Human Immunology[JOURNAL]
Sun
200 papers
Identification of a novel multi epitope vaccine against human herpes virus 7 (HHV-7) to combat CNS disorders in children and adolescents using subtractive proteomics and immunoinformatic approaches.
Naveed M, Ali A, Aziz T … +7 more , Ali N, Asim M, El Hadi Mohamed RA, Al-Hoshani N, Alwethaynani MS, Sagini HA, Alkhatib SN
Hum Immunol · 2026 May · PMID 41905024 · Publisher ↗
Human herpesvirus 7 (HHV-7) is a very common pathogen associated with neurological and systemic disorders, particularly in children and adolescents. Although it has a wide range and a heavy disease burden across the glob...
Human herpesvirus 7 (HHV-7) is a very common pathogen associated with neurological and systemic disorders, particularly in children and adolescents. Although it has a wide range and a heavy disease burden across the globe, there has been no generation of a vaccine against HHV-7. Antivirals currently present are very limited in their application because of toxicity and inefficacy in targeting latent infections. Here, we report a study that will create a new multiepitope vaccine against HHV-7 using immunoinformatics approaches. A computational pipeline was adapted to design a multiepitope vaccine targeting three transmembrane glycoproteins (Envelope Glycoprotein B, Envelope Glycoprotein M, and U21 Glycoprotein) selected because of their antigenicity, non-allergenicity, and non-toxicity. B-cell and T-cell epitopes were identified, and a vaccine construct was assembled using adjuvants and linkers. Molecular docking and molecular dynamics (MD) simulations were used to evaluate the stability of the vaccine construct during its interaction with immune receptors. Immune simulations estimated the elicited humoral and cellular responses, whereas population coverage analysis ensured global applicability. The study construct showed a very high degree of antigenicity and stability with about 85 % population coverage. Molecular docking studies showed very high-grade interactions between the vaccine and the immune receptors, with HLA-B showing the most stable complex. The MD simulation studies showed that the vaccine maintained its shape throughout the study in spite of time, maintaining stable Root Mean Square Deviation (RMSD) and compact Radius of Gyration (Rg) values for over 100 ns. Immune simulations highlighted robust IgG1 responses, memory cell formation, and a Th1-biased cytokine profile, including high levels of IFN-γ and IL-2. These results indicate that the vaccine has the potential to elicit long-term immunity. This in silico research has come up with a multiepitope vaccine candidate for HHV-7 that appears very promising because of the immune response it has the potential to elicit, structural stability, and significantly broader population coverage. Compared to earlier studies, this includes a lot of MD simulations and immune profiling to substantiate the efficacy of the vaccine. Future in vitro and in vivo experimental studies will be required to validate these computational findings and to assess the biological efficacy and safety of the proposed vaccine candidate.
Characterization of an inherited HLA-B gene deletion in a candidate for hematopoietic cell transplantation.
Chi L, Blackburn PR, Siskar AN … +5 more , Wirtz C, Edwards J, Bullard K, Beck C, Arnold PY
Hum Immunol · 2026 May · PMID 41905023 · Publisher ↗
Accurate high-resolution genotyping of HLA genes for hematopoietic cell transplant (HCT) recipients provides critical information for matching and donor selection. We describe unusual family typing for a pediatric transp...
Accurate high-resolution genotyping of HLA genes for hematopoietic cell transplant (HCT) recipients provides critical information for matching and donor selection. We describe unusual family typing for a pediatric transplant candidate which revealed that the patient and mother did not share a common HLA-B allele, although all other class I and class II HLA alleles inherited on the maternal haplotype were detected. Copy number analysis of hybrid capture next generation sequencing data showed 2 copies each of HLA-A, C, MICA, MICB, DRB1, DQA1, DQB1, DPA1, and DPB1, but revealed HLA-B allele hemizygosity in both the patient and mother. Binary alignment mapping to the HLA-B consensus sequence showed a drop in coverage in the 5' untranslated region, approximately 300 base pairs upstream of exon 1. Germline whole genome sequencing performed on DNA from a skin punch biopsy from the patient confirmed an ∼ 85 kb deletion spanning the entire HLA-B gene locus. This case highlights the importance of family/haplotype studies and copy number analysis in workup for HCT and suggests that HLA locus deletions, although rare, may be underappreciated. Furthermore, haplotypes with deleted alleles may not be accurately reflected in population frequencies and donor search algorithms.
Next-Generation regulatory T cell therapies: Translational considerations for inflammatory bowel disease.
Gonzalez MM, Kim GB, Maharlooei MK … +4 more , Nikhat S, Hamdan FH, Gustafson MP, Faubion WA
Hum Immunol · 2026 May · PMID 41881906 · Publisher ↗
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Association between ADAM33 gene polymorphisms and asthma in the Zhuang population of China.
Qin ZM, Huang XM, Wei X … +2 more , He ZY, Deng JM
Hum Immunol · 2026 May · PMID 41865645 · Publisher ↗
OBJECTIVE: To explore the potential association between five single nucleotide polymorphisms (SNPs) (rs44707, rs612709, rs598418, rs2280089, and rs574174) in the ADAM33 gene and asthma susceptibility in the Zhuang popula...
OBJECTIVE: To explore the potential association between five single nucleotide polymorphisms (SNPs) (rs44707, rs612709, rs598418, rs2280089, and rs574174) in the ADAM33 gene and asthma susceptibility in the Zhuang population of Guangxi, China. METHODS: A single-center case-control study was conducted involving 155 asthma patients and 106 healthy controls. Genotyping of the five ADAM33 SNPs were performed using multiplex PCR capture and next-generation sequencing. Association analyses of genotype, allele, and haplotype distributions were conducted, with adjustments for potential confounding factors (age, sex, height, and weight) and Bonferroni correction for multiple testing. Hardy-Weinberg equilibrium (HWE) was verified in the control group to assess population representativeness. RESULTS: The genotype distributions of all five SNPs in the control group were consistent with HWE (P > 0.05). Before covariate adjustment, significant differences were observed between the case and control groups in the genotype and allele frequencies of rs44707 (genotype: χ = 7.180, P = 0.028; allele: χ = 5.344, P = 0.021), rs612709 (genotype: χ = 6.548, P = 0.029; allele: χ = 7.060, P = 0.008), and rs598418 (genotype: χ = 8.750, P = 0.013; allele: χ = 7.607, P = 0.006). No significant differences were found in the genotype or allele frequencies of rs2280089 and rs574174 between the two groups (P > 0.05). After adjusting for covariates, multiple genetic models (allele, homozygous, recessive) of rs44707, rs612709, and rs598418 still showed significant associations with asthma (P < 0.05). After Bonferroni correction, allele frequency differences retained significance for rs612709 (P = 0.040) and rs598418 (P = 0.030), but not for rs44707 (genotype P = 0.140; allele P = 0.105). Haplotype analysis revealed that the frequency of the GGGGC haplotype was significantly higher in the case group than in the control group (χ = 6.177, OR = 1.603, 95 % CI: 1.104-2.329, P = 0.013), but this significance was not retained after Bonferroni correction (P = 0.065). CONCLUSION: This study provides preliminary evidence that rs44707, rs612709, and rs598418 in the ADAM33 gene may be associated with asthma susceptibility in the Zhuang population of Guangxi. The GGGGC haplotype shows a trend of potential association with increased asthma risk, but this finding requires further verification. Given limitations of single-center design, small sample size, these observations require cautious interpretation. Larger multi-center studies with stratified cohorts and functional validation are needed to confirm the role of ADAM33 genetic variants in asthma among this ethnic group.
Beyond HLA: An adaptive nanopore sequencing assay for simultaneous HLA and blood group profiling in transplantation.
Grasedieck S, McIntyre L, Roulis E … +5 more , Hamadeh Z, Murphey C, Lane WJ, Keown PA, Sherwood KR
Hum Immunol · 2026 May · PMID 41831333 · Publisher ↗
AIM: Transplantation is a life-saving therapy but carries significant risks, including rejection, graft-versus-host disease, infection, and malignancy, which can lead to graft failure and death. These complications arise...
AIM: Transplantation is a life-saving therapy but carries significant risks, including rejection, graft-versus-host disease, infection, and malignancy, which can lead to graft failure and death. These complications arise from the interaction between the recipient's immune system and the transplanted organ, requiring long-term toxic drugs to prevent immune injury. Traditional genetic pre-transplant assessment focuses on ABO and 11 human leukocyte antigen (HLA) genes, but advancing technologies now allow for the assessment of many more genes relevant to transplant success. METHODS: Using Oxford Nanopore Technology's (ONT) adaptive sampling approach, we have built a comprehensive proof-of-principle test to preemptively profile blood group and HLA phenotypes at the DNA sequence and methylation level. This test does not require preamplification, enrichment or enzymatic conversion, and can be easily adapted to enrich up to 10 % of the human genome, including the complete HLA locus (5.5 Mb) and all currently listed International Society of Blood Transfusion (ISBT) blood group genes. RESULTS: This rapid all-in-one test currently achieves up to 370x (median 250x) region of interest coverage at a 4-day turnaround and a data quality that is suitable for blood group and HLA genotyping, which matched or outperformed gold standard assays. CONCLUSIONS: As a field, we have dramatically reduced early post-transplant immune injury using molecular diagnostics and structural biology. Here, we demonstrate proof-of-concept of a personalized transplant risk assessment, which can be adapted to profile additional genes or genomic regions within minutes and yields multi-genic typing data at a 4-day turnaround. This approach represents the next step in refining precision medicine, improving patient outcomes, reducing healthcare costs, and enhancing life quality for transplant recipients.
Assessing the reliability of the PAK-LX HLA Class I bead in platelet transfusion compatibility testing.
Enten H, Liacini A, Janes D … +3 more , Stedem R, Gaule L, Berka N
Hum Immunol · 2026 May · PMID 41825092 · Publisher ↗
PURPOSE: PAK-LX, a Luminex-based assay for detecting platelet-specific glycoproteins and HLA class I antibodies, has shown limited reliability for HLA immunization. A prior study reported a 37% discrepancy compared to th...
PURPOSE: PAK-LX, a Luminex-based assay for detecting platelet-specific glycoproteins and HLA class I antibodies, has shown limited reliability for HLA immunization. A prior study reported a 37% discrepancy compared to the single antigen bead (SAB) assay. The current study expands the cohort size to further investigate this discrepancy and uncover patterns that may explain the divergence. METHODS: A total of 137 individuals from two American Red Cross Histocompatibility laboratories (Charlotte, NC and Portland, OR) were screened using both PAK-LX (Werfen, Inc) and SAB (ThermoFisher, Inc). Data included demographics, antibody positivity, discordance rates, mean fluorescence intensity (MFI), and calculated panel reactive antibody (cPRA). RESULTS: SAB detected HLA class I antibodies in 73% of participants; 36% showed discordance, with 98% being PAK-LX false negatives. Mean cPRA among discordant cases was 29% (range: 2-96%). Missed antibodies had MFIs typically below 6,000 but ranged from 2,000 to 19,000. CONCLUSION: PAK-LX demonstrates reduced sensitivity for the detection of HLA class I antibodies compared with single-antigen bead (SAB) assays and may fail to identify HLA alloantibodies implicated in immune-mediated platelet transfusion refractoriness. Accordingly, PAK-LX should not be used as a standalone screening assay, and confirmatory testing with SAB is recommended when immune-mediated platelet refractoriness is suspected.
Association between IL-17A (rs2275913), IL-4 (rs2070874), NLRP3 (rs10754558) polymorphisms and COVID-19 in a cohort of professionals who worked in the first pandemic wave.
Silva Vieira MCD, Marcelino BDR, Abrahão Silva MJ … +4 more , Sardinha DM, Sousa Bispo SK, Gondim Costa Lima LN, Batista Lima KV
Hum Immunol · 2026 May · PMID 41812550 · Publisher ↗
INTRODUCTION: Host genetic polymorphisms in inflammatory mediators may influence COVID-19 clinical outcomes. This study investigated associations between IL-17A (rs2275913), IL-4 (rs2070874), and NLRP3 (rs10754558) polym...
INTRODUCTION: Host genetic polymorphisms in inflammatory mediators may influence COVID-19 clinical outcomes. This study investigated associations between IL-17A (rs2275913), IL-4 (rs2070874), and NLRP3 (rs10754558) polymorphisms and COVID-19 presentation in professionals exposed during the first pandemic wave in the Brazilian Amazon. METHODS: A total of 189 participants were classified as asymptomatic (AS) or symptomatic (SI), with symptomatic individuals further stratified according to pulmonary involvement assessed by chest computed tomography. Genotyping was performed using PCR and Sanger sequencing. Associations were evaluated through bivariate analyses and multivariate logistic regression adjusted for age, sex, comorbidities, and occupational exposure. RESULTS: In bivariate analyses, the G/G genotype and G allele of rs2275913 (IL-17A) were significantly more frequent among individuals with pulmonary involvement. However, this association did not remain statistically significant after multivariate adjustment. No significant associations were observed for IL-4 or NLRP3 polymorphisms. Age and comorbidities were associated with severity in subgroup analyses, and comorbidities showed a biological trend toward increased symptomatic risk, but these variables were not independently associated in adjusted models. CONCLUSIONS: The rs2275913 polymorphism in IL-17A may contribute to pulmonary involvement in COVID-19; however, the absence of independent significance in multivariate analysis and sample size limitations indicate that these findings should be considered exploratory. Larger, well-powered studies are required to clarify the role of host genetic variation in COVID-19 severity.
Pre-existing influenza antibodies, younger age, and increased CD4 T predict influenza vaccination responses in transplant recipients.
Rollenhagen C, Parvathinathan G, Stedman MR … +9 more , Chalasani G, Birdwell KA, Sanders ML, Ramkumar M, Higdon LE, Ye N, Santos JJS, Hensley SE, Maltzman JS
Hum Immunol · 2026 May · PMID 41812549 · Full text
Recipients of kidney transplants require lifelong immunosuppression therapy which is associated with a reduced response to vaccinations. We conducted a longitudinal study of influenza vaccination in US Veteran kidney tra...
Recipients of kidney transplants require lifelong immunosuppression therapy which is associated with a reduced response to vaccinations. We conducted a longitudinal study of influenza vaccination in US Veteran kidney transplant recipients and correlated demographic factors and T cell characteristics to the immunological outcome of the vaccination. Our data suggest that a consistent history of annual vaccination during the 3 years prior is linked to an increase in influenza antibodies prior to vaccination. High influenza titers post-vaccination are associated with younger age, increased CD4 T cells and pre-existing anti-influenza IgG levels but no association of CMV serostatus or immunologically aged T cells was detected. Thus, preexisting IgG antibodies, age, and CD4 T cells could serve as predictors for the successful influenza vaccination in this at-risk population informing targeted interventions to improve vaccine responses, prevent infections, and reduce influenza-associated comorbidities.
FALSE POSITIVE REACTION AGAINST 73ID EPLET IN SINGLE ANTIGEN BEAD ASSAY.
Noronha IH, Gebarse-DeLima M, Bottino LZMF … +3 more , Lima ACM, Fantini R, de Marco R
Hum Immunol · 2026 May · PMID 41797096 · Publisher ↗
The purpose of this study was to investigate possible false-positive reactions against HLA-A*31:01, -A*33:01, and -A*33:03 beads in One Lambda single antigen bead assay (OL-SAB) solely explained by the 73ID eplet (73ID p...
The purpose of this study was to investigate possible false-positive reactions against HLA-A*31:01, -A*33:01, and -A*33:03 beads in One Lambda single antigen bead assay (OL-SAB) solely explained by the 73ID eplet (73ID profile). As this eplet is also present in A*02:11, not represented in the OL-SAB panel, the reactivity with HLA-A31, -A33 has been used as surrogate for A*02:11 antibodies. The study included sera from seven patients with the 73ID profile that were tested with untreated and acid-treated OL-SAB, adsorption/elution (A/E) experiment and flow cytometry crossmatch (FCXM). The results showed increased MFI in acid treated beads, lack of antibody recovery in A/E assays, negative FCXM with all cells. These data indicate that the 73ID eplet is only accessible in denatured HLA molecules. Therefore, the reactivities solely against HLA-A31, -A33 in the OL-SAB are likely false-positive and are not reliable surrogate markers for A*02:11 antibodies.
Association of IL4 and IL17A genetic polymorphisms with COVID-19 severity in a southern Brazilian population.
Drehmer MN, Castro GV, Lazzari DD … +9 more , Pinto Guimarães LS, Sortica VA, Possuelo LG, Moura Valim AR, Costa GSD, Gambin I, Genro JP, Netto Muniz YC, Lindenau JD
Hum Immunol · 2026 May · PMID 41797095 · Publisher ↗
COVID-19 has demonstrated marked differences in clinical manifestations and outcomes, with severe cases presenting excessive inflammatory responses known as cytokine storms. Polymorphisms in cytokine genes, such as inter...
COVID-19 has demonstrated marked differences in clinical manifestations and outcomes, with severe cases presenting excessive inflammatory responses known as cytokine storms. Polymorphisms in cytokine genes, such as interleukin-4 (IL4) and interleukin-17A (IL17A), may influence immune responses and contribute to disease severity. This study investigated the association between the IL4 -34C/T and IL17A -197G/A polymorphisms and COVID-19 severity in a population from Southern Brazil. A total of 528 individuals were included, with 157 severe and 371 mild cases. DNA was extracted from buccal swabs and blood samples, and genotyping was performed using TaqMan assays. Associations were assessed using univariate and multivariate logistic regression analyses, adjusted for confounders. The IL4 -34C/T TT genotype was significantly associated with a reduced risk of severe COVID-19 (OR = 0.33, P = 0.036), suggesting a protective role. This polymorphism was also linked to dysgeusia and anosmia (PR = 1.46, P = 0.020), symptoms more common in mild cases. Conversely, the IL-17A -197G/A GG genotype was associated with increased risk of severe disease (OR = 2.66, P = 0.028) and respiratory symptoms (PR = 1.27, P = 0.048). These findings highlight the role of IL4 and IL17A polymorphisms in modulating COVID-19 severity and clinical presentation, underscoring the complexity of immune responses to SARS-CoV-2.
Sex-specific and tissue-resolved interpretation is mandatory for X-linked immune gene association studies.
Ural Z
Hum Immunol · 2026 May · PMID 41795478 · Publisher ↗
Abstract loading — click title to view on PubMed.
Susceptibility associations of HLA class II gene polymorphisms in oral submucous fibrosis derived oral squamous cell carcinoma.
Tan Y, Xiao Y, Huang X … +5 more , Liu M, You C, Ye Y, Tan J, Hu C
Hum Immunol · 2026 Apr · PMID 41785825 · Publisher ↗
OBJECTIVE: This study aimed to explore associations between human leukocyte antigen (HLA) class II (DRB1, DQB1, DPB1) alleles and haplotypes and susceptibility to oral submucous fibrosis (OSF) and its progression to oral...
OBJECTIVE: This study aimed to explore associations between human leukocyte antigen (HLA) class II (DRB1, DQB1, DPB1) alleles and haplotypes and susceptibility to oral submucous fibrosis (OSF) and its progression to oral squamous cell carcinoma (OSCC). METHODS: 54 OSF-derived OSCC patients, 53 OSF patients, and 56 healthy controls were enrolled. HLA class II genes were typed using polymerase chain reaction-sequence-specific primers (PCR-SSP). Allele and haplotype frequencies, as well as linkage disequilibrium (LD), were calculated. Allele and haplotype frequencies, as well as relative risks across groups, were compared. RESULTS: 4 HLA class II alleles and 5 haplotypes were identified as associated with altered risks of OSCC and OSF. Compared to the controls, OSCC patients had lower frequencies of DPB1*02, DPB1*04, DPB1*05, DRB1*16-DPB1*02, and DRB1*16-DPB1*05, notably reducing the risk of OSCC (all OR < 1, P < 0.05), and a higher frequency of DRB1*14-DPB1*02, significantly increasing the risk of OSCC (OR > 1, P < 0.05). OSF patients had a higher frequency of DRB1*10, which was positively associated with OSF (OR > 1, P < 0.05). Compared to OSF patients, OSCC had lower frequencies of DRB1*10, DPB1*02, DPB1*04, and DPB1*05, showing a negative correlation with OSCC risk (all OR < 1, P < 0.05), and higher frequencies of DRB1*11-DQB1*06 and DRB1*14-DPB1*02, noticeably increasing the risk of OSCC (all OR > 1, P < 0.05). CONCLUSIONS: This study suggests potential associations: HLA-DRB1*10, DPB1*02, DPB1*04, DPB1*05, DRB1*16-DPB1*02, and DRB1*16-DPB1*05 could potentially exert a protective effect against OSF-derived OSCC. In contrast, DRB1*14-DPB1*02 significantly increases the risk of OSCC, whereas DRB1*11-DQB1*06 and DRB1*14-DPB1*02 may promote progression from OSF to OSCC. Additionally, DRB1*10 is a potential susceptibility gene for OSF but may also inhibit progression from OSF to OSCC.
Roles of full-length and Δα1 HLA-G isoforms in NK-cell regulation and vascular SARS-CoV-2 infection.
Schiuma G, Roux DT, Beltrami S … +10 more , Ferraresi M, Pezzi G, Strazzabosco G, Gentili V, Passaro A, Molina JMS, Baroni M, Bortolotti D, Carosella ED, Rizzo R
Hum Immunol · 2026 Apr · PMID 41764826 · Publisher ↗
Human Leukocyte Antigen-G (HLA-G) is a key immunomodulatory molecule with multiple isoforms, including recently identified variants lacking the α1 domain (HLA-G Δα1). The absence of the α1 domain may reduce immune inhibi...
Human Leukocyte Antigen-G (HLA-G) is a key immunomodulatory molecule with multiple isoforms, including recently identified variants lacking the α1 domain (HLA-G Δα1). The absence of the α1 domain may reduce immune inhibition, particularly of Natural Killer (NK) cells, which are often suppressed during viral infections such as SARS-CoV-2. This suggests a novel immune regulatory mechanism that could mitigate COVID-19-related complications, including coagulopathies. This study investigates the influence of full-length and Δα1 HLA-G isoforms in NK-cell activity in vitro during SARS-CoV-2 infection and whether their expression associates with viral persistence and coagulopathy in COVID-19 patients, using vascular specimens retrieved from surgical procedures. RCC7 cell lines engineered to express either the full-length or Δα1 form of HLA-G were infected with Omicron SARS-CoV-2 to assess NK cell-mediated cytotoxicity in a co-culture system. Contrary to full-length, Δα1 HLA-G only partially inhibited NK activation, allowing greater cytotoxicity and higher IFN-I/II expression. To evaluate clinical relevance, vascular tissues from coagulopathic COVID-19 patients were analyzed for in situ SARS-CoV-2 persistence and HLA-G isoform expression. SARS-CoV-2 negative tissues more frequently expressed Δα1 and displayed higher systemic interferon (IFNs) levels. Among infection-positive cases, Δα1 expression was also associated with stronger IFN-β and IFN-γ responses. These in vivo trends mirror in vitro findings, supporting a model in which full-length HLA-G dampens NK-mediated clearance of infected vascular cells, favoring viral persistence and potentially contributing to immunothrombosis, while Δα1 permits enhanced antiviral immunity. Overall, these findings identify distinct immunomodulatory roles for HLA-G isoforms in SARS-CoV-2 infection. The Δα1 variant exhibits reduced inhibitory potency, partially preserving NK-cell antiviral functions and modulating interferon responses, whereas full-length HLA-G may facilitate vascular viral persistence and coagulopathy. HLA-G isoform profiling may thus represent a novel biomarker and therapeutic target in COVID-19 associated vascular pathology.
Impact of NQO1, GSTM1 and GSTT1 genetic variants on susceptibility and relapse in childhood acute lymphoblastic leukemia.
Pereira NS, Fujita TC, Coral de Oliveira CE … +3 more , Trigo FC, Panis C, Amarante MK
Hum Immunol · 2026 Apr · PMID 41747561 · Publisher ↗
Acute lymphoblastic leukemia (ALL) is a multifactorial malignancy influenced by genetic and environmental factors. Polymorphisms in detoxification enzymes such as NQO1, GSTM1, and GSTT1 may modulate susceptibility and tr...
Acute lymphoblastic leukemia (ALL) is a multifactorial malignancy influenced by genetic and environmental factors. Polymorphisms in detoxification enzymes such as NQO1, GSTM1, and GSTT1 may modulate susceptibility and treatment response. This case-control study evaluated 74 children with ALL and 115 cancer-free controls from southern Brazil. Genomic DNA was analyzed for NQO1 rs1800566 (C609T) by PCR-RFLP and for GSTM1 and GSTT1 by multiplex PCR. Plasma glutathione (GSH) levels were measured spectrophotometrically. Genotype distributions were consistent with Hardy-Weinberg equilibrium. No significant associations were observed between NQO1 rs1800566, GSTM1, or GSTT1 polymorphisms and ALL susceptibility (CT genotype OR = 0.88, 95 % CI = 0.46-1.72, p = 0.74; GSTM1 null OR = 0.70; GSTT1 null OR = 1.12). However, the NQO1 T allele was linked to a lower relapse rate (p = 0.03), suggesting a potential protective role. Mean plasma GSH levels were higher in ALL patients (17.41 nmol/L) than in controls (12.16 nmol/L), though unrelated to genotype or outcome. Overall, NQO1, GSTM1, and GSTT1 variants were not associated with ALL risk, but the NQO1 rs1800566 polymorphism may influence relapse, possibly via altered quinone metabolism. Larger multiethnic studies integrating genetic and pharmacogenomic data are warranted to clarify their role in ALL pathogenesis.
Identification of HLA-DR linear antibody epitopes in transplant patient sera using a multiplexed peptide immunoassay.
Ameer M, Mehta DK, Cohen GS … +4 more , Kallarakal M, Bettinotti MP, Larman HB, Krummey SM
Hum Immunol · 2026 Apr · PMID 41740531 · Publisher ↗
Molecular mismatch analysis is increasingly used to assess donor-recipient compatibility in transplantation. We sought to determine if reactivity against continuous HLA-DR epitopes could be directly measured using a pept...
Molecular mismatch analysis is increasingly used to assess donor-recipient compatibility in transplantation. We sought to determine if reactivity against continuous HLA-DR epitopes could be directly measured using a peptide-based immunoassay. We used sequence and informatics analysis to identify putative short linear epitopes in two polymorphic regions surrounding amino acid (aa) position 30 and 70 of HLA-DRB1*07:01 and HLA-DRB1*08:01, respectively. We tested sera from patients who were HLA antibody negative, HLA class II antibody positive for irrelevant antigens, or positive for the HLA-DR7 or -DR8 antigen by Single Antigen Bead testing. Among HLA-DR7 reactive sera, we found that 9/18 (50%) were above a positive threshold for one or both peptide epitopes, while 7/19 (36%) sera were positive for at least one HLA-DR8 peptide epitopes. This proof-of-concept study demonstrates that short peptide targets can be used to identify HLA antibody reactivity, which could be used to directly interrogate HLA epitope-level humoral alloimmunity.
Immunological functions of Th17 Cells in colon cancer: From pathogenic mechanisms to emerging treatments.
Abuhassan Q, Atoom AM, Rekha MM … +5 more , Kanwar JB, Bavanilatha M, Arora V, Sinha A, Khazratov A
Hum Immunol · 2026 Apr · PMID 41740530 · Publisher ↗
Colon cancer (CC) constitutes a significant global health challenge, characterized by increasing incidence and mortality rates that underscore the necessity for continued investigative efforts. Inflammation-driven cellul...
Colon cancer (CC) constitutes a significant global health challenge, characterized by increasing incidence and mortality rates that underscore the necessity for continued investigative efforts. Inflammation-driven cellular and molecular processes are fundamentally implicated in the CC development, progression and pathogenesis. Among these immune effectors, T helper 17 (Th17) cells, a distinct subset of CD4 T lymphocytes, are integral to inflammatory and autoimmune responses and modulate antitumor immunity. In CC, Th17 cells exhibit a dualistic function; they may promote tumorigenesis by sustaining chronic inflammation or exert antitumor effects by enhancing cytotoxic immune response. Notably, critical gaps persist in understanding how Th17 plasticity dynamically governs the balance between immune surveillance and tumor immune evasion, representing a central unresolved controversy in CC progression. Furthermore, while extensive research has shown that Th17 cells interact with the tumor microenvironment (TME) and cancer stem cells (CSCs), the specific mechanisms behind these interactions that facilitate metastasis, invasion, and cellular proliferation are still not fully understood. Several studies have documented an increased proportion of Th17 cells in the peripheral circulation of CC patients. However, conflicting clinical evidence regarding their prognostic significance highlights a major translational challenge for patient stratification and targeted intervention. This review consolidates novel perspectives on the multifaceted contributions of Th17 to CC initiation, progression, and therapy, emphasizing targeted interventions to disrupt inflammatory axes and improve outcomes.
Revisiting HLA-G in solid organ transplantation: Mechanistic insights and translational advances.
Ajith A, Mulloy LL, Gani I … +4 more , Jayaprasad AG, Sreekumar A, Horuzsko DD, Horuzsko A
Hum Immunol · 2026 Apr · PMID 41724096 · Publisher ↗
Human leukocyte antigen-G (HLA-G) is a non-classical MHC class I molecule with potent immunoregulatory functions that plays a central role in promoting allograft acceptance. Unlike classical HLA molecules, HLA-G displays...
Human leukocyte antigen-G (HLA-G) is a non-classical MHC class I molecule with potent immunoregulatory functions that plays a central role in promoting allograft acceptance. Unlike classical HLA molecules, HLA-G displays limited polymorphism, restricted tissue distribution, and strong inhibitory signaling through receptors such as ILT-2, ILT-4, and KIR2DL4 on T cells, NK cells, B cells, dendritic cells, and myeloid populations. Across kidney, liver, heart, and lung transplantation, increased HLA-G expression-whether membrane-bound or soluble-consistently correlates with reduced acute rejection, lower alloimmune activation, and enhanced long-term graft survival. Recent multi-omics, structural, and mechanistic studies have expanded the HLA-G landscape by identifying alternative isoforms, including HLA-GΔα1 a naturally occurring variant lacking the α1 domain. Emerging evidence suggests that HLA-GΔα1 retains partial receptor-binding capacity and may uniquely modulate myeloid and regulatory cell networks. Therapeutic interest in HLA-G has rapidly grown, including in synthetic α3-domain peptides, recombinant HLA-G proteins, and HLA-G-expressing mesenchymal stem cell platforms that induce durable operational tolerance in preclinical models. This review synthesizes recent advances in HLA-G biology, its clinical relevance in solid organ transplantation, the evolving understanding of HLA-GΔα1 isoforms, and the translational strategies targeting this pathway to achieve stable, rejection-free graft function.
Imputing HLA-G high-resolution alleles and regulatory haplotypes from exomes and SNP array data.
Barbosa RM, Brito Silva NDS, Meyer D … +4 more , Bourguiba-Hachemi S, Donadi EA, Vince N, Castelli EC
Hum Immunol · 2026 Apr · PMID 41724095 · Publisher ↗
HLA-G encodes an immune checkpoint molecule with restricted expression in immune-privileged tissues and pathological conditions. It exhibits limited coding diversity but substantial regulatory-region variation influencin...
HLA-G encodes an immune checkpoint molecule with restricted expression in immune-privileged tissues and pathological conditions. It exhibits limited coding diversity but substantial regulatory-region variation influencing expression levels. Strong linkage disequilibrium across HLA-G creates a structured genetic architecture in which regulatory and coding variants co-segregate into well-defined haplotypes, enabling the imputation of complete HLA-G haplotypes from partial genomic data. We developed imputation models to predict HLA-G 4-field alleles, promoter, and 3'UTR haplotypes from whole-exome sequencing and SNP array data using HIBAG. Multi-ethnic reference panels were constructed from 5,347 individuals from three diverse cohorts (1000 Genomes, Human Genome Diversity Project, and Brazilian SABE cohort). Models were validated through cross-validation and independent datasets. Exome-based imputation achieved high accuracy (>99%) for common alleles (frequency > 1%), with mean posterior probabilities exceeding 0.95. SNP array-based models showed slightly lower but still robust performance (>95% accuracy). Our approach enables simultaneous prediction of coding and regulatory sequences, providing comprehensive functional information from datasets that do not capture the complete HLA-G diversity. These models facilitate HLA-G analysis in widely available genomic datasets lacking introns and regulatory regions (tumor exomes, SNP arrays), enabling investigation of HLA-G's role in immune regulation, transplantation, cancer, and pregnancy complications without full-gene sequencing.
The immunosuppressive role of HLA-G extracellular vesicles in bone marrow of infiltrating tumors: the lesson learned from neuroblastoma and multiple myeloma.
Airoldi I, Soncini D, Marimpietri D … +2 more , Cea M, Morandi F
Hum Immunol · 2026 Apr · PMID 41713114 · Publisher ↗
It is now clearly established that extracellular vesicles (EV)s represent important players in the regulation of bone marrow (BM) microenvironment during cancer progression, and anti-tumor responses. Indeed, healthy cell...
It is now clearly established that extracellular vesicles (EV)s represent important players in the regulation of bone marrow (BM) microenvironment during cancer progression, and anti-tumor responses. Indeed, healthy cells and neoplastic cells crosstalk through a dynamic transfer of extracellular vesicles in the tumor microenvironment including the BM. The mechanisms underlying reflect the peculiar features of EVs that carry bioactive cargo like proteins and non-coding RNAs on short and long distance to reprogram tumor microenvironment and modulate the immune response. In this context, we and others reported that tumor-derived EVs are equipped on the surface with immune-checkpoint and immunosuppressive molecules such as HLA-G. These EVs are often associated with disease progression, tumor metastases, and poor clinical outcome and their role in neuroblastoma (NB) and multiple myeloma (MM) is here reported. Although NB and MM are very different tumors in terms of origin and age of diagnosis, they share the common feature that grow up into the BM causing a dysregulation of the BM microenvironment. EVs take part in this process.
Single-cell transcriptomics reveals targeted modulation of inflammatory repertoire by SOCE blockers.
Stephanou A, Mantri M, Shankaranarayanan D … +9 more , Li C, Lagman M, Xiang J, Pan C, Sun Y, Muthukumar T, Machaca K, De Vlaminck I, Suthanthiran M
Hum Immunol · 2026 Apr · PMID 41690207 · Publisher ↗
Store-operated calcium entry (SOCE) plays a critical role in regulating intracellular calcium signaling and is essential for immune cell functions. SOCE blockade with the pyrazole derivative BTP2 has been explored as an...
Store-operated calcium entry (SOCE) plays a critical role in regulating intracellular calcium signaling and is essential for immune cell functions. SOCE blockade with the pyrazole derivative BTP2 has been explored as an anti-inflammatory strategy in preclinical models, and Zegocractin (CM4620) is under clinical investigation as a CRAC channel inhibitor with activity in multiple tissues, including immune cells. However, the cell type-specific consequences of SOCE blockade under defined activation contexts remain incompletely understood. Here, we used multiplexed single-cell RNA sequencing to investigate the effects of two prototypic SOCE blockers, BTP2 and CM4620, on polyclonally stimulated, normal human peripheral blood mononuclear cells (PBMCs) in a phytohemagglutinin (PHA)-driven T-cell activation model. The data revealed that SOCE blockade suppressed cytotoxicity-associated transcriptional programs in CD8 effector T cells and natural killer (NK) cells, restoring them to levels comparable to unstimulated cells. At the same time, SOCE blockade allowed CD4 regulatory T cells to retain transcriptional signatures associated with immune regulation. These results indicate that, in this experimental model, SOCE blockade dampens cytotoxic programs while maintaining tolerance signatures, suggesting a potential avenue for targeted immune modulation in transplantation and other immune-mediated conditions. SIGNIFICANCE STATEMENT: Store-operated calcium entry (SOCE) is essential for immune activation, but broad immunosuppression can cause significant side effects. Using single-cell transcriptomics in a phytohemagglutinin (PHA)-driven T-cell activation model, we show that SOCE blockade with BTP2 or CM4620 suppresses pro-inflammatory and cytotoxic programs in CD8 effector T cells and NK cells while preserving tolerance-associated pathways in CD4 regulatory T cells. These findings suggest that SOCE blockade may provide a more targeted form of immune modulation, warranting future head-to-head comparisons with conventional immunosuppressants. Our results highlight the potential of SOCE blockers to reduce immune-mediated damage while maintaining tolerance, motivating further functional and translational studies in transplantation and other immune-mediated conditions.
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