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关键词： AIDS/HIV   Immunotherapy   Infectious disease   NK cells  

摘要： BACKGROUND:NK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function, and thus may reduce viral reservoirs. METHODS:To determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given three 6 mcg/kg doses of N-803 subcutaneously. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose. RESULTS:We found a non-statistically significant ~0.50 median log reduction in the frequency of viral(v)RNA+ and vDNA+ cells/g in the 6 participants with baseline and post-treatment LNs. In the ileum, we observed reductions of vRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells, and between NKG2A expression on NK cells and the frequency of vRNA+ cells. CONCLUSIONS:Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.

关键词： human leukocyte antigen   tuberculosis   local ancestry   admixture   KhoeSan  

摘要： Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 x 10(-6), OR = 0.437, SE = 0.182) in the HLA-DPB1 gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.

摘要： Purpose:We previously reported that suspensions of CIITA-/- monkey induced pluripotent stem cell-derived retinal pigment epithelium (moiPSC-RPE) that lacks expression of major histocompatibility complex (MHC) class Ⅱ avoided rejection without systemic immunosuppression. RPE strips represent a novel graft formulation for RPE impairment diseases that may enable mass engraftment but potentially increase rejection risk. This study evaluated host immune responses to allogeneic CIITA+/+ and CIITA-/- moiPSC-RPE strips in MHC-mismatched transplantation in monkey eyes with RPE damage, without systemic immunosuppression. Methods:RPE strips were generated from CIITA+/+ and CIITA-/- moiPSC-RPE. Following RPE ablation using a microsecond pulse laser, two RPE strips were transplanted into each eye at 1- to 3-week intervals. One monkey received CIITA+/+ moiPSC-RPE strips, while another received CIITA-/- moiPSC-RPE strips. Graft status was monitored through routine ophthalmic examinations, and immunohistologic evaluation was conducted after 5 months. Results:Fluorescein angiography revealed evident leakage in eyes with CIITA+/+ RPE strips beginning 1 to 2 months posttransplantation, with optical coherence tomography showing bulging at the graft site, indicating immune cell accumulation. Immunostaining confirmed the presence of immune cells (CD4, CD8, Iba1, IFN-γ, MHC class II, and CD20) at CIITA+/+ RPE strip grafts. In contrast, CIITA-/- RPE strip transplants showed no signs of rejection in either eye over 5 months and minimal immune cell presence at the graft site. Conclusions:Allogeneic transplantation of CIITA-/- RPE strips may reduce rejection risk in RPE-ablated disease model eyes, suggesting potential clinical benefits of MHC class II-deficient RPE grafts, particularly for diseases with inflammatory pathology.

关键词： Disease severity system   Hierarchical intervention   IgA vasculitis nephritis   Immune function   Inflammatory factors  

摘要： The objective of this study is to study the effects of a disease severity-based nursing intervention in children with immunoglobulin A (IgA) vasculitis nephritis, including recombinant human interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). A sample of 104 children treated at the Nephrology Department from May 2021 to May 2023 was selected for this study. The division into groups depended on distinct nursing approaches: the control group (n = 52) received conventional intervention, including basic skin care, dietary advice, and parental communication, without disease severity stratification. The research group (n = 52) received a three-level intervention (grade I, nurse-patient ratio 1:6, 12-hourly rounds, UV irradiation once daily;grade II, nurse-patient ratio 1:3, 9-hourly rounds, protein-restricted diet;grade III, nurse-patient ratio 1:1, 6-hourly rounds, liquid diet and continuous UV) based on severity. Both groups received standardized medications. Comparative analysis was conducted before intervention, 2 weeks, and 4 weeks to evaluate immune function, inflammatory factors, and renal function indicators. Initially, no statistically significant differences in immune indicators, inflammatory factors, or renal function indicators were observed in both groups (p > 0.05). After receiving care for 2 and 4 weeks, the research group displayed notably higher levels of CD3(+) and CD4(+) T cells in differentiated clusters (p < 0.05). Additionally, the research group demonstrated lower levels of natural killer cells, IgA, immunoglobulin G (IgG), and immunoglobulin M (IgM) (p < 0.05). Furthermore, IFN-gamma, IL-6, and TNF-alpha levels were notably lower in the research group (p < 0.05). Key renal function indicators, including erythrocyte count, microalbuminuria (mALB), 24-h urine protein quantity, and serum beta(2)-microglobulin (beta(2)-MG), were significantly reduced in the research group (p < 0.05). Systematic hierarchical

关键词： COVID-19   cryopreservation   engraftment   graft versus host disease   hematopoietic stem cell transplantation  

摘要： The coronavirus disease 2019 (COVID-19) pandemic created major challenges for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Scientific societies and authorities recommended cryopreserving grafts before starting conditioning regimens, despite limited data on the clinical impact. The Italian Group for Bone Marrow Transplantation (GITMO) conducted a registry-based study involving 3492 patients who underwent allo-HSCT between March 2018 and September 2021. The cryopreserved cohort (n = 976) included patients who received cryopreserved grafts during the pandemic and was compared to the historical cohort (n = 2516). Graft cryopreservation was associated with a lower day 30 incidence of neutrophil and platelet engraftment (adjusted sHR = 0.8 and 0.7, p = 0.031 and p < 0.001, respectively) and delayed hematopoietic recovery. However, primary graft failure rates at day +30 were similar in the cryo and historical cohort (4% vs. 5%, respectively;p = 0.337), also after adjustment (RR = 1.19, p = 0.518). Day 100 incidence of grade II-IV acute GVHD was comparable between the two groups (adjusted sHR = 1.2, p = 0.194). Regarding chronic GVHD incidence, we found that it was higher in patients aged < 18 years in the cryo group (adjusted sHR = 3.9, p = 0.002), but lower in those aged 18-55 years (adjusted sHR = 0.7, p = 0.008). Cumulative incidence of relapse did not differ between historical and cryo cohort (adjusted sHR 1.0. p = 0.943), as well as non-relapse mortality (adjusted sHR 1.1, p = 0.196) and relapse-free survival (adjusted sHR = 1.1, p = 0.197). However, a shorter overall survival was observed in the cryopreserved group (adjusted HR = 1.2, p = 0.038). Transplant centers should carefully balance the benefits and drawbacks of cryopreservation in allo-HSCT.

关键词： HLA-DR beta-chains   coronavirus   genetic   histocompatibility antigen classes   in silico model   polymorphism  

摘要： The high variability of human leukocyte antigen () genes results in each molecule having distinct antigenic peptide binding capacities, potentially influencing the immune response to SARS-CoV-2. This study aimed to investigate associations between (, ) and () polymorphisms and COVID-19 severity in a South Brazilian population, and to evaluate the binding affinity of alleles to viral peptides. A cross-sectional study included 503 unvaccinated patients with RT-qPCR-confirmed COVID-19: 145 non-severe, 129 severe, and 229 critical. typing was performed using PCR-SSO and Luminex™ technology. The allelic group was significantly associated with protection against severe and critical cases, while was associated with increased risk; both remained significant after Bonferroni correction. Other allelic groups were associated with disease outcomes but lost significance after correction: and (risk); and , , and (protection). In silico analysis revealed that the allele group showed a higher proportion of strong binders, mostly from non-structural proteins, while binders, though fewer in number, were concentrated in the M protein. These results suggest functional differences in antigen presentation and reinforce the relevance of , particularly , in modulating COVID-19 severity.

关键词： NLR   PHR   PLR   Psoriasis vulgaris   SII  

摘要： Background and objective IL-17 and IL-23 inhibitors are widely used as biological agents in patients with psoriasis vulgaris to suppress inflammation and reduce disease severity. This study aimed to examine changes in inflammatory parameters, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), systemic inflammation index (SII), platelet/hemoglobin ratio (PHR), and red cell distribution width/platelet ratio (RPR), as well as the Psoriasis Area and Severity Index (PASI), in psoriasis patients receiving biological therapy (IL-17 and IL-23 inhibitors). Materials and methods This retrospective study included 110 patients with psoriasis vulgaris treated with IL-23 (risankizumab, guselkumab or IL-17 inhibitors ( secukinumab, and ixekizumab). Disease severity was assessed using the PASI score. Hematological parameters (NLR, PLR, SII, PHR, and RPR) and PASI values of the patients were recorded and analyzed at baseline (month 0) and during treatment (month 6). Results A significant decrease was observed in NLR, SII, and PHR values during treatment. NLR decreased significantly from 2.43 +/- 1.25 at baseline to 2.12 +/- 0.81 at month 6 (p = 0.002). Both IL-17 and IL-23 groups significantly reduced NLR (p = 0.044, p = 0.029, respectively). SII decreased significantly from 695 +/- 390 at baseline to 588 +/- 288 at month 6 (p = 0.002). Both groups significantly reduced SII levels (p = 0.044, p = 0.018, respectively).PHR decreased significantly from 19.8 +/- 6.60 at baseline to 19.2 +/- 6.58 at month 6 (p = 0.033).PASI score significantly decreased during treatment (p < 0.001). Conclusion The significant reduction in NLR and SII levels in both the IL-17 and IL-23 groups suggests that these markers may be used together rather than separately in treatment follow-up. The significant decrease in PHR levels may indicate that IL-17 and IL-23 inhibitors contribute to reducing cardiovascular disease risk in patients with psoriasis vulgaris and promote a favorable

关键词： Ankylosing Spondylitis   Arthritogenic Peptides   HLA-B*14   HLA-B*27   Mass Spectrometry   Peptide Repertoires   cross-reactivity  

摘要： The human major histocompatibility complex class I (HLA-I) gene HLA-B*27 is the main risk factor for the rheumatic disease ankylosing spondylitis (AS) through an unknown mechanism. However, in African populations, where B*27 is rare, the B*14:03 allotype is strongly associated with AS, while B*14:02, which only differs from B*14:03 at one residue (L156R), is not associated with the disease. Here, we have used large-scale mass spectrometry-based peptide sequencing to analyze the peptidomes of HLA-B*14:03, HLA-B*14:02, and HLA-B*27:05, obtaining more than 2000 peptide ligands for each molecule. Remarkably, we found 1011 ligands shared by the AS-associated HLA-B*27:05 and -B*14:03 alleles and not by the non-AS-associated B*14:02 allele. Surprisingly, although B*14:03 and B*27:05 differ by 15 amino acids in their peptide binding domain, they show a large overlap of their ligands (64 and 43% respectively), while B*14:03 and B*14:02, which differ by only one residue, show a lower degree of overlap (33-35%). B*14:03 peptide repertoire most resembles that of B*27:05 at the P1, P2, and P5 positions of the peptides, and differs most at the C-terminal position, where B*14:03 is more restrictive than B*27:05. We have modeled how the change at residue 156 of the two B*14 alleles could have a long-range indirect effect on residues P1, P2, and P5 of the peptide ligands, explaining the different amino acid distribution observed between the two B*14 subtypes at those positions. Most of the 1011 specific ligands of B*14:03 and B*27:05 presented R/K/A/G at P1, R at P2, and L/F at the C-terminal position. Of these 1,011 peptides, 10 have been previously identified as presented by the three HLA-B*27 subtypes most strongly associated with AS and are absent in non-associated subtypes, while four peptides from the HLA 169-181 region-previously implicated in the autoimmune pathogenesis of AS-were also identified, suggesting that differential peptide binding may influence disease development

关键词： IFN-γ   helminth   intestinal immunity   microbiota   neutrophils   stroma  

摘要： IFN-γ function during a type-2 helminth infection remains enigmatic. Westfall et al. found an unexpected role for IFN-γ in limiting tissue damage during intestinal infection by Heligmosomoides polygyrus bakeri (Hpb). IFN-γ produced by CD8+ T cells stimulates stromal cells directly to recruit neutrophils, where they prevent tissue damage caused by the worms.