搜索结果：Journal of human immunity

Oncostatin M (OSM) receptor beta (OSMRβ), encoded by OSMR, is a cytokine receptor subunit required for signaling by OSM and IL-31. We identified 10 affected individuals from seven unrelated families with germline biallelic loss-of-function variants in OSMR who shared a phenotype of early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. All patient-derived OSMRβ variants failed to localize to the cell surface, resulting in selective loss of OSM-dependent signaling. Patient cells showed markedly reduced OSM-induced phosphorylation of STAT1, STAT3, and STAT5, while signaling through other IL-6 family receptor complexes remained intact. Transcriptomic profiling of patient primary dermal fibroblasts revealed consistent downstream effects, including loss of interferon-responsive and inflammatory gene programs. Re-expression of wild-type OSMR restored receptor surface expression, STAT activation, and transcriptional responses, confirming a causal loss-of-function mechanism. Together, these findings establish biallelic OSMR deficiency as a novel primary atopic disorder.

Gain-of-function (GOF) mutations in the STAT1 gene result in heightened interferon signaling and impaired IL-17 immunity. While chronic mucocutaneous candidiasis (CMC) remains the hallmark feature, affected individuals often display a broader phenotype including viral infections, mycobacterial susceptibility, and autoimmune diseases. We describe a 4-year-old girl who initially presented with abdominal pain and was diagnosed with acute appendicitis. During surgery, marked mesenteric lymphadenopathy was discovered, and histopathology revealed acid-fast bacilli. Mycobacterium tuberculosis was confirmed by gastric fluid PCR, prompting initiation of anti-tuberculosis therapy. Her past medical history included hospitalization for herpes zoster and recurrent episodes of oral candidiasis during febrile illnesses. Immunologic evaluation showed normal immunoglobulin levels, vaccine responses, oxidative burst, and lymphocyte proliferation. However, low NK cells, reduced recent thymic emigrants, and decreased class-switched memory B cells were noted. Genetic testing revealed a previously unreported heterozygous STAT1 variant (p.Thr387Arg), classified as likely pathogenic according to ACMG criteria with a CADD score of 23.4. Parental genetic testing was negative, suggesting a de novo mutation. Although STAT1 phosphorylation could not be assessed, the proportion of IL-17-producing CD4⁺ T cells was markedly reduced, supporting impaired Th17 immunity. Based on clinical, immunologic, and genetic findings, a clinical and immunological phenotype consistent with STAT1 GOF was established. One year later, the patient developed arthritis and was diagnosed with systemic lupus erythematosus (SLE) based on autoantibody positivity and low complement levels. During follow-up, she also developed hemophagocytic lymphohistiocytosis (HLH), further reflecting severe immune dysregulation. Ruxolitinib was initiated as bridging therapy, resulting in partial clinical improvement, and hematopoietic stem cell transplantation (HSCT) was planned as definitive therapy. This report describes a novel STAT1 variant consistent with a gain-of-function phenotype associated with disseminated tuberculosis and early-onset SLE, expanding the clinical and molecular spectrum of this disorder. In children presenting with overlapping infectious and autoimmune features, underlying inborn errors of immunity should be considered.

Just as the Phantom orchestrates events from the shadows of the Paris Opera House, innate lymphoid cells (ILC) operate behind the scenes of the immune system, shaping immune responses without the antigen specificity of their T cell counterparts. While more understudied than their better-known T cell counterparts, these enigmatic cells serve as first responders to infection and tissue disruption, playing crucial roles in mucosal immunity and homeostasis-packing an iron-fist punch under a velvet glove. However, in the context of inborn errors of immunity (IEI)-a diverse group of over 500 monogenic disorders affecting immune function-the role of ILC remains largely unmasked. While traditionally overlooked, recent patient studies reveal that ILC dysfunction contributes to disease pathogenesis in at least 19 distinct IEI, raising critical questions: Are ILC indispensable protectors, or do they represent a redundant act within the immune repertoire? How do they respond to standard treatments such as hematopoietic stem cell transplantation (HSCT)? In this review, we unveil the hidden roles of ILC in IEI, analyzing their developmental and functional defects, their role in immune dysregulation, and their therapeutic potential. Much like the Phantom's elusive presence, ILC may hold the key to understanding immune resilience and designing novel treatments for immunocompromised patients.

Inborn errors of immunity (IEI) are genetic disorders that not only heighten infection risk but also disrupt immune regulation, frequently leading to lymphoid tissue overgrowth known as lymphoid proliferations (LPD). We retrospectively reviewed 38 patients with genetically or clinically confirmed IEI and persistent LPD, comparing those with nonneoplastic/reactive hyperplasia to those who developed overt lymphoid neoplasm (lymphoma). Overall, 26% developed lymphoma-predominantly classical Hodgkin lymphoma or diffuse large B cell lymphoma-often after earlier IEI onset. Immunophenotyping and principal component analysis revealed that patients with common variable immunodeficiency developing Hodgkin lymphoma shared a distinctive T cell profile, differing from immunocompetent lymphoma cases. Centralized histologic re-evaluation reclassified several presumed lymphoma as nonneoplastic/reactive hyperplasia and identified Castleman-like and germinal center transformation patterns in nonneoplastic/reactive LPD. Notably, elevated blood IgM and circulating T follicular helper cells mirrored IgM deposits and PD-1+ T cells in lymph nodes. These findings highlight the importance of an integrated approach involving clinical, genetic, and pathological reviews to improve IEI diagnosis and avoid overtreatment.

Gastrointestinal tract tuberculosis (GIT-TB) is a rare form of TB, but one that poses a serious challenge in diagnosis and management, particularly in the setting of severe immunosuppression. We present a case of intestinal TB in a 3-mo-old immunosuppressed infant whose chief complaints were progressive abdominal distension and failure to thrive with features of intestinal obstruction and a diagnosis of GIT-TB confirmed on histology and culture. The resulting serious complications despite surgery included short bowel syndrome, enterocutaneous fistulae, and cholestasis necessitating the use of total parenteral nutrition and a modified parenteral TB treatment regimen. During the 2-mo stay in hospital, the patient developed irreversible liver failure and azotemia, eventually succumbing to these complications. This case highlights the importance of early recognition and treatment of GIT-TB to prevent adverse outcomes. Further, there is a need to investigate for immunodeficiency in such presentations, particularly in young infants. The challenges encountered by the clinicians underscore the importance of the development of World Health Organization guidelines on the specific management of GIT-TB.

Coronavirus disease 2019 (COVID-19) severity is closely associated with dysregulated inflammatory responses, with cytokines and chemokines emerging as key mediators and potential early biomarkers of adverse clinical outcomes. A retrospective study on 103 RT-PCR-confirmed COVID-19 patients during the first pandemic wave (January-May 2020) was performed to evaluate the prognostic value of a panel of cytokines and chemokines measured at hospital admission. Samples and clinical data were collected at the Department of Public Health and Infectious Diseases, Sapienza University of Rome, and sent to Istituto Superiore di Sanità for further characterization. Serum concentrations of IL-1β, IL-6, IL-8, IL-10, TNF-α, CCL3, and CXCL10 (IP-10) were quantified using multiplex ELISA. Associations with in-hospital mortality, intensive care unit (ICU) admission, and a composite outcome (death or ICU admission) were assessed using multivariable logistic regression. ICU admission occurred in 6.8% of patients and mortality in 11.7%. Among inflammatory mediators, CXCL10 emerged as the strongest predictor of adverse outcomes. In adjusted models, each 1,000 pg/mL increase in CXCL10 was associated with increased odds of death (OR 1.26; 95% CI 1.17-1.35), ICU admission (OR 1.13; 95% CI 1.06-1.21), and the composite outcome (OR 1.21; 95% CI 1.12-1.31). Elevated respiratory frequency and blood urea nitrogen were also independently associated with worse outcomes, while TNF-α tended to be associated with ICU admission. Conversely, IL-6 and other cytokines were not significant predictors in the multivariable models. These findings identify CXCL10 as a key early immunological predictor of COVID-19 severity, suggesting that its integration with clinical parameters may improve risk stratification and guide targeted management. CXCL10 may also represent a potential therapeutic target, warranting validation in larger prospective studies.

Incomplete thermal ablation (iTA) for hepatocellular carcinoma (HCC) fosters an immunosuppressive microenvironment driving local recurrence, yet the metabolic cues linking tissue injury to immune evasion remain undefined. Bile acids, particularly lithocholic acid (LCA), are elevated post-ablation, but their functional role in HCC recurrence is unknown. Here, we investigate whether LCA accumulation after iTA promotes tumor recurrence by suppressing antitumor immunity and identify the underlying molecular mechanism. Orthotopic and subcutaneous HCC models were subjected to iTA. Bile acid metabolomics, multicolor flow cytometry, and immunofluorescence staining were performed. Human residual HCC specimens were analyzed for vitamin D receptor (VDR) expression, macrophage polarization and invariant natural killer T (iNKT) cell density. For mechanistic studies, tumor-associated macrophage (TAM)-specific conditional knockdown of Vdr or Socs3, along with iNKT cell co-culture systems, were employed. The therapeutic efficacy of tauroursodeoxycholic acid (TUDCA), a bile acid modulator that counteracts LCA-mediated effects, was evaluated in vivo. iTA markedly elevated intrahepatic LCA levels, which correlated with M2-like TAM polarization and reduced iNKT tumor infiltration. LCA functioned as a VDR agonist in TAMs, transcriptionally upregulating suppressor of cytokine signaling 3 (SOCS3) and suppressing C-X-C motif chemokine ligand 16 (CXCL16). This VDR-SOCS3-CXCL16 axis was necessary and sufficient for impaired iNKT chemotaxis, as genetic ablation of VDR or SOCS3 in TAMs restored CXCL16 secretion. Conversely, LCA treatment inhibited iNKT cell chemotaxis and interferon-γ secretion, which were restored by exogenous CXCL16 supplementation. In human residual HCC, post-ablation tissues exhibited M2-like TAM polarization, and VDR+ TAM density inversely correlated with intratumoral iNKT cells. Pharmacologically, TUDCA remodeled the bile acid pool, suppressed LCA-VDR signaling, reinstated CXCL16 expression, reprogrammed TAMs toward an M1-like phenotype, and significantly inhibited post-ablation tumor growth. We identify a hitherto unknown metabolic-immune checkpoint: iTA-induced LCA activates macrophage VDR, triggering SOCS3-mediated epigenetic suppression of CXCL16 and evading iNKT surveillance. TUDCA resets this checkpoint by restoring CXCL16 expression and iNKT function. Thus, targeting this axis with TUDCA represents a readily translatable adjunctive strategy to abrogate post-ablation HCC recurrence.

Human adenoviruses (HAdVs) are major etiological agents of acute respiratory infections (ARIs); however, population-level immunity to primary genotypes in South Korea remains unclear. We applied a micro-neutralization enzyme-linked immunosorbent assay to assess neutralizing antibodies against HAdV-3, -4, -7, and -55 in sera from 800 healthy individuals. Seropositivity was highest for HAdV-3 (79.3%), followed by HAdV-4 (47.3%), HAdV-55 (30.1%), and HAdV-7 (21.3%). HAdV-3 exhibited both high prevalence and titers, whereas HAdV-4 exhibited predominantly low titers. HAdV-7 and -55 exhibited lower seroprevalence, with moderate nAb levels observed among seropositive individuals. Seroprevalence was similar across age and sex, except for a significant decline in HAdV-55 among individuals aged ≥ 50 years. These findings provide large-scale seroepidemiological data on ARI-associated HAdV genotypes in South Korea.

The first wave of Coronavirus disease 2019 (COVID-19), driven by the global emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), severely affected Spain with high infection and mortality rates across the country. Although numerous common and rare genetic variants affecting immune-related pathways have been associated with susceptibility to infection and severe disease, the contribution of complement system remains comparatively understudied. In this work, we analyzed the frequencies and severity associations of complotype-related common polymorphisms and rare complement variants in whole-exome sequencing data from a Spanish cohort accounting for 154 adults hospitalized due to severe COVID-19. Our results indicate that the CFHR4 rs7417769 (p.N209S) and CFH rs1061170 (p. Y402H) common polymorphisms are significantly associated with protection against acute respiratory distress syndrome (ARDS), while the C3 rs2230199 (p.R102G) and MASP2 rs7255087 (p.D120G) polymorphisms respectively correlated with low and high C3 levels. The marked over-representation of the C1R rs117402032 and C8A rs143523574 polymorphisms and increased frequency of heterozygous carriers of alleles previously associated with low FCN2 and FCN3 levels, suggest a link beween defective complement activation and increased rates of SARS-CoV-2 infection and support a pivotal role for the lectin pathway in the pathogenesis of COVID-19. Together, these results demonstrate that common variants in complement genes modulate susceptibility to severe COVID-19 and its clinical complications. They also identify promising, testable genetic biomarkers with potential utility not only for SARS-CoV-2, but also for preparedness against future emerging infectious threats.

This issue of the Journal of Human Immunity features a study (https://doi.org/10.70962/jhi.20250227) reporting the long-awaited first case of autosomal recessive human CTLA-4 deficiency. Here, the features of this patient are compared and contrasted to those in CTLA-4 haploinsufficient patients, patients treated with CTLA-4 inhibitors, and Ctla4 -/- mice.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with immune evasion being a key driver of treatment resistance and poor prognosis. The tripartite motif-containing (TRIM) family of E3 ubiquitin ligases plays critical roles in regulating tumor immunity, but the functional relevance and molecular mechanisms of most TRIM members in LUAD remain elusive. Here, we integrated multi-omics analyses with functional experiments to systematically investigate the prognostic value and immunoregulatory role of TRIM family in LUAD. We identified TRIM59 as an independent poor prognostic factor, with its high expression correlating with an immunosuppressive tumor microenvironment (TME). Mechanistically, TRIM59 interacts with interferon regulatory factor 3 (IRF3) and promotes its ubiquitination and proteasomal degradation, thereby inhibiting the IRF3-STING pathway and downstream anti-tumor interferon production. Single-cell analyses revealed cell-type-specific functions of IRF3: in tumor cells, IRF3 may suppresses immune-activating gene expression and modulates proliferation; in tumor-infiltrating T/NK cells, IRF3 negatively regulates pro-inflammatory signaling. Collectively, our findings establish the TRIM59-IRF3 axis as a novel regulatory pathway driving LUAD immune evasion, providing a promising prognostic biomarker and therapeutic target for enhancing immunotherapy efficacy.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a group of genetically determined disorders characterized by severe and fulminant systemic inflammation, cytopenia, and multiple organ involvement. A dexamethasone-and-etoposide-based HLH-2004 protocol is widely used to treat pHLH, yet often fails to produce the disease control required for the next treatment step: hematopoietic stem cell transplantation (HSCT). We report on the use of the interferon gamma inhibitor emapalumab in seven children aged 6-39 months with pHLH. Three patients received emapalumab at an average starting dose of 1.7 mg/kg and had no active HLH by median day 28. Four patients received emapalumab at an average starting dose of 7.2 mg/kg and had no active HLH by median day 14 (P = 0,0015). We suggest that the higher starting dose of emapalumab, as well as its combination with Janus kinase inhibitors, might increase the remission rate in pHLH and the success of subsequent HSCT.

Leukocyte adhesion deficiency, type I (LAD-I) is a rare inborn error of immunity characterized by recurrent, severe infections/inflammation and poor wound healing. Little is known about the patient/family experience of severe LAD-I. We conducted a multiple-case study exploring the burdens of illness, caregiving, and treatment in severe LAD-I. Nine caregivers (parents) representing five families with ≥1 child with severe LAD-I participated in individual, in-depth interviews. Memoing and inductive/deductive coding were used to analyze and compare each family's experience. The caregivers described frequent and severe infections, physical and social restrictions, a complex journey to diagnosis, rearranging life around severe LAD-I, financial strain, isolation, and uncertainty. Treatment burden varied by treatment type. This multiple-case study highlights how severe LAD-I affects patients and families. As the first study to address the humanistic burden of LAD-I in patients and caregivers, it is an important contribution to the literature on LAD-I and qualitative methods for investigating the burden of rare disease on families.

Xenotransplantation of porcine cells, tissues or organs offers a promising strategy to address the critical shortage of human donor organs. However, cross-species pathogen transmission, instant blood-mediated inflammatory reaction (IBMIR)-related liver injury, chronic over-immunosuppression, and long-term safety remain major challenges in porcine islet xenotransplantation. In this study, we performed a clinical trial aimed to evaluate the biosafety of neonatal porcine islet xenotransplantation in patients with type 1 diabetes. Ten recipients were assigned to two groups receiving non-encapsulated neonatal islet cell clusters via the jugular-hepatic-portal vein at mean doses of 6354 ± 835 IEQ/kg and 11 600 ± 1100 IEQ/kg, respectively. Donor pigs originated from a highly inbred, PERV-C-negative colony reared in designated pathogen-free (DPF) conditions, with rigorous pathogen and PERV screening. Immunosuppression included mycophenolate mofetil, tacrolimus, belatacept, and autologous regulatory T-cell therapy, combined with tocilizumab. Continuous low-dose heparin was infused via a portal vein catheter was used for 7 days as anticoagulation therapy. Recipients and spouses were monitored for over 5 years, with 7 followed for more than 10 years. No PERV transmission or transplant-related infections were detected in any recipient or contact during long-term follow-up. The procedure was safe and well-tolerated, with only transient liver function and coagulation changes and mild adverse events. Both groups showed reduced exogenous insulin requirements and markedly lower hypoglycemia incidence, with better glucose control in the higher-dose group. This study demonstrates that DPF PERV-C-free neonatal porcine islet xenotransplantation is biologically safe and partially effective, supporting its value as a reliable donor source and foundational platform for advancing clinical islet xenotransplantation. ClinicalTrials.gov identifier: NCT03162237.

CHAPLE disease is a monogenic disorder in which CD55 deficiency drives gastrointestinal pathology. How CD55 deficiency affects adaptive immunity is unknown. Herein, molecularly, we characterize eight patients with genetically novel CD55 deficiency. Clinically, all patients developed early-onset protein-losing enteropathy, frequently complicated by thrombotic events, inflammatory bowel disease-like lesions, and recurrent respiratory infections. Ex vivo, immunophenotyping revealed disruption of the B cell compartment, marked by depletion of transitional B cells, expansion of CD21lo B cells, and accumulation of class-switched memory B cells and plasmablasts, while T cell subsets were largely preserved. In vivo, eculizumab rapidly resolved intestinal pathology, normalized serum albumin and immunoglobulin levels, and re-established a normal B cell profile. Furthermore, C5 inhibition enabled effective humoral protection and optimal pneumococcal vaccine responses. Together, these findings establish complement inhibition as central to B cell homeostasis in CHAPLE disease.

Genomic testing has transformed the diagnosis and management of inborn errors of immunity (IEIs). Despite its rapid uptake, there remains limited guidance for clinicians on which patients should undergo testing. The Australasian Society of Clinical Immunology and Allergy (ASCIA) has developed evidence-based guidelines to support clinicians in identifying individuals who may benefit from genomic testing for suspected IEI. This guideline paper reviews current literature and reports expert consensus to provide practical recommendations on patient selection, testing modalities, and interpretation of results. It outlines clinical scenarios where genomic testing is most likely to yield actionable insights, including early-onset, severe, or atypical immune presentations and familial patterns suggestive of heritable immune dysfunction. The ASCIA guidelines aim to support genomic testing decision-making and ultimately improve diagnostic accuracy, access to timely interventions, and outcomes for individuals with IEI across Australasia and internationally.

Background: Macrophage migration inhibitory factor (MIF) is a critical modulator of the tumor immune microenvironment (TME). Its clinical significance in head and neck squamous cell carcinoma (HNSCC) remains controversial because of HPV-dependent tumor biology and the limitations of single-timepoint biomarker assessments. This preliminary study evaluates whether dynamic changes in circulating MIF (ΔMIF) in an HPV-stratified longitudinal cohort reflect disease severity and treatment response. Methods: Ninety-six serial serum samples were analyzed from 27 HNSCC patients (22 HPV-positive, 5 HPV-negative) from diagnosis through therapy and follow-up. Serum MIF and anti-HPV16 E7 IgG were quantified by ELISA, and ΔMIF was defined as the change in MIF concentration between consecutive visits. Results: Baseline MIF did not correlate with clinical stage in the total cohort (p = 0.63). However, 56% of HPV-positive patients exhibited a positive correlation between elevated MIF and advanced stage. Following chemoradiotherapy, the HPV-negative group showed a consistent and significant decline in MIF (mean ΔMIF = -1.23, p = 0.031), corresponding with no evidence of disease (NED). In contrast, the HPV-positive group showed heterogeneous trajectories (mean ΔMIF = +0.21, p = 0.94), with several patients demonstrating paradoxical declines in MIF during active disease or relapse, followed by recovery upon reaching NED. In select cases, MIF dynamics were closely synchronized with anti-E7 IgG levels. Conclusions: Serum MIF dynamics are strongly dependent on HPV status. While MIF serves as a reliable therapy-monitoring marker in HPV-negative HNSCC, it may play a complex and paradoxical immunomodulatory role in HPV-positive disease. These preliminary findings support the need for larger prospective, HPV-stratified trials.

Chronic granulomatous disease (CGD) is an inborn error of immunity of caused by pathogenic variants of genes encoding components of the phagocyte NADPH oxidase complex, resulting in defective reactive oxygen species production and impaired microbial killing. We conducted a multicenter evaluation of 39 Colombian patients with CGD from 32 unrelated kindreds, describing their clinical, microbiological, and genetic characteristics. Genetic analyses were performed for 31/39 patients and identified variants of the following genes: CYBB (n = 22), CYBA (n = 3), NCF1 (n = 1), NCF2 (n = 1), and NCF4 (n = 4). All but three of the patients had symptoms, the exceptions being individuals with p40 phox deficiency. BCG-related complications occurred in eight patients, pulmonary tuberculosis in four, and Salmonella spp. bacteremia in 12 of 17 patients with Salmonella infections. Colombian patients with CGD had clinical and microbiological profiles similar to those reported across Latin America. The genetic findings broaden the regional variant spectrum and emphasize the need for earlier diagnosis and better access to specialist testing.

Newborn screening (NBS) for severe combined immunodeficiency (SCID), based on quantifying T cell receptor excision circles (TRECs), has been increasingly implemented in screening programs worldwide. Unlike many other disorders in NBS, TREC-based screening detects many secondary findings and additional causes for T cell lymphopenia other than SCID. The clinical follow-up of SCID patients has been well implemented and documented, but newborns with other forms of T cell lymphopenia pose a new challenge for pediatric immunologists on how to offer optimal clinical management. Systematic evaluation of follow-up outcomes is crucial to establish consensus on clinical management of these patients. Here, we present clinical follow-up data of 6.5 years of NBS for SCID in the Netherlands, aiming to identify key challenges and provide recommendations. These results underscore the importance of preventing overtreatment and avoiding unnecessary prolonged follow-up and highlight the value of appropriate genetic testing and counseling. Finally, we demonstrate the critical role of international data exchange in establishing evidence-based recommendations.