on 53 PT specimens using RT-PCR and NGS to evaluate method concordance. RESULTS: Each PT challenge included 7-15 participating laboratories. Of the 55 specimens, 52 (95%) reached 100% phenotype consensus. RT-PCR and NGS results were highly concordant, with only one phenotype discrepancy (Aw vs A2). Six novel O alleles were identified in 9 specimens. CONCLUSION: Despite limitations such as incomplete gene coverage and lack of standardized references, ABO genotyping achieved 100% phenotype prediction accuracy in this PT study. These findings demonstrate that PT programs provide a robust framework for assessing and monitoring the analytical performance of ABO genotyping assays as laboratories increasingly adopt this technology for clinical transplantation testing.
Recurrent spontaneous abortion: integrated bioinformatics and histological validation identify FURIN and NEDD4 as ferroptosis-associated endometrial markers.
Han X, Feng YY, Wang L
Hum Immunol · 2026 Jun · PMID 42361446 · Publisher ↗
BACKGROUND: Unexplained recurrent spontaneous abortion (RSA) affects 1-2% of couples and lacks reliable molecular markers. Emerging evidence links ferroptosis-a form of iron- and lipid-peroxide-driven cell death-to impai...
BACKGROUND: Unexplained recurrent spontaneous abortion (RSA) affects 1-2% of couples and lacks reliable molecular markers. Emerging evidence links ferroptosis-a form of iron- and lipid-peroxide-driven cell death-to impaired decidualisation, a core defect in RSA. OBJECTIVE: To identify ferroptosis-associated genes and pathways in endometrial tissue from RSA patients and to verify their clinical relevance with histological and transcript-level validation. METHODS: Public micro-array datasets (GSE26787, training; GSE165004, external test) were normalized and analysed with limma. Differentially expressed genes (DEGs) were intersected with 484 ferroptosis-related genes (FerrDb) to obtain ferroptosis DEGs (Ferr-DEGs). Functional enrichment (GO, KEGG), protein-protein interaction (STRING) and least-absolute-shrinkage-and-selection-operator (LASSO) regression prioritised hub genes. Immune-cell infiltration was quantified by single-sample GSEA. Diagnostic performance was evaluated with 5-fold cross-validated ROC curves. Independent wet-lab validation used immunohistochemistry (H-score) and ΔΔCt-qPCR in 10 RSA versus 10 control FFPE endometrial samples. RESULTS: Fifteen Ferr-DEGs (9 up-, 6 down-regulated) were enriched for oxidative-stress response, FoxO and cAMP signaling. FURIN and NEDD4 emerged as hub genes (network degree >25); a two-gene logistic model achieved a cross-validated AUC = 0.93 (95% CI 0.86-0.99) in the training set and 0.80 in the external set. ssGSEA revealed increased Th1-cell infiltration in RSA (adjusted q < 0.05). Tissue validation confirmed elevated FURIN and NEDD4; GPX4 was unchanged. Spearman ρ between H-score and ΔΔCt was 0.66 (FURIN) and 0.71 (NEDD4). CONCLUSION: Concordant up-regulation of FURIN and NEDD4, coupled with Th1 skewing, delineates a ferroptosis-permissive endometrial micro-environment in RSA. These genes merit prospective evaluation as molecular classifiers or therapeutic entry points.
A perspective on ABO incompatible transplantation.
Kahlyar H, Hogan C, Roxby D … +2 more , Badrick T, Vanniasinkam T
Hum Immunol · 2026 Jun · PMID 42349243 · Publisher ↗
ABO blood group compatibility is a critical factor in solid organ and haemopoietic stem cell transplantation. In ABO-incompatible (ABOi) transplantation, recipient anti-A and/or anti-B antibodies may bind to donor red ce...
ABO blood group compatibility is a critical factor in solid organ and haemopoietic stem cell transplantation. In ABO-incompatible (ABOi) transplantation, recipient anti-A and/or anti-B antibodies may bind to donor red cell or endothelial A and B antigens triggering complement activation, potentially leading to antibody-mediated rejection (ABMR) and early graft loss. Measurement of these isohaemagglutinins by antibody titration is therefore essential for assessing transplant suitability and guiding desensitisation strategies. However, a major limitation of ABO antibody titration is the lack of international standardisation. Multiple assay platforms and variations in techniques, reagents, incubation conditions and endpoint definitions lead to significant inter-laboratory variability, potentially influencing transplant eligibility decisions and clinical outcomes. This review examines current laboratory issues associated with ABO antibody titration, including methodological variability, interpretation of titres, and biological factors influencing antibody expression. Alternative analytical and evolving approaches including flow cytometry-based assays, solid-phase platforms and complement-binding antibody testing are also discussed. Finally, future directions are considered, including assay standardisation, improved risk stratification, molecular ABO typing technologies, modification of ABO antigen expression, and international collaboration to improve the reliability of ABO antibody assessment and transplant outcome in ABO-incompatible kidney and stem cell transplantation.
Classical HLA allele and haplotype frequency estimates in US populations.
Gragert L, Madbouly A, Bashyal P … +4 more , Wadsworth K, Kempenich J, Bolon YT, Maiers M
Hum Immunol · 2026 Jun · PMID 42341485 · Publisher ↗
The human leukocyte antigen (HLA) system is the primary determinant of donor selection in allogeneic hematopoietic cell transplantation (HCT) and plays a central role in solid organ transplantation, immune-mediated disea...
The human leukocyte antigen (HLA) system is the primary determinant of donor selection in allogeneic hematopoietic cell transplantation (HCT) and plays a central role in solid organ transplantation, immune-mediated disease studies, evolutionary population genetics, and immunotherapy. Large-scale sampling of registry participants reflecting major US ancestry groups allows for characterization of the complex landscape of HLA haplotype diversity for the classical HLA class I (HLA-A, HLA-B, HLA-C) and HLA class II (HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) genes. Here we present nine-locus classical HLA allele and haplotype frequency estimates for five broad (Black, White, Asian or Pacific Islander, Hispanic and Native American) and 21 detailed US populations based on 9,671,082 donors with targeted genotyping by DNA-based methods. Frequency estimation used an expectation-maximization (EM) framework specifically adapted to handle mixed-resolution and ambiguous HLA genotyping data. Advancements in next-generation sequencing provide extensive HLA genotyping, offering new insights into the haplotype structure and diversity of the human MHC complex, expanding knowledge especially for HLA class II haplotypes. Population analyses reveal that the most common haplotypes are predominantly population-specific, with only three haplotypes shared across the top 100 lists of all five broad population groups, and that Black populations exhibit the greatest nine-locus haplotypic diversity, a pattern that persists after controlling for differences in registry sample size. These frequencies, derived from the largest US cohort to date, support clinical decision-making and research in histocompatibility, immunogenetics, and transplantation and are publicly available at https://zenodo.org/records/17966993.
High KIR diversity in Uganda and Botswana children living with HIV.
Mukisa J, Kyobe S, Amujal M … +17 more , Jacqueline W, Katagirya E, Diphoko T, Sebetso G, Mwesigwa S, Mboowa G, Retshabile G, Williams L, Mlotshwa B, Matshaba M, Jjingo D, Kateete DP, Joloba ML, Mardon G, Hanchard N, Hollenbach JA, Collaborative African Genomics Network (CAfGEN) of the H3Africa Consortium
Hum Immunol · 2026 Jun · PMID 42320219 · Publisher ↗
Killer-cell immunoglobulin-like receptors (KIRs) are critical regulators of the innate immune system and are found on the surfaces of natural killer (NK) cells. The KIR encoding genes, located on chromosome 19q13.4, are...
Killer-cell immunoglobulin-like receptors (KIRs) are critical regulators of the innate immune system and are found on the surfaces of natural killer (NK) cells. The KIR encoding genes, located on chromosome 19q13.4, are genetically diverse and associated with HIV progression. However, there is limited knowledge on the diversity of KIR from Uganda and Botswana HIV-infected paediatric cohorts. We applied next-generation sequencing technologies on 312 participants (Uganda: n = 246, Botswana: n = 66), Pushing Immunogenetics to the next-generation (PING) bioinformatics pipeline, logistic regression in Python for Population genetics (PyPOP) software to characterize allelic, allotypic, and disease associations. We found distinct patterns of KIR diversity between the cohorts (normalized to n = 50): the Ugandan cohort had 156 alleles compared to 99 in Botswana. Using the Ewens-Watterson test, exploratory analyses found that KIR3DL2 showed significant positive deviation towards homozygosity among long-term non-progressors (LTNPs) in the Uganda cohort, while KIR3DL1/S1 significant balancing selection among LTNPs in the Botswana cohort. Additionally, the Bw4-80I HLA ligand was more frequent in Ugandan LTNPs than Rapid Progressors (RPs) (39.2% vs 29.2%, P-value: 0.029). No KIR/HLA alleles were significantly associated with HIV disease progression after adjustment for multiple testing in the Ugandan cohort. Our study findings expand knowledge of the KIR genetic diversity in African populations.
Low levels of soluble HLA-G as an immunological feature associated with type 2 diabetes mellitus and its microvascular complications.
Khalaf NF, Salman IN, Ad'hiah AH … +1 more , Zulkafli NES
Hum Immunol · 2026 Jun · PMID 42309010 · Publisher ↗
Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade inflammation, and soluble HLA-G (sHLA) molecules are effective immunomodulators in controlling inflammation. However, sHLA-G role in T2DM pathogenesis...
Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade inflammation, and soluble HLA-G (sHLA) molecules are effective immunomodulators in controlling inflammation. However, sHLA-G role in T2DM pathogenesis and its microvascular complications (MICs: peripheral neuropathy [PN], nephropathy [NE], and retinopathy [RT]) lacks scientific evidence. This case-control study examined serum sHLA-G levels in 34 newly-diagnosed patients (ND), 30 patients without MICs (DM), 30 PN patients, 30 NE patients, 30 RT patients, and 60 healthy controls. A significant decrease in sHLA-G levels was observed in T2DM patients, particularly ND, DM, PN, and RT patients, compared to controls. However, in terms of disease association and discriminatory measures, sHLA-G may be more valuable in ND and DM than in MICs (PN, NE, and RT). This preliminary study concluded that T2DM and its MICs were linked to low sHLA-G levels and suggested that sHLA-G is a potential immunomodulator associated with T2DM, particularly ND and DM.
Investigation of human leukocyte antigen alleles as risk factors for cryptococcal disease in Ugandan individuals with HIV.
Skipper CP, Dai B, Borges B … +13 more , Augusto DG, Gerlach E, Tukundane A, Tadeo K, Pastick KA, Williams DA, Kabahubya M, Rajasingham R, Nalintya E, Meya DB, Boulware DR, Hollenbach J, Nielsen K
Hum Immunol · 2026 Jun · PMID 42289175 · Full text
Cryptococcus neoformans is an opportunistic fungal infection and a leading cause of HIV-associated meningitis, contributing significantly to AIDS-related mortality, especially in Africa. Despite advancements in treatment...
Cryptococcus neoformans is an opportunistic fungal infection and a leading cause of HIV-associated meningitis, contributing significantly to AIDS-related mortality, especially in Africa. Despite advancements in treatment, case fatality rates remain high, emphasizing the need for a better understanding of host immune responses. This study investigated the association between variation in the human leukocyte antigen (HLA) genes and the risk of cryptococcal disease in Ugandan individuals with HIV. We first described the allele prevalence in a prospectively enrolled Ugandan population using next-generation sequencing at a four-field resolution for classic HLA class I and II genes. We then conducted a case-control analysis involving 137 participants categorized as: 1) disseminated cryptococcosis but without meningitis, 2) cryptococcal meningitis, and 3) controls with similar degree of HIV disease but without cryptococcal infection. Across 66 unique alleles that met criteria for analysis, we found no significant associations between HLA variation and altered risk of disseminated cryptococcosis or cryptococcal meningitis after adjusting for multiple comparisons. However, before multiple comparisons correction, HLA-DPB1*04:01 demonstrated lower odds ratios for both disseminated disease and cryptococcal meningitis. Using public online databases, we analyzed predicted Cryptococcus peptide binding to HLA-DPB1*04:01 with predicted interferon-gamma responses and identified 121 viable peptides-leading us to hypothesize a role for the leading epitopes. This research underscores the need to further investigate the importance of the HLA system for host-pathogen interactions in HIV-associated cryptococcal disease.
Polymorphisms in immune checkpoint genes might influence bladder cancer risk and clinical outcome.
Andrzejczak A, Krajewski W, Jaskuła E … +5 more , Chorbińska J, Tomkiewicz A, Małkiewicz B, Szydełko T, Karabon L
Hum Immunol · 2026 Jun · PMID 42284619 · Publisher ↗
BACKGROUND: In addition to well-established immune checkpoints (ICs), such as CTLA-4, PD-1, PD-L1, increasing attention is being directed toward next-generation ICs, including TIM-3, Gal-9, LAG-3, BTLA, HVEM, and CD160....
BACKGROUND: In addition to well-established immune checkpoints (ICs), such as CTLA-4, PD-1, PD-L1, increasing attention is being directed toward next-generation ICs, including TIM-3, Gal-9, LAG-3, BTLA, HVEM, and CD160. Single nucleotide polymorphisms (SNPs) within IC-related genes may contribute to dysregulation of inhibitory pathways and impair anti-tumor immune responses. This study aimed to evaluate the association between selected IC gene variants and susceptibility to bladder cancer (BC). PATIENTS AND METHODS: A total of twelve SNPs located in TIM-3, LGALS9, BTLA, HVEM, and CD160 genes were genotyped using TaqMan assays in 314 BC patients and over 520 healthy controls (HC). Genotype distributions were analyzed under multiple genetic models, and associations with clinicopathological parameters were assessed using multivariate logistic regression. RESULTS: Genotype distributions of BTLA polymorphisms (rs2705511, rs1982809, rs9288953) differed between BC patients and HC, suggesting potential associations with BC risk. Stratified analyses revealed sex-specific effects, with variants in BTLA (rs1982809), HVEM (rs1886730, rs2234167, rs8725), and CD160 (rs231375) showing potential associations with susceptibility among women. Additionally, SNPs in BTLA and HVEM were nominally associated with recurrence and high-grade tumors, while CD160 and LGALS9 variants were potentially linked to primary tumor occurrence. However, these associations lost statistical significance after correction for multiple comparisons. CONCLUSIONS: Although the observed associations did not remain significant after multiple testing correction, the results suggest that genetic variation within BTLA, HVEM, and CD160 genes may still play a biologically relevant role in BC susceptibility and disease progression. These findings underscore the potential importance of IC pathways in BC pathogenesis and warrant further investigation in larger, well-powered studies.
An integrated immunogenetic network architecture linking antigen processing and innate immune activation in Ankylosing spondylitis.
Martínez-Flores K, Zamudio-Cuevas Y, López-Macay A … +1 more , Fernández-Torres J
Hum Immunol · 2026 Jun · PMID 42269371 · Publisher ↗
Ankylosing spondylitis (AS) is a polygenic inflammatory disease in which antigen presentation and innate immune activation converge. While HLA-B27 is the strongest genetic determinant, other loci, such as ERAP1, DEFB1, M...
Ankylosing spondylitis (AS) is a polygenic inflammatory disease in which antigen presentation and innate immune activation converge. While HLA-B27 is the strongest genetic determinant, other loci, such as ERAP1, DEFB1, MICA, and NLRP3, also contribute to disease susceptibility through coordinated mechanisms. However, the higher-order interaction structure integrating these pathways is not well understood. A case-control study analyzed nine variants in the DEFB1, HLA-B, ERAP1, MICA, and NLRP3 genes. Linkage disequilibrium (LD) was evaluated using D' and r statistics to identify structured haplotypic blocks. Epistatic interactions were assessed using multifactor dimensionality reduction (MDR), and interaction information metrics were used to quantify synergistic effects. Structured LD blocks were observed within ERAP1 variants, whereas cross-locus LD was limited. MDR analysis revealed that the strongest synergistic interaction was between DEFB1 rs11362 and NLRP3 rs3806268 (21.9% of the total positive epistatic information), followed by DEFB1 rs1800972 and ERAP1 rs27044 (11.0%), suggesting the presence of coordinated barrier-inflammasome and barrier-antigen processing axes. These findings indicate that AS is characterized by a multilayered immunogenetic network in which epithelial defense, antigen processing, cytotoxic activation, and inflammasome signaling interact synergistically to shape immune dysregulation.
Translational Gaps in Immuno-AI: From algorithmic accuracy to clinical trust.
Oisakede EO, Ayo Daniel RI, Olawuyi OF … +3 more , Alabi JO, Analikwu CC, Olawade DB
Hum Immunol · 2026 Jun · PMID 42269370 · Publisher ↗
Artificial intelligence has shown remarkable promise in predicting patient responses to immune checkpoint inhibitors across cancers. However, despite high statistical performance, clinical translation remains minimal. Th...
Artificial intelligence has shown remarkable promise in predicting patient responses to immune checkpoint inhibitors across cancers. However, despite high statistical performance, clinical translation remains minimal. This disconnect between algorithmic accuracy and clinical adoption, termed the translational gap, reflects unresolved challenges in validation, interpretability, and regulatory integration. This review critically examines key barriers preventing translation of Immuno-AI systems from research prototypes to clinically trusted decision-support tools. It analyzes methodological, regulatory, ethical, and infrastructural factors limiting implementation and proposes strategies for developing clinically trustworthy AI in immuno-oncology. A structured literature search was conducted across PubMed, Embase, Scopus, and Web of Science for studies published 2018-2025 reporting AI or machine learning models predicting ICI response or toxicity in human cohorts. Narrative synthesis was applied, focusing on translational bottlenecks. Three dominant factors underpin the translational gap: (1) insufficient external and prospective validation, leading to overestimation of model performance; (2) limited interpretability and absence of explainable frameworks suitable for clinical use; and (3) regulatory and infrastructural immaturity, including lack of harmonised standards for adaptive AI systems. These limitations contribute to absence of clinician confidence and hinder regulatory approval. Bridging the translational gap in Immuno-AI requires a shift from model-centric optimisation to system-level accountability. Clinically trustworthy AI must be validated across institutions, designed for interpretability, and governed by transparent, ethical frameworks. Collaborative efforts among researchers, clinicians, and regulators are essential to ensure future Immuno-AI systems achieve algorithmic excellence, clinical credibility, and social legitimacy.
Challenges of chimerism analysis using Next-Generation sequencing in a patient with complex chromosomal alterations.
Li X, Qama E, Ramesh KH … +9 more , Krishnamurthy K, Azad AK, Naeem C, Paroder M, Wang Y, Goldfinger M, Cooper D, Goldstein DY, Colovai AI
Hum Immunol · 2026 Jun · PMID 42259007 · Publisher ↗
The impact of chromosomal abnormalities on chimerism analysis by next generation sequencing (NGS) has not been explored. Here we report a case of cutaneous T-cell lymphoma (CTCL)/ Sézary syndrome with unusual chimerism f...
The impact of chromosomal abnormalities on chimerism analysis by next generation sequencing (NGS) has not been explored. Here we report a case of cutaneous T-cell lymphoma (CTCL)/ Sézary syndrome with unusual chimerism findings caused by genotypic abnormalities of the leukemic cells. Cytogenetics analysis indicated a near-triploid karyotype with multiple numerical and structural abnormalities in the leukemic cells. Allogeneic stem cell transplantation was considered. Chimerism testing was performed using NGS-based One Lambda Devyser Chimerism assay. In pre-transplant samples containing leukemic cells, chimerism analysis indicated out-of-range variant allele frequencies (VAF) at 9 out of 11 heterozygous DNA markers. In contrast, a pre-transplant sample with no detectable leukemic cells showed normal allele ratios. After transplantation, the absence of circulating leukemic cells allowed accurate assessment of donor chimerism. However, the possibility that leukemia recurrence may impact the accuracy of chimerism results has to be considered in follow-up testing.
Association of the IL6 rs1800795 polymorphism with COVID-19 clinical severity in a Brazilian population.
Rocha GD, Silva ATP, Armstrong ADC … +2 more , Souza CDF, Carmo RF
Hum Immunol · 2026 Jun · PMID 42251847 · Publisher ↗
A dysregulated inflammatory response is a central mechanism underlying severe COVID-19, with elevated serum IL-6 and TNF-α levels consistently associated with increased disease severity and mortality. Growing evidence in...
A dysregulated inflammatory response is a central mechanism underlying severe COVID-19, with elevated serum IL-6 and TNF-α levels consistently associated with increased disease severity and mortality. Growing evidence indicates that host genetic factors influence individual susceptibility to adverse outcomes. We investigated the association of the rs1800795 (IL6) and rs1800629 (TNF) polymorphisms with COVID-19 severity in patients from Northeast Brazil with confirmed SARS-CoV-2 infection. This cross-sectional study included 642 patients classified as critical (n = 224), severe (n = 306), or convalescent controls (n = 112). Genotyping was performed using TaqMan assays. Genetic analysis revealed significant differences in rs1800795 allele frequency (p = 0.018) and in the CC versus GC + GG genotype comparison (adjusted p = 0.032) across clinical groups. Multinomial logistic regression showed that carriers of the GC or GG genotypes had an increased risk of severe (OR = 5.84; 95% CI = 1.93-17.7; p = 0.002) and critical COVID-19 (OR = 3.57; 95% CI = 1.15-11.1; p = 0.028) compared with CC carriers, independent of major confounders. No significant association was observed for TNF rs1800629. These findings support an association between the IL6 rs1800795 polymorphism and COVID-19 clinical severity, highlighting the relevance of immunogenetic factors in COVID-19 outcomes.
Viral-Induced autoimmune Disorders: Mechanistic insights and emerging concepts.
Rajalingam A, Ganjiwale A
Hum Immunol · 2026 Jun · PMID 42248032 · Publisher ↗
Autoimmune disorders (ADs) result from a complex interaction of genetic predisposition and environmental triggers, with viral infections identified as primary causes. This review summarizes current evidence on how viruse...
Autoimmune disorders (ADs) result from a complex interaction of genetic predisposition and environmental triggers, with viral infections identified as primary causes. This review summarizes current evidence on how viruses-including Epstein-Barr Virus (EBV), Enteroviruses, and SARS-CoV-2-initiate and worsen autoimmunity. We explore established mechanisms such as molecular mimicry, bystander activation, and epitope spreading, while highlighting the emerging roles of maladaptive trained immunity and cytokine storms in chronic inflammation. Additionally, we discuss the bidirectional relationship between gut microbiota dysbiosis and virus-induced immune failure. Understanding these layered interactions is crucial for developing biomarker-driven diagnostic and treatment strategies.
Cannabidiol modulates classical and non-classical hla expression in human choriocarcinoma cell line.
Martínez KI, Palma MB, Sepúlveda FJ … +3 more , Carosella ED, García MN, Riccillo FL
Hum Immunol · 2026 Jun · PMID 42248031 · Publisher ↗
Cannabidiol (CBD) modulates diverse signaling pathways with potential relevance to tumor immune escape; however, its impact on the regulation of classical and non-classical HLA class I molecules remains incompletely unde...
Cannabidiol (CBD) modulates diverse signaling pathways with potential relevance to tumor immune escape; however, its impact on the regulation of classical and non-classical HLA class I molecules remains incompletely understood. Here, we examined the effects of CBD on HLA expression in JEG-3 choriocarcinoma cells, focusing on cannabinoid-related receptors and intracellular Ca signaling. CBD increased the expression of classical HLA class I genes, most notably HLA-C, while reducing HLA-G levels, a non-classical HLA class I molecule associated with local immunosuppressive functions. Receptor profiling revealed constitutive expression of CB1 and CB2, whereas GPR55 and PPARγ expression became detectable only after CBD exposure. Receptor inhibition assays showed that HLA-G downregulation was selectively attenuated by CB1 blockade, with no meaningful contribution from CB2 or GPR55. In contrast, CBD-induced HLA-C upregulation was significantly attenuated by GPR55 and CB2 inhibition, while remaining unaffected by CB1 blockade, suggesting distinct receptor-associated pathways for classical and non-classical HLA regulation. Calcium chelation using BAPTA further demonstrated that HLA-G modulation was highly sensitive to intracellular Ca reduction, whereas classical HLA expression required higher BAPTA concentrations to be affected. Altogether, these findings support the possibility that CBD may promote coordinated immunomodulatory effects associated with differential regulation of classical and non-classical HLA molecules through receptor-associated and calcium-sensitive signaling pathways.
Immune tolerance: Parallels between pregnancy and kidney transplantation.
Agrawal S
Hum Immunol · 2026 Jun · PMID 42248030 · Publisher ↗
Pregnancy represents a unique immunological paradox in which the maternal immune system must tolerate the semi-allogeneic fetus expressing paternal antigens. The success of pregnancy depends on a highly coordinated netwo...
Pregnancy represents a unique immunological paradox in which the maternal immune system must tolerate the semi-allogeneic fetus expressing paternal antigens. The success of pregnancy depends on a highly coordinated network of immune tolerance mechanisms, encompassing the placental barrier, chemokine-guided leukocyte migration, restricted alloantigen presentation, regulatory T cells, tolerogenic natural killer cells, immune checkpoint molecules, and both hormonal and metabolic adaptations. In contrast, achieving long-term acceptance of transplanted organs-referred to as "operational tolerance"-remains a formidable clinical challenge that typically necessitates lifelong immunosuppression. Contemporary strategies to induce tolerance focus on the deletion or anergy of donor-reactive immune cells and the utilization of regulatory T cells to suppress rejection. Additional approaches, including co-stimulatory blockade, cell-based therapies, and induction of mixed chimerism via donor stem cell transplantation, seek to replicate these tolerance mechanisms. Ongoing clinical immune monitoring and emerging interventions-such as the inhibition of T-cell signaling, modulation of costimulatory pathways, and targeted expansion of regulatory T cells-are being actively investigated to improve rejection control and foster long-term tolerance. Both pregnancy and organ transplantation challenge the immune system to tolerate foreign antigens. Pregnancy achieves this through specialized placental barriers and regulatory immune adaptations, whereas transplantation relies on immunosuppression because natural tolerance is rare. Key concepts include immune regulation, the role of regulatory T cells, and emerging therapies targeting immune pathways. This review selectively compares these core mechanisms to clarify how lessons from each context can inform strategies for optimizing maternal health and long-term graft success.
Differential distribution of HLA-A, HLA-B, and HLA-DRB1 allele groups in Iranian pediatric and adult patients with acute lymphoblastic Leukemia: A Case-Control study.
Ghandehari F, Mirzaei F, Meri S … +2 more , Vojdani R, Kalantar K
Hum Immunol · 2026 Jun · PMID 42242099 · Publisher ↗
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Biological differences between pediatric and adult ALL suggest that inherited immunogenetic factors, such as HLA polymorphisms, may influence suscep...
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Biological differences between pediatric and adult ALL suggest that inherited immunogenetic factors, such as HLA polymorphisms, may influence susceptibility in an age-dependent manner. We evaluated associations between HLA-A, HLA-B, and HLA-DRB1 allele groups and ALL among pediatric and adult populations in Iran. This case-control study included 383 ALL patients and 379 age- and sex-matched healthy controls, stratified into pediatric (125 cases, 122 controls) and adult (258 cases, 257 controls) groups. HLA typing was performed by low-resolution SSP-PCR. In the pediatric cohort, HLA-A*11 was more frequent in controls than cases (15.16% vs 9.2%; p = 0.04), suggesting a possible protective association, while HLA-B*14 was increased in cases (5.6% vs 1.64%; p = 0.028), indicating potential susceptibility. In the adult cohort, HLA-A*26 (7.2% vs 3.49%; p = 0.008) and HLA-B*41 (4.67% vs 1.55%; p = 0.004) were more frequent in controls, indicating protective associations, whereas HLA-B*57 was more frequent in cases (2.33% vs 0.58%; p = 0.034), suggesting increased risk. In the pooled analysis, HLA-A*11 was more frequent in controls than cases (13.32% vs 9.79%; p = 0.031), suggesting a possible protective association. HLA-A*26 (7.12% vs 3.79%; p = 0.004) and HLA-B*55 (3.56% vs 1.44%; p = 0.008) were more frequent in controls, indicating protective associations. Conversely, HLA-A*24 (12.4% vs 16.84%; p = 0.014), HLA-B*57 (0.66% vs 1.96%; p = 0.026), were increased in cases, indicating risk allele groups. A*01-B*35-DRB1*11 haplotype was enriched in patients, while A*02-B*18-DRB1*11 and A*33-B*18-DRB1*11 were more frequent in controls.. Also, a statistically significant borderline association was detected for HLA-DRB1*13 (4.88% vs 7.31%; p = 0.048). In conclusion, this study identified distinct distribution patterns of HLA allele groups between Iranian pediatric and adult ALL patients.
Comprehensive analysis of TNF-alpha gene polymorphism: a computational approach.
Gaba K, Pushkarna S, Malhotra P … +3 more , Kumar A, Suneja P, Dang AS
Hum Immunol · 2026 Jun · PMID 42242098 · Publisher ↗
BACKGROUND: TNF-alpha, a potent cytokine produced by immune cells, regulates inflammation and immune responses. Understanding the genetic variations in TNF-alpha gene nsSNP and regulatory SNPs within the UTRs can help in...
BACKGROUND: TNF-alpha, a potent cytokine produced by immune cells, regulates inflammation and immune responses. Understanding the genetic variations in TNF-alpha gene nsSNP and regulatory SNPs within the UTRs can help in elucidating the mechanisms of disease pathogenesis. OBJECTIVE: Present study involved a comprehensive analysis of the TNF-alpha gene to identify deleterious SNPs within its UTR and coding region. METHODS: TNF alpha gene's SNPs data were retrieved from dbSNP and subsequently evaluated using various in-silico tools to predict their pathogenic effects. RESULTS: A total of 2262 SNPs evaluated, three substitutions were consistently predicted to be deleterious and were mapped to evolutionarily conserved residues with significant effects on protein structure. Analysis of UTR variants identified 13 pathogenic SNPs, which showed potential to disrupt transcription factor binding sites and protein binding sites, thereby exerting significant regulatory effects on TNF-alpha expression. CONCLUSION: This study provides comprehensive computational evidence that both coding and regulatory SNPs of TNF-alpha gene may have significant functional implications, influencing protein structure and gene regulation. Only a handful of SNPs have been explored extensively; however, others are completely neglected. Research focusing on other identified potentially pathogenic variants is required to comprehend the impact of TNF-alpha gene on various diseases.
Assay-dependent discordance in detecting a rare HLA-DPB1 allele: long-range PCR vs. hybrid capture NGS.
Rozar K, Cano P, Verma D … +2 more , Wendel J, Iozzino C
Hum Immunol · 2026 May · PMID 42214264 · Publisher ↗
Next-generation sequencing (NGS) has become fundamental to high-resolution HLA typing, but methodological differences between long-range PCR (LR PCR) and hybrid capture (HC) approaches can lead to discrepant results. Thi...
Next-generation sequencing (NGS) has become fundamental to high-resolution HLA typing, but methodological differences between long-range PCR (LR PCR) and hybrid capture (HC) approaches can lead to discrepant results. This study examined cases where an allele identified as DPB1*13:01 by LR PCR was assigned DPB1*107:01 by HC. This discordance was attributed to both primer-site mutations and incomplete coverage of non-coding regions in LR PCR, resulting in allele dropout and preferential amplification. Conversely, typing by HC captures full genomic regions and minimizes PCR-generated errors, enabling accurate allele assignment. Findings indicate that DPB1*107:01 may be more prevalent than current CIWD classifications suggest, while broader implications include the need for proficiency testing programs to incorporate method-specific grading criteria that reflect the diversity of available typing technologies. This study underscores the importance of comprehensive genomic coverage for accurate HLA typing and supports the expanded adoption of HC-based sequencing in clinical laboratories.
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