The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
MODY (Maturity-Onset Diabetes of the Young) is characterized by autosomal dominant mode of inheritance, early onset of diabetes in the absence of autoimmunity directed to pancreatic β-cells, impaired insulin secretory capacity, however, maintained over time, and extra-pancreatic manifestations in some patients. Its prevalence has been estimated 0.6% to 6.5% of all diabetes in Europe and the USA. Pathogenic variants in the genes encoding glucokinase or transcription factors HNF1A or HNF4A are responsible for the majority of cases of monogenic forms of diabetes referred to as MODY. The objective of the French National Diagnosis and Care Protocol (PNDS, Protocole National de Diagnostic et de Soins) dedicated to GCK-MODY (formerly MODY2), HNF1A-MODY (MODY3), and HNF4A-MODY (MODY1) is to provide to health professionals a guide for optimal management and care of patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Thorough analysis of personal and family history, clinical examination and biochemical testing are key to raise the diagnosis, which has to be confirmed by molecular analysis. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. Overall, the management of patients with MODY requires the collaboration of several health care providers.
CD8+ T-cells are crucial for controlling and resolving SARS-CoV-2 infection, yet their epitope specificity and relationship to COVID-19 disease severity remain incompletely understood. We performed comprehensive longitudinal profiling of antigen-specific CD8+ T-cell populations using DNA-barcoded peptide-HLA multimers, analysing 553 SARS-CoV-2 epitopes across globally prevalent HLA alleles in patients with mild and severe COVID-19. Functional and phenotypic characterisation was performed using multidimensional single-cell analysis and detailed cytokine profiling. The impact of post-infection COVID-19 vaccination on T-cell memory was also assessed. Severe and mild COVID-19 were associated with robust yet distinct patterns of CD8+ T-cell activation. In the acute phase, severe disease was characterised by a broader T-cell repertoire (139 unique epitopes) with a median frequency of 1.4% (IQR 0.2-5.0) and a high-frequency of immunodominant epitope-specific T-cells that exhibited reduced cytotoxic profile. In contrast, patients with mild COVID-19 mounted responses against a more limited set of epitopes (98 unique epitopes), partially overlapping with those observed in severe disease, with a median T-cell frequency of 0.7% (IQR 0-1.9) and displayed a stronger cytotoxic phenotype and functional state. Over time, the memory T-cell compartment contracted to a restricted subset of immunodominant epitopes in the two patient groups and COVID-19 vaccination further enhanced frequencies of spike-specific T-cells independent of prior disease severity. These findings delineate the epitope-specific frequency, function, and persistence of antigen-specific T-cell populations during SARS-CoV-2 infection, highlighting how differential activation, rather than magnitude alone, shapes immune outcomes across disease severities and other viral infections. This work was supported by the Independent Research Fund Denmark (DFF-Sapere Aude, 2066-00044B), the EU Horizon Europe REACT project (101057129), the European Research Council (ERC) Starting Grant MIMIC (101045517), and the Danish National Research Foundation (DNRF170).
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. 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. 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). 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/mm3, 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). 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 epidemiology of primary autoimmune diseases of the central nervous system is poorly described in Caribbean and Afro-descendant children. We studied the incidence, clinical and biological characteristics, immunological profiles, and prognosis of these diseases in Martinique. We conducted a descriptive, retrospective, monocentric, population-based study from January 2010 to July 2024 including all children aged 0-17 years hospitalized for autoimmune encephalitis, multiple sclerosis, neuromyelitis optica spectrum disorder (NMOSD), or myelin oligodendrocyte glycoprotein-associated disease (MOGAD) in the pediatric units of the Martinique University Hospital. The sequelae were assessed using an Expanded Disability Status Scale score. Twenty-five children were hospitalized for primary autoimmune disease of the CNS in Martinique and 16% were admitted to intensive care. The median age at onset was 14 years (2-17 years). The incidence rates found were 0.34 per 100,000 person-years (95% confidence interval 0.09-0.88) for NMOSD and 0.52 per 100,000 person-years (0.19-1.13) for MOGAD, and 0.60 per 100,000 person-years (0.24-1.24) for multiple sclerosis. The immunological profile of NMOSD/MOGAD was 70% seropositive (4 aquaporin-4 and 3 myelin oligodendrocyte glycoprotein). First-line treatment was high-dose corticosteroid therapy in most cases (88%). Long-term sequelae were rare in our population and mortality was null. Our study showed an increase in the incidence of NMOSD diseases compared to international studies and no significant difference in the incidence rates of the other autoimmune disorders of the CNS in children. Outcomes were comparable to European and North American countries in our population. The immunological profile showed a high proportion of anti-aquaporin-4 antibodies compared to the literature.
Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing pancreatic beta-cells. Recently, the immune-provoking role of stress-related neoantigens has become evident. Neoantigens unlikely contribute to central tolerance and therefore hold strong immunogenic potential, but their role in peripheral immune regulation is unknown. Here, we sought proof of concept that Tregs can be generated against islet neoantigen INS-DRiP that results from stress-induced ribosomal misreads of insulin mRNA. Tregs were induced from naïve CD4 T cells isolated from a healthy donor and co-cultured with monocyte-derived tolerogenic DCs either pulsed with neoantigen INS-DRiP or native autoantigen (proinsulin-peptide C19A3) that can induce Tregs in T1D patients. Their phenotypes, cytokine profiles and suppressive capacity were compared. Tregs induced against neoantigen completely inhibited proliferation of naïve T cells upon cognate antigen-pulsed DC stimulation, which was indistinguishable from Tregs induced against C19A3. Phenotype and cytokine profiling showed co-clustering of native autoantigen- and neoantigen-specific Tregs, and distinction from T cells generated with antigen-pulsed proinflammatory instead of tolerogenic DCs. Naïve T cells exist against islet neoantigen that can be primed to become Tregs despite the high immunogenic potential of neoantigen. Induction of immune regulation to neoantigens may be useful as immune intervention or prevention of T1D.
Esophageal cancer (EC) results in high mortality due to difficulty in early diagnosis, particularly in low- and middle-income countries, including the African EC belt typified by high prevalence, early onset, and poor prognosis. While the precise etiological factors remain unknown, emerging data suggest links to the oral microbiota. In this study, we conducted a secondary analysis using V4 16S rRNA sequencing from a cross-sectional study of treatment-naive, newly diagnosed EC patients (N = 103) and healthy controls (N = 108) residing in agricultural regions of Ethiopia. We report that the salivary microbiota in the healthy Ethiopian controls is highly diverse, forming two functionally distinct community clusters differing in diversity, composition, and absolute abundance. Microbiota composition was associated with sex and alcohol consumption, but not age. Comparisons against groups from geographically distinct populations representing Tanzania, Uganda, Venezuela, and the United States (N = 641) showed that cluster 2 resembled other East African populations, while cluster 1 was unique to the Ethiopian cohort. Both EC subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, were associated with a loss of microbial diversity and an increased probability of having a cluster 2 microbiota (adjusted OR = 2.9 [95% CI 1.5-5.9]). Classifiers trained to discriminate healthy and EC samples were further validated on two external EC cohorts from China (N = 161). Models trained on the Ethiopian cohort could predict disease status in an external cohort of mid- and late-stage ESCC from China (AUROC = 0.70 ± 0.03 [mean ± SD]), demonstrating the generalization of microbial features of ESCC across populations.IMPORTANCERecent reports in North America and China have correlated oral microbiota composition with esophageal cancer, although the translation of this knowledge into the African esophageal cancer belt is hampered by a lack of data on the oral microbiota of East Africans and limited cross-cohort comparative analyses validating the utility of these biomarkers. We report that the human salivary microbiota is a meaningful biomarker of later-stage esophageal cancer that transcends geography and ethnicity and may provide utility for large-population screening. A lower-diversity and lower-abundance salivary microbiota correlated with esophageal cancer warrants further investigation to understand the role of oral microbes in mediating carcinogenesis.
Inflammatory rheumatic diseases (IRDs) present substantial risks of infection-related comorbidities during pregnancy. This study evaluates the knowledge, experience, and perceptions of healthcare professionals concerning the prevention of these risks. An international, cross-sectional survey was administered using the SurveyMonkey platform. The survey was disseminated to healthcare professionals specializing in rheumatology, obstetrics, infectious diseases, internal medicine, general practice, and related disciplines through social media channels. Developed in accordance with European Alliance of Associations for Rheumatology (EULAR) recommendations, this survey comprised 30 questions, including multiple-choice, Likert-type, and open-ended formats. A total of 201 healthcare professionals from thirty-six countries participated in the study, with rheumatologists comprising the majority (n = 145, 72.1%). Systemic lupus erythematosus (n = 183), systemic vasculitis (n = 141), and rheumatoid arthritis (n = 86) were identified as the diseases associated with the highest risk of infection-related comorbidities. The most frequently recommended infectious conditions for screening included Hepatitis B (n = 142), urinary tract infections (n = 141), and Hepatitis C (n = 129). The primary risk factors were uncontrolled disease activity (n = 176), high-dose corticosteroid use (n = 164), and high disease severity (n = 162). The most significant systemic barriers were insufficient number of specialists (n = 156), and absence of multidisciplinary teams (n = 155). This study identifies structural and educational deficiencies in the management of infection-related comorbidities among pregnant patients with IRD. The results underscore the need for targeted clinical guidelines, enhanced multidisciplinary care models, and expanded pre-pregnancy counseling.
Genome-wide association studies implicate the PTPN2 gene locus (18p11.21) in risk for several autoimmune diseases, including inflammatory bowel disease. Through genetic fine mapping, we identified the single-nucleotide polymorphism rs80262450 in the PTPN2 gene as the putative causal variant. Analysis of GTEx tissue samples and genetically engineered myeloid cell lines carrying risk and nonrisk alleles of rs80262450 demonstrated increased expression of the PTPN2 splice isoform 4 (PTPN2.4), suggesting that the rs80262450 enhances disease susceptibility by favoring production of PTPN2.4. Furthermore, we found that PTPN2.4 contains a nuclear export sequence (NES) that leads to its retention in the cytoplasm. Differential localization of PTPN2.4 isoform results in a distinct protein binding profile revealed by mass-spectrometry analysis, and its overexpression increased TNF-α. PTPN2.4 knockdown reduced pro-inflammatory cytokines in human macrophages. Mutations within the NES motif abolished the unique localization and function of PTPN2.4. Lastly, increased expression of PTPN2.4 was found in Crohn's disease tissues, demonstrating its involvement in the disease. Together, we identified the pathogenic isoform PTPN2.4 as a novel driver of intestinal inflammation and a potential target to attenuate inflammation in IBD.
PSA testing is widely used for the early detection of prostate cancer (PCa), but its low specificity leads to overdiagnosis and unnecessary interventions. Proclarix, a novel blood test combining serum levels of prostate specific antigen (PSA), percentage of free PSA (%fPSA), Cathepsin D (CTSD) and Thrombospondin 1 (THBS1) with age into a risk score, aims to improve risk stratification by predicting clinically significant PCa (csPCa). This study evaluated its diagnostic performance in a Danish population using retrospective serum samples collected consecutively from patients with suspected PCa. Proclarix' ability to reduce biopsies and detection of clinically insignificant PCa (ciPCa, defined as Grade Group < 2) was assessed in men with a PSA 2-10 ng/ml and a prostate volume of ≥ 35 ml (targeted population) compared with the percentage of free PSA (%fPSA) and the European Randomized Study of Screening for Prostate Cancer Risk Calculator (ERSPC-RC). The secondary analysis included the performance of Proclarix' and Proclarix density compared with the %fPSA and PSA density (PSA-D) in a broader population with a PSA 2-20 ng/ml regardless of both prostate volume and DRE (extended population). Proclarix score is considered negative when it's below the cutoff 10%. In the targeted population (n = 373), a negative Proclarix test significantly reduced the probability of csPCa from 27% (pretest) to 5% (posttest, 95%CI: 0-10%), (p < 0.028) outperforming %fPSA (posttest 14%, 95%CI: 4-24%) and ERSPC-RC (posttest 20%, 95%CI: 4-36%). For the diagnosis of csPCa, Proclarix had a significantly (p < 0.01) greater specificity of 22% (95%CI: 17-27%) at 97% sensitivity (95%CI: 94-100%) and 95% NPV (95%CI: 90-100%) than did %fPSA and the ERSPC-RC, with 14% (95%CI: 10-18%) and 7% (95%CI: 4-11%) specificity, respectively. In the extended population (n = 656), Proclarix density had significantly (p < 0.01) greater specificity (39%, 95%CI: 35-44%) than did PSA-D (32%, 95%CI: 27-36%) at an equal sensitivity of 90%. Proclarix reduces prostate biopsies and ciPCa detection while maintaining a low risk of missing csPCa.
Age-related macular degeneration (AMD) is the third most common form of blindness in the Western world, with a predicted 288 million individuals affected worldwide by the year 2040. Both genetic and biochemical evidence point toward complement overactivation, through a diminished regulatory capacity, at the back of the eye, causing inflammation and tissue damage that helps drive this devastating disease. While much historic effort has gone into understanding the loss of regulatory control by complement factor H and factor H-like protein 1, recent studies have uncovered an emerging role of the factor H-related proteins and their capacity for driving forward complement amplification. FHR gene deletions have been shown to be protective against AMD, and increased circulating levels of FHR proteins have been found to associate with their deposition in the back of the eye at the site of disease pathogenesis. Here, we will explore the current understanding of FHR and their association with AMD risk, possible mechanisms by which they promote inflammation and extracellular matrix remodeling, and the potential effectiveness of their targeting as a novel therapeutic strategy for reducing the risk of AMD.
<sec><title>BACKGROUND</title>Data on the benefits of thoracic surgery for the treatment of pulmonary TB (PTB) are scarce. The majority of studies pertain to patients with multi- or extensively drug-resistant TB. We conducted this Europe-wide survey to evaluate attitudes towards thoracic surgery in TB care.</sec><sec><title>METHODS</title>We compiled a questionnaire of 17 questions on the respondents and their patients and on the modalities, indications, and outcomes of adjunctive surgery for PTB. The questions were distributed via the Tuberculosis Network European Trials Group (TBnet), ESCMID Study Group for Mycobacterial Infections (ESGMYC), and the European Society of Thoracic Surgeons (ESTS).</sec><sec><title>RESULTS</title>We received answers from 63 participants in 23 countries of the WHO European region. Surgery was mainly perceived to be reserved for specific clinical situations such as a differential diagnosis of cancer, a cavity with fungi/sequester, or a scarred stenosis of the draining bronchus. We observed substantial variations of attitudes towards surgical treatment between different specialties.</sec><sec><title>CONCLUSION</title>This study underscores a case-specific approach to adjunctive thoracic surgery in PTB. Differences in surgical availability and treatment attitudes suggest a need for specific, standardised guidelines. Future studies should aim to clarify the role of certain procedures and measure long-term outcomes of surgical treatment.</sec>.
In surgical treatment of head and neck squamous cell carcinoma (HNSCC), resection with adequate tumor-free margins is a fundamental challenge. Epithelial cell adhesion molecule (EpCAM/CD326) is substantially overexpressed in HNSCC representing a potential target for fluorescence-guided delineation of HNSCC. EpCAM expression was assessed in vitro on squamous cell carcinomas of the upper aerodigestive tract (SCC-UADT) and fibroblasts employing immunostaining with anti-EpCAM antibodies VU1D9 and MT201/adecatumumab (clinically validated). Whole tumor analyses of EpCAM expression were conducted in patient samples with primary and recurrent HNSCC. Confocal microscopy was used for EpCAM expression analyses upon immunostaining in cultured patient HNSCC resection samples using IRDye800CW-labeled MT201. Immunostaining with VU1D9 and MT201 revealed a high, consistent, and specific expression of EpCAM on SCC-UADT in vitro. Human whole tumor analyses showed high and consistent EpCAM expression (primary: 9/9 > = 80%; recurrent: 6/9 > = 80%) and significantly elevated near-infrared fluorescence intensities for IRDye800CW-VU1D9 and IRDye800CW-MT201 in HNSCC as compared to non-malignant tissue (2-7 fold vs. mucosa; 6-20 fold vs. HNSCC-associated stroma). Translational postoperative immunostaining of live cultured patient HNSCC samples using the clinically validated IRDye800CW-MT201/adecatumumab enabled microscopical differentiation of HNSCC from adjacent non-malignant tissue (fluorescence intensity ratios HNSCC vs. mucosa: 7,66 ± 1,26; and vs. HNSCC-associated stroma: 50,97 ± 8,24)). IRDye800CW-labeled anti-EpCAM antibodies allow experimental microscopic delineation of HNSCC from non-malignant tissue. As a future outlook, these probes might improve tumor resection in near-infrared fluorescence-guided surgery of primary and recurrent HNSCC.
Due to fundamental differences in B cell development between birds and mammals, knowledge of avian plasma cells (PCs) remains scarce, and PC-specific markers have been lacking. We isolated leukocytes from the Harderian gland (HG), a lacrimal gland rich in PC-like cells, and identified a subset of large CD45med cells. Plasma cell identity was confirmed by low Pax5, high Blimp-1 expression, and characteristic morphology. These cells lacked B lineage marker chB6 but expressed surface BCRs, with a predominant class switch toward IgA and a small fraction of IgYpos cells. Expression of activation marker CD57 and cycling cells indicate incomplete terminal differentiation. The CXCR4high PCs localized to CXCL12-rich HG-areas, supporting conservation of the CXCL12-CXCR4 axis for PC-migration and retention. HG PCs exhibited a switch from BAFF-R to TACI expression, suggesting BAFF-TACI signaling may compensate for the absence of BCMA/APRIL in chickens and mediate PC survival. High levels of IL-6, BAFF, and CXCL12 in HG tissue further indicate the presence of survival niches. This study establishes a method to isolate chicken PCs, defines their phenotype as FSChigh/CD45med/sIgpos/CD57pos/CXCR4high/TACIlow, and reveals conserved and species-specific aspects of mucosal PC biology, providing a foundation for functional studies and improved poultry vaccine strategies.
Ciltacabtagene autoleucel (cilta-cel) is a BCMA-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory multiple myeloma (RRMM). Following the CARTITUDE-1 results in heavily pretreated patients, the randomized phase 3 CARTITUDE-4 trial demonstrated superior progression-free survival (PFS) and overall survival for cilta-cel compared with standard of care in lenalidomide-refractory patients after one to three prior lines, leading to label expansion in 2024. However, real-world data characterizing outcomes in this earlier-line indication are lacking. We analyzed all patients with RRMM receiving standard-of-care cilta-cel between 2022 and 2025 from the German Registry for Stem Cell Transplantation and Cellular Therapy. Patients were stratified by prior lines of therapy into an Early group (1-3 prior lines) and a Late group (> 3 prior lines). The primary endpoint was PFS. Secondary endpoints included overall response rate, response conversion, and safety outcomes including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, and non-relapse mortality. Prognostic associations were assessed using restricted cubic spline Cox regression and univariable Cox models. Of 606 patients, 177 (30%) were treated in the Early and 429 (70%) in the Late setting. The overall response rate was 91% and 88%, with complete response in 63% and 54%, respectively. The 12-month PFS was 79% for Early and 70% for Late cilta-cel. Depth of response was the strongest predictor of PFS in both cohorts, with patients maintaining complete response showing 100% PFS at 12 months irrespective of treatment line. Extramedullary disease was adversely prognostic in both groups, whereas high-risk cytogenetics were not associated with inferior PFS in the Early group. Non-ICANS neurotoxicity occurred less frequently in the Early group (3% versus 8%), while non-relapse mortality was comparable (6% versus 7%). This analysis demonstrates that cilta-cel in earlier lines of therapy achieves deep responses and high PFS consistent with the CARTITUDE-4 trial. These results provide real-world evidence for the deployment of cilta-cel as early as first relapse and may be a benchmark outside prospective trials.
As key regulators of mucosal immunity, innate lymphoid cells (ILCs) are involved in tissue homeostasis, inflammation, and repair. Studying ILCs within their native microenvironment remains challenging due to the low abundance of these tissue-resident immune cells. Here, we applied cyclic multiplex immunofluorescence, namely multiepitope ligand cartography (MELC), in a systemic IL-33-induced type 2 inflammation model to spatio-temporally characterize ILC phenotype and localization in mouse lungs. Niche analysis with all identified cell types resulted in four distinct niches and an expansion of a mixed B and Plasma cell (BPC)/blood endothelial cell (BEC) niche, while the niche predominated by blood endothelial cells decreased at IL-33 day 3. Spatial neighborhood and coenrichment analyses revealed ILC2 accumulation in myeloid-rich peri-lymphatic niches at early time points of IL-33-mediated inflammation. ILC2s were in direct contact with activated alveolar macrophages and lymphatics. While they expressed ICOS under homeostatic conditions, pronounced expression of MHCII at days 1 and 3 of IL-33 stimulation was observed. Unlike ILC2s, NK cells/ILC1s were coenriched near blood vessels, next to B cells and plasma cells. Our findings demonstrate the utility of spatial multiplex imaging for dissecting rare immune cell localization and phenotypes and uncover dynamic, tissue-specific remodeling of ILC niches during early type 2 inflammation.
Multiple myeloma (MM) develops through asymptomatic precursor stages characterized by progressive remodeling of the bone marrow (BM) immune microenvironment and disruption of bone homeostasis. To delineate changes in natural killer (NK) cell states during disease evolution, we investigated coordinated immune-tumor remodeling by integrating NK cell functional states with plasma cell-intrinsic susceptibility programs derived from CRISPR-based screens across healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed MM patients. The integration of NK cell state-associated gene signatures with plasma cell transcriptional programs revealed stage-specific co-variation between immune and tumor compartments. Public single-cell RNA sequencing datasets were interrogated to resolve NK cell heterogeneity, identifying cytotoxic CD56dim and regulatory CD56bright subsets. NK cell dynamics displayed stage-dependent changes, with early expansion followed by the contraction of CD56dim cells in BM, whereas CD56bright cells showed predominantly compositional remodeling. Within the CD56bright subset, transcriptional changes included an increased expression of KLRC1 (encoding NKG2A), subsequently validated by multiparametric flow cytometry. In parallel, plasma cell programs associated with NK sensitivity progressively decreased along disease stages, supporting tumor adaptation to immune pressure. The NKG2A ligand HLA-E displayed selective expression within CD16+ monocytes and followed a distinct variable pattern across disease stages, highlighting a microenvironmental contribution to NK cell regulation. Collectively, these findings indicate a coordinated process of immune-tumor co-evolution, characterized by dynamic remodeling of NK cell states and plasma cell susceptibility, with the NKG2A-HLA-E axis emerging as a central interface during MM progression.
Growing evidence has linked bullous pemphigoid (BP) to immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, the immunological features of ICI-associated BP (ICI-BP) are not yet fully elucidated. In order to characterize the humoral response in ICI BP patients and investigate whether their epitope profile differs from idiopathic BP (IBP), 53 ICI-BP patients were enrolled, immunologically characterized and compared with 59 IBP patients. ICI-BP had a distinctive IgG humoral profile, with reduced reactivity toward BP230 and recognition of multiple BP180 epitopes beyond the immunodominant extracellular noncollagenous 16A domain (NC16A). Specifically, reactivity to BP180 ectodomain was present in 94% of ICI-BP and 78% of IBP (p=0.044). Moreover, BP180 C-terminal epitope was more frequently targeted in ICI-BP than IBP (72% vs 41%, p=0.002). Notably, the combined use of an in-house BP180 ectodomain ELISA and the commercial BP180 test increased diagnostic sensitivity from 83% to 100%. Enhanced IgG reactivity toward nonimmunodominant epitopes, and especially C-terminal epitope recognition, characterize the humoral immune response in ICI-BP. Our data suggest that combining NC16A and fulllength BP180 ectodomain ELISAs may help reduce diagnostic delay in ICI-BP patients, in whom a timely diagnosis is crucial to appropriately manage the disease and ultimately avoid discontinuation of cancer therapy.
The activating receptor NKp30 is important in NK cell killing of cancer cells. Here, we demonstrated that a pair of splice signals in the Ig domain exon of human NKp30 is largely conserved among primates and placental mammals and produces an alternatively spliced NKp30 ectodomain (NKp30-S) with an in-frame, nonartefactual deletion of 25 amino acid residues. Transfection yielded NKp30-S bands in NKL cells but not in 293T cells, suggesting that the splicing mechanism is cell-specific. Molecular modeling indicated that the overall folding of NKp30-S is maintained compared with NKp30. NKp30-S was expressed at the cell surface but did not bind to the NKp30 ligand B7H6 in soluble fusion protein or reporter cell assays. Single-cell RNA sequencing showed that NKp30-S transcription was not restricted to major NK cell subsets but suggested that a small fraction of blood NK cells expressed only the NKp30-S splice variant. The ratio of NKp30-S to full-length transcript was increased after activation of blood NK cells with IL-2 or IL-15 or crosslinking with anti-CD16 antibody, suggesting that this unique splicing mechanism, not seen in other Ig superfamily proteins, is regulated and may play a role in modulating NK cell responsiveness toward B7H6+ cancer cells in vivo.
Clinical trials have demonstrated the effectiveness of baricitinib, an oral selective Janus kinase 1/2 inhibitor, for patients with moderate-severe atopic dermatitis, but data from real-world practice are limited. This non-interventional cohort study evaluated clinician- and patient-reported disease severity over 16 weeks using 3 national atopic dermatitis registries: BioDay (Netherlands), SCRATCH (Denmark) and TREATgermany (Germany). Absolute scores for Eczema Area and Severity Index (EASI) and itch Numerical Rating Scale (Itch-NRS) were assessed at baseline and follow-up (Week 13/16) for each registry and for the overall pooled cohort. Descriptive analyses, generalized linear mixed modelling and meta-analysis approaches were applied to complete-case and multiply-imputed datasets. In total, 264 patients (89 BioDay, 117 SCRATCH, 58 TREATgermany) were included. Results showed improvements in EASI, with 58%, 68% and 62% achieving EASI≤7 at Week 13/16 in BioDay, SCRATCH and TREATgermany, respectively. In the pooled cohort, the proportion was 62% (95% CI: 50-73%). The pooled mean EASI change was -7.8 [14.4,-1.1]. Effectiveness was generally observed in both biologic-naïve and -experienced patients. Notable heterogeneity was observed, particularly for Itch-NRS, with the proportion achieving NRS≤4 ranging from 20% (BioDay) to 71% (TREATgermany). These real-world findings support the effectiveness of baricitinib while also highlighting variability in patient outcomes.