Human Immunology[JOURNAL]
Sun
200 papers
Reduced socs2 expression and elevated IL-4/IL-23 levels in multiple sclerosis patients: Implications for immune dysregulation.
Sedeño Monge V, Santos López G, Bautista Rodríguez E … +7 more , Rosas Murrieta NH, Hernández Reyes A, González Hernández MF, Rodríguez Rivera A, Madrazo Cabo JM, Benítez Salazar JM, Gallardo Pérez MM
Hum Immunol · 2026 Jul · PMID 42202484 · Publisher ↗
Multiple sclerosis (MS) is an autoimmune, chronic, and demyelinating disease of the central nervous system. Dysregulated cytokine signaling, particularly through the suppressor of cytokine signaling (SOCS) family, is imp...
Multiple sclerosis (MS) is an autoimmune, chronic, and demyelinating disease of the central nervous system. Dysregulated cytokine signaling, particularly through the suppressor of cytokine signaling (SOCS) family, is implicated in MS pathogenesis. This study evaluates the expression of SOCS genes, and plasma levels of interleukins IL-23 and IL-4 in patients with MS. Blood samples were collected from MS patients and controls, and expression of the CIS, SOCS2, SOCS4, and SOCS6 genes was analyzed by RT-qPCR, and cytokine levels of IL-23 and IL-4 were measured using ELISA. A significant reduction in SOCS2 expression was observed in MS patients compared to controls (p = 0.03), with SOCS2 showing the greatest downregulation among the SOCS genes analyzed (0.694-fold; p = 0.00002). In female patients, SOCS2 and CIS expression levels were reduced compared with healthy females (0.726- and 0.655-fold, respectively), with SOCS2 showing significance (p = 0.03). Plasma levels of IL-4 (2.69 pg/mL) and IL-23 (58 pg/mL) were significantly higher in MS patients than in controls (p = 0.02 and p = 0.04, respectively), with IL-23 levels markedly higher than IL-4 (p = 0.0001). These findings suggest that SOCS2 may modulate immune responses in MS and could represent a potential target for future therapeutic strategies.
Rare variants in inborn errors of immunity genes in young adults with severe COVID-19: Insights from a Brazilian cohort.
Barros de Oliveira Sá MV, Rocha GD, Silveira Oliveira PR … +24 more , Campos TL, Lisbôa Furtado GT, Galdino Galisa SL, Silva AS, Moura P, São Pedro RB, Tavares NM, Boaventura VS, Nunes S, Bonyek-Silva I, Caldas JR, Roma EH, Almeida JR, Silva AA, Baccin T, Castro AC, Rosario Vallinoto AC, da Silva R, Melo Dos Santos EJ, Garcia CC, Slhessarenko RD, Armstrong ADC, Carmo RF, Silva Vasconcelos LR
Hum Immunol · 2026 Jul · PMID 42190421 · Publisher ↗
BACKGROUND: Host genetic variability, particularly involving inborn errors of immunity (IEI), has emerged as a critical determinant of interindividual differences in COVID-19 severity, yet comprehensive genomic character...
BACKGROUND: Host genetic variability, particularly involving inborn errors of immunity (IEI), has emerged as a critical determinant of interindividual differences in COVID-19 severity, yet comprehensive genomic characterization of IEI-related variants in admixed Latin American populations remains scarce. OBJECTIVE: To characterize rare pathogenic variants in IEI-related genes among previously healthy young Brazilian adults with severe COVID-19 and to evaluate their association with clinical outcomes and genetic ancestry. METHODS: We performed whole-genome sequencing on 161 unrelated Brazilian adults aged 18-60 years, without comorbidities, who required intensive care unit admission for severe COVID-19 across six Brazilian states. A targeted analysis of 504 IEI-related genes, defined by the 2024 International Union of Immunological Societies (IUIS) classification, was conducted using a stringent variant filtering pipeline incorporating predicted functional impact, population rarity (minor allele frequency ≤ 0.01 in gnomAD v4.1 and the 1000 Genomes Project), Combined Annotation-Dependent Depletion (CADD) scores > 15, Gene Damage Index < 13.84, and pathogenicity classification according to American College of Medical Genetics and Genomics (ACMG) guidelines. Ancestry proportions were estimated using ADMIXTURE (K = 3). RESULTS: We identified 49 unique pathogenic or likely pathogenic (P/LP) variants across 37 IEI genes in 45 patients (27.9% of the cohort), comprising 21 pathogenic (42.9%) and 28 likely pathogenic (57.1%) variants. The most frequent molecular consequences were missense variants (n = 21, 42.9%), followed by frameshift (n = 10, 20.4%), stop-gained (n = 9, 18.4%), and splice-site variants (n = 8, 16.3%). Complement deficiencies constituted the largest IEI category (8 variants, 16.3%), followed by phagocyte defects and bone marrow failure (7 variants each, 14.3%). The most frequently affected gene was CFTR (n = 6 variants), and the PMS2 c.2186_2187del frameshift variant was shared among eight unrelated patients, representing the most recurrent variant in the cohort. Seven variants were entirely absent from gnomAD global and Americas databases, including novel variants in FANCA, MVK, TPP2, ELANE, TGFBR1, TCIRG1, and CARD9. Notably, the MVK c.658A > T nonsense variant was identified in two unrelated patients despite its complete absence from reference databases. Ancestry analysis revealed a tri-hybrid profile (European 60.5%, African 26.6%, Amerindian 13.0%), with no significant association between IEI variant carrier status and any ancestry component (all p > 0.6). Strikingly, IEI variant carriers exhibited significantly lower rates of circulatory shock (20.0% vs. 52.6%; OR = 0.23, 95% CI 0.10-0.51, p < 0.001) and acute respiratory distress syndrome (40.0% vs. 61.2%; OR = 0.42, 95% CI 0.21-0.85, p = 0.021) compared to non-carriers, alongside higher absolute lymphocyte counts (median 1,055 vs. 866 cells/mm, p = 0.024). In-hospital mortality did not differ significantly between groups (11.1% vs. 24.1%; OR = 0.39, 95% CI 0.14-1.09, p = 0.082). CONCLUSIONS: These findings demonstrate that rare IEI-related germline variants are present in a substantial proportion of previously healthy young adults with life-threatening COVID-19 and suggest that IEI-associated immune attenuation may modulate disease phenotype by dampening hyperinflammatory responses-potentially protecting against cytokine storm-driven complications while still predisposing to severe illness through impaired viral clearance. This study underscores the relevance of host immunogenetic profiling in admixed populations for understanding the pathophysiology of severe infectious diseases.
The role of the renal immune microenvironment in multisystem diseases.
Jiang X, Miao X
Hum Immunol · 2026 Jul · PMID 42166836 · Publisher ↗
BACKGROUND: Dysregulation of the renal immune microenvironment contributes to kidney pathology and also exerts widespread effects on multiple systems, including the intestinal, respiratory, cardiovascular, and nervous sy...
BACKGROUND: Dysregulation of the renal immune microenvironment contributes to kidney pathology and also exerts widespread effects on multiple systems, including the intestinal, respiratory, cardiovascular, and nervous systems, as well as tumors. Therefore, a deeper understanding of how the renal immune microenvironment influences multisystem disease progression is of great significance. METHODS: This review is based on relevant literature retrieved from databases including PubMed and Web of Science. It systematically summarizes and integrates research advances on the role of the renal immune microenvironment in multisystem diseases and its therapeutic targets. A narrative review approach was adopted, incorporating a broad range of experimental and clinical studies, without following the formal systematic review paradigm. RESULTS: When dysregulated, the renal immune microenvironment may serve as an important node in systemic inflammation, potentially contributing to disease progression across multiple organ axes. In the gut axis, inflammatory mediators have been associated with disrupt intestinal barrier integrity and microbiota homeostasis. In the lung axis, they may contribute to cytokine storms and mitochondrial signaling abnormalities. In the cardiac axis, systemic dissemination of pro-inflammatory mediators and macrophage lipid metabolic reprogramming may accelerate atherosclerosis and heart failure. In the brain axis, pathogenic mechanisms involve microglia-driven neuroinflammation as well as impaired clearance and toxic accumulation of pathogenic proteins. In the context of tumors, microenvironmental dysregulation may promote cancer progression through both systemic immunosuppression and local immune evasion. CONCLUSION: The renal immune microenvironment is not merely a passive reflector of systemic immunity but also an active participant in local and remote disease pathogenesis. Targeting its cellular and molecular components offers potential for treating both primary renal disorders and systemic immune-related conditions.
Genetic associations between asthma and type 2 inflammatory diseases: Insights from pleiotropic loci and genes: shared genetics of Type 2 Iinflammatory diseases: Shared Genetics of Type 2 Inflammatory Diseases.
Chen XR, Liu CT
Hum Immunol · 2026 Jul · PMID 42143449 · Publisher ↗
BACKGROUND: Type 2 inflammatory diseases (T2IDs) often coexist, but their shared genetic basis remains unclear. This study explores common genetic basis between asthma and other T2IDs and identifies pleiotropic loci and...
BACKGROUND: Type 2 inflammatory diseases (T2IDs) often coexist, but their shared genetic basis remains unclear. This study explores common genetic basis between asthma and other T2IDs and identifies pleiotropic loci and mechanisms. METHODS: Using genome-wide association study (GWAS) summary statistics, we assessed genetic correlation between asthma and four T2IDs (allergic conjunctivitis [AC], allergic rhinitis [AR], pollen allergy [PA], atopic dermatitis [AD]) via cross-trait pleiotropy analysis, followed by functional, tissue-specificity, and multi-trait colocalization analyses. RESULTS: Significant genetic correlations were detected in all four trait pairs. Pleiotropy analysis under the composite null hypothesis (PLACO) identified 21 pleiotropic loci, with 2 colocalized (PP.H4 > 0.75). Notable pleiotropic loci were identified, such as 4q24 (MANBA, UBE2D3, and CISD2) and 19q13.2 (SNRPA, RAB4B, MIA-RAB4B, and EGLN). MAGMA revealed 49 candidate pleiotropic genes involved in synaptic structure/function and cellular organization. Tissue enrichment analysis, stratified LD score regression (S-LDSC), and summary data-based Mendelian randomization (SMR) analysis revealed that pleiotropic mechanisms play significant roles in the brain, spleen, whole blood, and EBV-transformed lymphocytes. Hyprcoloc implicated distinct lymphocyte subtypes in shared mechanisms between asthma and AD. CONCLUSIONS: We identified shared genetic loci and gene sets between asthma and T2IDs, offering insights into genetic mechanisms and potential therapeutic targets.
The "next" standard for ABO genotyping.
Joseph A, Mah HH, Vege S … +6 more , Baronas J, Halls JBL, Stowell SR, Yeung MY, Westhoff CM, Lane WJ
Hum Immunol · 2026 Jul · PMID 42114190 · Publisher ↗
BACKGROUND: ABO histocompatibility plays a critical role in red blood cell (RBC) transfusions and is of great importance in solid organ and hematopoietic stem cell transplantation. ABO is primarily typed from red blood c...
BACKGROUND: ABO histocompatibility plays a critical role in red blood cell (RBC) transfusions and is of great importance in solid organ and hematopoietic stem cell transplantation. ABO is primarily typed from red blood cell samples using serological reagents. However, stem cell donors are often screened using buccal swabs which cannot be used for serologic testing. Furthermore, serologic testing can be complicated by recent transfusions, weak reactions, or unusual reaction patterns, which require resolution. ABO genotyping can help in these circumstances. Here we show the development and validation of a targeted Next Generation Sequencing (NGS) ABO genotyping assay and companion interpretive software. STUDY DESIGN AND METHODS: Short-read NGS was performed on 237 samples (blood n = 237 and buccal swab n = 42) obtained for routine transplant work-up testing and 10 samples with complex and rare ABO with previous reference laboratory workups. Three samples selected to represent common heterozygous ABO allele combinations underwent long-read sequencing as a proof of principle. All data was analyzed by our bloodTyper software. RESULTS: The targeted NGS results for the solid organ and stem cell donor sample set was 99.3% (n = 287/289) concordant with serology with the two discordants likely being due to an unrecognized A and natural tissue-specific chimerism. In the complex and rare ABO samples NGS improved characterization of the ABO gene and uncovered important changes not initially found in the previous workups. Long-read sequencing was able to fully phase the three samples tested. CONCLUSION: Through use of standard NGS protocols and automated interpretive software, targeted NGS allowed for reliable genotyping of ABO allele haplotypes without subject matter expert intervention. As such, targeted ABO NGS should become the standard for ABO genotyping.
From discovery to precision tolerance: Re-imagining patient-matched regulatory T cells in shaping of a roadmap for personalized immune re-balancing.
Ahmad S, Aftab MN, Aslam MS
Hum Immunol · 2026 Jul · PMID 42102540 · Publisher ↗
The recognition of FOXP3 as the master regulator of regulatory T cells (Tregs) established the genetic and functional basis for peripheral immune tolerance. Contemporary advances in single-cell genomics and epigenetic ma...
The recognition of FOXP3 as the master regulator of regulatory T cells (Tregs) established the genetic and functional basis for peripheral immune tolerance. Contemporary advances in single-cell genomics and epigenetic mapping have further refined this landscape, revealing distinct, tissue-adapted Treg subsets and identifying the Treg-specific demethylated region (TSDR) as the critical molecular marker for durable lineage stability. The transition toward personalized Treg medicine has become feasible through an integrated pipeline that maps individual cellular signatures and employs precision engineering. Transitioning to personalized Treg medicine requires an integrated pipeline combining antigen-specific CAR-Treg design, CRISPR-mediated epigenetic stabilization, and metabolic reprogramming. However, durable success hinges on navigating biological and translational hurdles, including lineage plasticity, receptor-driven exhaustion, and manufacturing bottlenecks. By integrating real-time TSDR monitoring and inducible safety switches like iCasp9, this framework translates mechanistic insights into context-matched, precision interventions. This roadmap provides a definitive strategy for restoring immune balance in autoimmunity and transplantation while addressing the complex constraints of modern living-cell therapies.
The paradigm shift of virtual crossmatch for deceased donor kidney allocation in the United States, 2015 - 2024.
Dolan TG, Hitchman KMK, Lunz JG … +1 more , Morris GP
Hum Immunol · 2026 Jul · PMID 42096763 · Publisher ↗
BACKGROUND: Virtual Crossmatch (VXM) analysis, a specialized evaluation of immunologic compatibility based on patient anti-HLA antibody testing and donor HLA genotyping, is an invaluable tool in organ transplantation. Wh...
BACKGROUND: Virtual Crossmatch (VXM) analysis, a specialized evaluation of immunologic compatibility based on patient anti-HLA antibody testing and donor HLA genotyping, is an invaluable tool in organ transplantation. While the utility of VXM has been clearly established, uncertainty persists regarding transitioning from traditional Cellular Crossmatch (CXM) testing to VXM as an independent pre-transplant assessment of immunologic compatibility. Here we examine allocation and transplant outcome data to identify changing patterns in use of VXM for deceased donor kidney transplantation in the United States (U.S.). METHODS: Organ Procurement and Transplantation Network data for 139,288 deceased donor kidney transplants performed in the U.S. between 2015 and 2024 was examined. Data analyzed included performance of prospective CXM, recipient sensitization, and 90-day outcomes. RESULTS: Transplantation of deceased donor kidneys without prospective CXM increased from 7.47% in 2015 to 47.16% of all kidneys in 2024, including 23.96% of the most highly sensitized patients (cPRA > 99.9%). Kidneys transplanted without prospective CXM had 90-day graft survival, outcomes comparable to transplants relying on CXM testing. CONCLUSIONS: This data demonstrates that despite the variability in how VXM is performed, VXM in the absence of traditional CXM is an increasingly utilized approach in kidney transplantation with safety comparable to traditional CXM testing.
Transplant of serologic A1 but genotype A2 kidneys to ABO O and B recipients is feasible and safe.
Thalji NM, Kapturczak M, Shaker T … +3 more , Chand R, Lane WJ, Murphey C
Hum Immunol · 2026 Jul · PMID 42091020 · Publisher ↗
BACKGROUND: Kidney transplants from ABO A2 donors to O and B recipients reduce wait times without compromising outcomes. Recent work shows that ABO genotyping more accurately identifies A2 donors than serologic methods....
BACKGROUND: Kidney transplants from ABO A2 donors to O and B recipients reduce wait times without compromising outcomes. Recent work shows that ABO genotyping more accurately identifies A2 donors than serologic methods. Here, we show that kidneys from donors labeled A1 by serology but genotyped as A2 can be safely transplanted to O and B recipients with favorable outcomes, expanding access for disadvantaged populations. METHODS: All O and B patients who received ABO A kidney transplants (N = 155, 2011-2025) were included in the study. All donors were genotyped as A2 or A2B and were stratified by serologic testing (anti-A lectin) as A or A. Genotyping was performed by real time PCR or next generation sequencing. Data were analyzed for biopsy-proven rejection, anti-HLA/anti-ABO antibodies, and allograft loss. RESULTS: 17 patients (11%) received kidneys from donors that were serologically identified as A. In this cohort allograft survival was 100%. No graft losses were attributed to ABO incompatibility. CONCLUSIONS: Transplanting kidneys from donors labeled A by serology but confirmed as A2 by genotyping into O and B recipients is safe and can expand the donor pool for disadvantaged candidates. Our findings support adopting ABO genotyping as a routine supplement to serologic testing.
Exploring the shared genetic architecture of migraine and autoimmune diseases.
Chen J, Wu Y, Liu M … +12 more , Fan Y, Cao T, Zhao L, Long K, Wang C, Wu L, Lv L, Li H, Chen X, Zhi L, He Y, Tao T
Hum Immunol · 2026 Jul · PMID 42081878 · Publisher ↗
BACKGROUND: Migraine (MIG) frequently co-occurs with autoimmune diseases (ADs), but the shared genetic basis underlying this comorbidity remains unclear. METHODS: Using publicly available GWAS summary statistics from Eur...
BACKGROUND: Migraine (MIG) frequently co-occurs with autoimmune diseases (ADs), but the shared genetic basis underlying this comorbidity remains unclear. METHODS: Using publicly available GWAS summary statistics from European populations, we applied an integrated framework to investigate the shared genetic architecture between MIG and seven ADs (SLE, UC, CD, PSC, T1D, RA, MS). Genetic correlations and polygenic overlap were evaluated using LDSC, HDL, and MiXeR. Shared pleiotropic loci were identified via PLACO and annotated with FUMA. Gene-level analyses were conducted using MAGMA, followed by PPI and pathway enrichment analyses. SMR was used to prioritize candidate genes. In addition, a PheWAS-guided Mendelian randomization framework and multi-trait colocalization analyses were performed. RESULTS: MIG showed significant positive genetic correlations with SLE and UC, but a negative genetic correlation with PSC. Cross-trait pleiotropy analysis identified 22 shared loci across three MIG-AD pairs, of which 8 showed colocalization evidence. MAGMA identified 182 pleiotropic genes, with strongest convergence for MIG-UC. Enrichment analyses implicated blood- and immune-related tissues and highlighted receptor tyrosine kinase, endocytosis, axon guidance, gliogenesis, and PI3K/AKT signaling. SMR prioritized candidate genes including INPP5B and CARD9. PheWAS-guided MR identified seven MIG-associated phenotypes, whereas subsequent multi-trait colocalization did not detect robust shared causal variants. CONCLUSIONS: MIG shares a selective and substantial genetic overlap with a subset of ADs, involving both immune-related and neurobiological mechanisms.
HLA DRB1*01:02 allele is associated with anti-AT1R antibodies production in kidney transplanted patients.
Carelli I, Romano A, Faini AC … +12 more , Caorsi C, Togliatto GM, Rosso CM, Mazzola G, Garino E, Alizzi S, Magistroni P, Biancone L, Cantaluppi V, Vaisitti T, Deaglio S, Amoroso A
Hum Immunol · 2026 Jun · PMID 42062116 · Publisher ↗
BACKGROUND: Kidney transplantation is lifesaving treatment for end-stage renal disease, yet immune-mediated complications limit long-term graft survival. Non-HLA antibodies (NHLA), particularly anti-Angiotensin type 1 re...
BACKGROUND: Kidney transplantation is lifesaving treatment for end-stage renal disease, yet immune-mediated complications limit long-term graft survival. Non-HLA antibodies (NHLA), particularly anti-Angiotensin type 1 receptor antibodies (AT1R-abs), are emerging mediators of graft injury. This study investigated whether selective HLA alleles influence AT1R-ab development in kidney transplant recipients. MATERIAL AND METHODS: We analyzed a cohort of 59 kidney recipients carrying the HLA-A*33:01-B*14:02-DRB1*01:02 haplotype and 52 controls. Pre- and post-transplant sera were tested for donor-specific anti-HLA antibodies via Luminex-based single antigen bead assay and AT1R-ab via enzyme-linked immunosorbent assay and categorized as positive (≥17 U/mL), intermediate (10.1-16.9 U/mL) and negative (≤10 U/mL). In silico analysis were performed to assess peptide binding to HLA haplotypes. RESULTS: AT1R-abs were markedly enriched in the DR1 patients, both pre- (p = 0.0009) and post-transplant (p < 0.0001), at variance with controls, who were rarely positive. In silico prediction revealed that HLA-DRB1*01:02, typically the involved DRB1*01 subtype of the above-mentioned haplotype, can present AT1R peptides with greater binding affinity. CONCLUSIONS: These results suggest a possible genetic link between HLA haplotypes and AT1R-ab development in kidney transplant recipients, probably due to a higher binding affinity of some AT1R-derived peptides to HLA-DRB1*01:02. Understanding this association may enable personalized immunosuppressive therapies.
Innovative multi-epitope vaccine development for rheumatoid arthritis via immunoinformatics.
ShadiDizaji A, Ghalamfarsa F, Cinisli KT … +8 more , Esmailnia G, Okkay U, Hacimuftuoglu A, Sagsoz ME, Fazli Y, Jannesar R, Warda M, Taskin M
Hum Immunol · 2026 Jun · PMID 42035672 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent joint inflammation, pain, and progressive disability, affecting millions worldwide. Current therapies, including anti-inflammatory and immun...
Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent joint inflammation, pain, and progressive disability, affecting millions worldwide. Current therapies, including anti-inflammatory and immunosuppressive agents, provide symptomatic relief but fail to offer long-term disease control or immune tolerance, highlighting the need for innovative therapeutic strategies. Here, we present a novel multi-epitope vaccine designed using immunoinformatics to target key RA-associated molecules-TNF-α, IL-23R, PTPN22, PADI2, and PADI4-critical drivers of inflammation and autoimmunity. The vaccine incorporates Melittin and GP96 as adjuvants to enhance immunogenicity while minimizing toxicity. Comprehensive in silico analyses, including epitope prediction, antigenicity, allergenicity, and physicochemical profiling, were performed to ensure safety and efficacy. Molecular docking and dynamics simulations demonstrated stable interactions with Toll-like receptor 9 (TLR9), suggesting effective immune activation. Furthermore, computational cloning and codon optimization confirmed high expression potential in a bacterial vector. In silico immune simulations predicted a Th1-biased response with sustained B-cell memory, supporting the vaccine's potential to modulate pathogenic immune responses in RA. This study provides a rational framework for a multi-targeted immunotherapeutic approach, leveraging computational methods to accelerate vaccine development. While experimental validation is necessary, these findings lay the foundation for next-generation RA vaccines capable of disrupting autoimmune cascades at multiple levels, offering a promising path toward durable disease management.
Activating KIR3DS1: A key driver of KIR3DL1/HLA-Bw4-linked risk in CML.
Basirat M, Mokhtari M, Abadi HG … +1 more , Farjadian S
Hum Immunol · 2026 Jun · PMID 42034883 · Publisher ↗
BACKGROUND: Killer-cell immunoglobulin-like receptors (KIRs) regulate natural killer (NK) cell development and operate by interacting with their cognate ligands, human leukocyte antigen class I (HLA-I) molecules. KIR and...
BACKGROUND: Killer-cell immunoglobulin-like receptors (KIRs) regulate natural killer (NK) cell development and operate by interacting with their cognate ligands, human leukocyte antigen class I (HLA-I) molecules. KIR and HLA-I gene diversity and their independent inheritance can modulate NK cell activity, thereby impacting susceptibility to hematologic malignancies. METHODS: The presence of 11 KIR genes and their cognate HLA-I ligands was examined using PCR-SSP in 100 CML patients and 181 healthy controls. The distribution of each gene and diverse KIR/HLA-I combinations was compared between the two groups. RESULTS: The results of this study disclosed a notably higher frequency of the activating (a)KIR3DS1 gene, the C4T4 subset, and the T4 gene cluster in CML patients compared with controls. There was no remarkable difference between patients and controls in the various combinations of inhibitory (i)KIR genes and their corresponding HLA-I ligands. KIR3DL1(+)/HLA-Bw4(+) combination in the presence of 3DS1 was more common in patients, while the frequency of this combination in the absence of 3DS1 was more frequent among controls. Additionally, aKIR/HLA-I combinations like KIR3DS1(+)/HLA-Bw4(+) and KIR3DS1(+)/HLA-Bw4(+) were significantly associated with CML. Conversely, healthy individuals exhibited a higher frequency of HLA-Bw4, HLA-A Bw4, and HLA-Bw4 ligands in the absence of their activating receptor. The frequency of aKIR = 6 and aKIR/HLA-I ≥ 3 was significantly higher among patients. CONCLUSION: Our findings point to a potential link between aKIR genes and aKIR/HLA-I combinations with susceptibility to CML, while NK cells expressing iKIRs for their cognate HLA ligands without a corresponding aKIR can mediate effective antitumor responses.
Non-ABO red blood cell antibodies in transplant patients.
Wlosinski LC, Scott MA, Lucidi CA … +2 more , Ho CS, Gerlach JA
Hum Immunol · 2026 Jun · PMID 42019168 · Publisher ↗
BACKGROUND: Transplant patients may have circulating non-ABO red blood cell (RBC) antibodies, but the influence of RBC alloimmunization on solid-organ transplantation outside of the ABO blood group system is not well kno...
BACKGROUND: Transplant patients may have circulating non-ABO red blood cell (RBC) antibodies, but the influence of RBC alloimmunization on solid-organ transplantation outside of the ABO blood group system is not well known. Though RBC antigens have been identified in or on cells other than RBCs, the incidence of non-ABO RBC antibodies in transplant patients has had limited investigation. Identification of non-ABO RBC antibodies in transplant patients may help clarify cases of suspected antibody-mediated rejection (AMR) when human leukocyte antigen (HLA) donor-specific antibodies (DSA) cannot be detected. STUDY DESIGN AND METHODS: This investigation tested for the presence and specificity of commonly encountered non-ABO RBC antibodies in the serum of transplant patients (heart, lung, and kidney), using standard hemagglutination antibody screening and antibody panel identification methods. RESULTS: Of 135 patients, six (4%) tested positive for clinically significant non-ABO RBC antibodies. The antibodies identified were anti-K and anti-Fy. DISCUSSION: This study provides new evidence for the transfusion and transplant community by documenting the frequency of non-ABO RBC antibodies in heart, lung, and kidney transplant patients, and is an important first step in determining the clinical significance of these antibodies in cases of suspected AMR when HLA DSAs are absent.
In silico design of a VacA-based multi-epitope Subunit Vaccine Candidate for immunoprotection against Helicobacter pylori.
Sundara Raman SK, Padelkar P, Jeyaraj G … +1 more , Jayaraman M
Hum Immunol · 2026 Jun · PMID 42013568 · Publisher ↗
Helicobacter pylori, a globally prevalent gastric pathogen associated with gastric carcinoma, ulcers of the bowel, and persistent gastritis where the vacuolating cytotoxin A (vacA), a major virulence factor, that promote...
Helicobacter pylori, a globally prevalent gastric pathogen associated with gastric carcinoma, ulcers of the bowel, and persistent gastritis where the vacuolating cytotoxin A (vacA), a major virulence factor, that promotes cellular damage and immune evasion. Despite increasing antibiotic resistance, no licensed vaccine exists for effective prevention or treatment. In present study, we implemented an all-encompassing immunoinformatic strategy in developing a novel vacA- driven multi-epitope subunit vaccine (MESV). Utilising the IEDB database, cytotoxic as well as helper T-cell epitopes were determined based on the vacA sequence of proteins and examined for antigenic properties, non-allergenicity and nontoxic effects. The mapped epitopes were coupled via AAY and GPGPG linkers, with the 50S ribosomal protein L7/L12 incorporated as an N-terminal adjuvant through an EAAAK linker for enhancing immunogenicity. The designed vaccine construct comprised 257 amino acids, demonstrated an antigenicity score of 0.8287 along with non-allergenic property and exhibited a high solubility score of 0.9444. Structural modeling using trRosetta followed by refinement and validation through GalaxyRefine, ProSA, and PROCHECK confirmed a stable 3D conformation with desirable quality metrics reported (Z-score: -5.93; 94.4 % residues in favored regions). Molecular docking and molecular dynamics simulations using GROMACS demonstrated strong and stable binding with toll-like receptors (TLRs 2/4/5/9), especially TLR4 shows highest stability and binding affinity suggesting effective innate immune activation. Immune simulations predicted potent humoral and cellular responses characterized by elevated IgM, IgG, IFN-γ, and IL-2 levels, as well as long-term memory cell formation. Codon optimization (CAI: 0.98; GC: 49.4 %) and in silico cloning into the pET28a (+) vector indicated efficient potential expression in E. coli K12. Thus, the outcomes of our study propose the vacA-based MESV as a promising, stable, and immunogenic vaccine construct targeting H. pylori, warranting future in vitro and in vivo evaluation to substantiate its protective efficacy.
PD-1 high expression in T lymphocytes correlates with decreased survival in childhood B-cell precursor acute lymphoblastic leukemia.
Andrade CO, Silva Nascimento CID, Aragao-Santos JC … +5 more , Fernandez TS, Mendes-da-Cruz DA, Noronha EP, Pombo-de-Oliveira MS, Terra-Granado E
Hum Immunol · 2026 Jun · PMID 41980397 · Publisher ↗
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common in pediatric malignancy. Despite high cure rates, relapse and treatment resistance remain major causes of mortality. Immune checkpoint molecules...
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common in pediatric malignancy. Despite high cure rates, relapse and treatment resistance remain major causes of mortality. Immune checkpoint molecules such as programmed death-1 (PD-1) have been implicated in T-cell dysfunction and immune evasion in cancer. In this study, we evaluated PD-1 expression on bone marrow CD4 and CD8 T lymphocytes from pediatric patients with BCP-ALL at diagnosis and investigated its association with clinical outcome. Flow cytometry analysis demonstrated significantly increased PD-1 expression, assessed as relative mean fluorescence intensity and as percentages of PD-1 low-density (PD-1) and high-density (PD-1) subsets, in patients compared with non-leukemic subjects. Survival analyses revealed that high frequencies of PD-1 CD4 and CD8 T lymphocytes were significantly associated with inferior overall survival, whereas higher proportions of PD-1 CD4 T cells were associated with improved survival. Thus, our study identified two distinguishable T-cell populations in the bone marrow of pediatric patients with BCP-ALL: PD-1 and PD-1. Furthermore, it demonstrated a correlation between high PD-1 expression on CD4 and CD8 T lymphocytes and survival in pediatric BCP-ALL. These results suggest that PD-1 may serve as a prognostic biomarker and a potential target for immune-based therapeutic strategies in BCP-ALL.
Shared genetic architecture between major depressive disorder and inflammatory bowel disease: Insights from large-scale genome-wide cross-trait analysis.
Ding Y, Luo Q, Yan X … +4 more , Deng C, Shen P, Xu Y, Zhang L
Hum Immunol · 2026 Jun · PMID 41956029 · Publisher ↗
BACKGROUND: Major depressive disorder (MDD) and inflammatory bowel disease (IBD) exhibit clinical associations, yet the cross-disease genetic links and shared mechanisms between them remain unclear. This study aims to ex...
BACKGROUND: Major depressive disorder (MDD) and inflammatory bowel disease (IBD) exhibit clinical associations, yet the cross-disease genetic links and shared mechanisms between them remain unclear. This study aims to explore the genetic associations between MDD and IBD and identify the shared risk loci, potential key tissues, and related genetic mechanisms. METHODS: Leveraging large-scale genome-wide association study (GWAS) summary statistics, we employed linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods to comprehensively evaluate the genetic correlation between MDD and IBD. We further conducted cross-trait pleiotropy analysis to identify shared pleiotropic loci and genes. Additionally, to explore potential associations between complex traits, we performed a series of functional annotation and tissue-specific analyses. Moreover, drug targets were explored via the SMR method. Finally, we employed immunological colocalization methods to investigate the immunological associations between these diseases. RESULTS: Our findings highlight a robust genetic correlation between MDD and IBD, including both UC and CD. A total of 1,604 potential pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10). Additionally, annotation analysis revealed 45 leading risk SNPs, among which 5 (rs9074, rs2477077, rs12427851, rs16841904, rs56059718) passed the causal colocalization test. Shared loci including 1q31.3, 3p21.31, and 6p22.1 have been identified. Gene-level analysis pinpointed pleiotropic genes such as BSN, DAG1, DENND1B, MED24, NICN1, and PSMD3. Pathway analysis revealed that the positive regulation of RNA metabolic process, T cell activation, FOXP3 target genes, and macromolecule biosynthetic processes play critical roles in these diseases. Gene-level tissue enrichment analysis indicated that pleiotropic mechanisms are pivotal in whole blood, spleen, brain (cerebellum and cerebellar hemisphere), and EBV-transformed lymphocytes. Finally, phenotype-level immunological colocalization analysis uncovered the immunological mediatory role of CD45 in the association between MDD and UC. CONCLUSION: This study provides evidence of a significant genetic correlation between MDD and IBD, and sheds light on the multilayered immune regulatory mechanisms underlying their comorbidity. These insights may have important implications for the prevention and management of patients with comorbid MDD and IBD.
CAR-NK cell therapy for overcoming antigen heterogeneity and immunosuppressive tumor microenvironments.
Qutub M, Premchandani T, Bhagat S … +5 more , Tatode A, Taksande J, Umekar M, Hussain UM, Khan R
Hum Immunol · 2026 Jun · PMID 41950641 · Publisher ↗
Chimeric antigen receptor engineered natural killer cells (CAR-NK) have emerged as a transformative strategy in cancer immunotherapy, offering MHC-independent cytotoxicity, reduced graft-versus-host disease risks, and al...
Chimeric antigen receptor engineered natural killer cells (CAR-NK) have emerged as a transformative strategy in cancer immunotherapy, offering MHC-independent cytotoxicity, reduced graft-versus-host disease risks, and allogeneic "off-the-shelf" applicability. This review synthesizes advancements in CAR-NK design, including fourth-generation "armored" constructs with cytokine secretion, metabolic reprogramming via mTOR/c-Myc modulation, and CRISPR-mediated knockout of inhibitory checkpoints (CISH). Clinical trials demonstrate efficacy in hematologic and solid tumors, with HER2-, B7-H3-, and NKG2D-targeted CAR-NK cells showing manageable toxicity and minimal cytokine release syndrome. Innovations such as non-viral gene delivery (Sleeping Beauty transposon, mRNA electroporation) and combinatorial approaches (immune checkpoint inhibitors, chemokine receptor integration) enhance tumor infiltration and persistence. Despite progress, challenges persist, including tumor heterogeneity, immunosuppressive tumor microenvironment barriers, and scalability of manufacturing protocols. This review critically evaluates preclinical and clinical data, highlighting emerging targets (EpCAM, CEA), engineering paradigms (logic-gated CARs, trogocytosis-mediated transfer), and strategies to counteract antigen loss and metabolic stress. By addressing knowledge gaps in TME modulation and standardizing clinical protocols, this work aims to catalyze interdisciplinary efforts to advance safer, durable CAR-NK therapies for refractory cancers.
Bone marrow and peripheral blood HLA-G in hematologic diseases presenting with impaired erythropoiesis: HLA-G in disorders with impaired erythropoiesis.
Carvalho B, Figueriedo-Pontes LL, Scheucher PS … +3 more , Calado RT, Traina F, Donadi EA
Hum Immunol · 2026 Jun · PMID 41946040 · Publisher ↗
The HLA-G molecule is expressed in few tissues and cells, such as erythroid precursors, in which it has been associated with cell signaling, maturation, and proliferation. Considering that the daily production of erythro...
The HLA-G molecule is expressed in few tissues and cells, such as erythroid precursors, in which it has been associated with cell signaling, maturation, and proliferation. Considering that the daily production of erythrocytes is massive, the bone marrow sHLA-G levels are higher than in peripheral plasma, and little attention has been devoted to the role of HLA-G in disorders presenting with defective erythropoiesis, we hypothesized that bone marrow could be a major source of sHLA-G to plasma. We investigated HLA-G (soluble-sHLA-G and membrane-bound) in patients presenting hematologic disorders with impaired erythropoiesis (n = 61, including myeloproliferative neoplasm-MPN, myelodysplastic neoplasm-MDS, aplastic anemia-AA, inherited bone marrow failure-BMF, secondary erythrocytosis-SE), and in healthy individuals. Indeed, sHLA-G levels (ELISA) in bone marrow of healthy individuals were higher compared to patients (p < 0.001), and we observed an overall positive correlation between bone marrow and peripheral blood sHLA-G (p < 0.05). The logistic regression showed that the lower sHLAG plasma bone marrow levels the greater the probability of developing impaired erythropoiesis (p < 0.001). In MDS patients and controls, HLA-G (flow cytometry) was expressed on myeloid precursor cells, followed by erythroid precursors and proerythroblasts, and was not expressed on differentiated erythroid cells. The use of recombinant erythropoietin (rEPO) in MDS patients (n = 3) increased the expression of HLA-G in myeloid precursors, in which HLA-G was normally expressed. Decreased bone marrow sHLA-G level is a shared feature among patients with impaired erythropoiesis and rEPO may increase HLA-G cell expression in MDS patients, corroborating the role of HLA-G along erythrocyte development.
Reverse vaccinology and immunoinformatics approaches driven designing of a novel multi-epitope mRNA vaccine against Toxoplasma gondii.
Siddiquee NH, Al Mamun MA, Dremit TI … +9 more , Ullah O, Ritu IJ, Shethe AK, Rochona NP, Tabrez S, Islam J, Mawa J, Shakil S, Mahdeen AA
Hum Immunol · 2026 Jun · PMID 41934706 · Publisher ↗
Toxoplasmosis is a zoonotic infectious disease caused by the intracellular apicomplexan parasite Toxoplasma gondii and primarily affects warm-blooded animals. Despite its global spread, the disease has limited therapeuti...
Toxoplasmosis is a zoonotic infectious disease caused by the intracellular apicomplexan parasite Toxoplasma gondii and primarily affects warm-blooded animals. Despite its global spread, the disease has limited therapeutic interventions. Chemotherapy can be used as a treatment, but there are potential side effects and contraindications. Despite several epitope-based in-silico vaccine studies, no mRNA-based vaccine has yet been explored. This study aims to design an mRNA vaccine using reverse vaccinology and immunoinformatics based on MIC1, MIC3, ROP29, and SAG1 proteins, which contribute to the attachment and activation processes of T. gondii. The selected epitopes achieved 100 % combined coverage worldwide. The favorable biophysical properties of the vaccine indicated its solubility and potential functional stability in the human body. The secondary and tertiary structural predictions of the refined vaccine revealed its well-stabilized configuration with a Ramachandran score of 80.9 % and a Z-score of -7.55. Docking analysis revealed a predicted high binding affinity toward TLR-2 and TLR-4 receptors. However, the lowest energy scores of -1000.5 kJ/mol and -1008.6 kJ/mol for TLR-2 and TLR-4, respectively, reflected highly favorable intermolecular interactions, which were further supported by MM-GBSA and molecular dynamics simulations. The vaccine showed cloning efficiency in Escherichia coli strains, and immune simulation predicted strong induction of B and T cells. Finally, the optimal and centroid structures of the designed mRNA vaccine were modelled. The vaccine developed in this study may serve as a probable future candidate against this parasite, reinforcing the need for additional in-vitro and in-vivo analyses.
The therapeutic potential of Dihydroartemisinin for autoimmune disease: Effects on the Th17/Treg balance.
Mao Y, Gao Y, Zhou J … +2 more , Yimin R, Zhao Y
Hum Immunol · 2026 May · PMID 41924761 · Publisher ↗
Autoimmune diseases (AID) are chronic inflammatory conditions resulting from aberrant recognition of self-antigens by the immune system. Appropriate ratios of the subsets of CD4 T cells, T helper cells 17 (Th17) and regu...
Autoimmune diseases (AID) are chronic inflammatory conditions resulting from aberrant recognition of self-antigens by the immune system. Appropriate ratios of the subsets of CD4 T cells, T helper cells 17 (Th17) and regulatory T cells (Treg), are necessary for immune homeostasis with imbalances associated with immune dysregulation and AID. These observations imply that restoration of Th17/Treg balance may represent a therapeutic approach for AID. Dihydroartemisinin (DHA) is a metabolite of artemisinin which has been shown to suppress excessive Th17 cell differentiation, restoring Th17/Treg balance and ameliorating AID. The current review summarizes recent progress on DHA and adjustment of Th17/Treg balance in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. Reference material was largely from that indexed in PubMed, Web of Science, China National Knowledge Infrastructure, Google Scholar and Wanfang Database between 2010 and 2025 with a few studies from 2008 and a focus on publications from the last five years.
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