Issues

Human ISG15 deficiency is a monogenic syndrome that poises individuals to a proapoptotic and profibrotic state that can lead to lung and skin damage with scarring and impaired function via chronic inflammation.

Here, Andersen and colleagues describe a patient with asthma, pulmonary aspergillosis, and elevated IgE homozygous for a deleterious variant in the oncostatin M receptor. The variant results in absence of OSMR surface expression and impaired OSM-induced STAT3 phosphorylation, suggesting that OSMR deficiency may underlie hyper-IgE syndrome, thereby representing a novel genetic etiology of autosomal recessive HIES.

Adolescents with inborn errors of immunity face school challenges across adaptation, understanding, coordination, and socialization. In a multi-informant survey (patients, parents, teachers, and classmates), we found a lack of absenteeism protocols, educator knowledge gaps, and limited school-healthcare coordination, despite positive peer acceptance. We propose co-developing standardized protocols with authorities and patient groups.

Severe neonatal T lymphopenia detected by newborn screening can reflect diverse underlying mechanisms. Ghosh et al. describe a monoallelic dominant-negative PSMB10 variant that impairs immunoproteasome assembly and is associated with transient neonatal T lymphopenia, highlighting a potentially dynamic and reversible form of early-life thymic dysfunction.

Bes-Berlandier et al. describe the characteristics and clinical outcomes of chronic granulomatosis disease patients undergoing hematopoietic stem cell transplantation (HSCT) within 2 years after an invasive mold infection (IMI) diagnosis. HSCT could be a promising curative option for progressive IMI, specifically in those with invasive aspergillosis.

Lyytikäinen et al. report two novel assays to characterize T cell function in two patients with DCLRE1C variants diagnosed with leaky SCID. The cell division assay is used to quantify radiosensitivity in patient T cells, and the DNA double-strand break repair assay is used to measure repair defects.

Wågström et al. report that poor pneumococcal antibody protection and low IgG2 levels predict the need for continuous immunoglobulin therapy in IgG subclass deficiency. Their findings highlight the delayed benefit of IgRT and suggest pneumococcal antibody profiling as a tool for guiding long-term treatment decisions.

In 13 cohorts of individuals with WNV infection, the risk of WNV encephalitis is increased 20 to >>2,000 times by circulating auto-Abs neutralizing type I IFNs, depending on the concentration and combination of type I IFNs neutralized and patient age.

Sethumadhavan, Mariasoosai, Yamakawa et al. report a novel TLR7 gain-of-function (GOF) variant associated with autoimmunity in a male patient, which further highlights TLR7's essential role in SLE pathogenesis. The L840R mutation may increase TLR7 binding with UNC93B1, which is a molecular mechanism that was not previously described for other TLR7 GOF or UNC93B1 mutations.

Assessment of UK XLA patients reveals that bronchiectasis, present in the majority of adults, is strongly associated with diminished quality of life. Without lung disease, patients experience largely normal QoL, emphasizing the critical role of respiratory health in outcomes.

We investigated tumorigenesis mechanisms through transcriptomic profiling and somatic variant analysis in tumor samples from six patients with XLP1. LPD associated with XLP1 may originate from polyclonal lymphocyte expansion, either in the presence or absence of EBV infection, and subsequently progress to malignancy through somatic variants.

Wakamatsu et al. assess transcriptional and cellular responses to rhG-CSF in reticular dysgenesis using single-cell RNA sequencing. The study demonstrates that rhG-CSF modestly expands hematopoietic progenitors, suppresses IFNγ signaling, and promotes B cell differentiation, suggesting potential benefits for infection control and immune development before transplantation.

This report outlines the clinical, genetic, and immunologic features of a novel FOXP3 missense variant causing severe, treatment-resistant IPEX in an infant, emphasizing the usefulness of quantifying TSDR-demethylated cells as an early biomarker of IPEX disease activity.

Rare variants in CYBB (encoding gp91^phox) are responsible for chronic granulomatous disease. We report a patient affected by multiple cerebral abscesses caused by Acanthamoeba sp. and complete gp91^phox deficiency. The respiratory burst evaluation is recommended in any child with a deep abscess.

Mutations in DNA helicase RECQL4 can cause immunodeficiency, including SCID. The T cell defects are intrinsic to the hematopoietic system and amenable to hematopoietic stem cell transplant. Radiosensitivity due to DNA-repair defects limits conditioning regimen options.

Ebens et al. demonstrate successful allogeneic hematopoietic cell transplant of CD40L deficiency using an asymptomatic carrier mother donor, with achievement of 32% CD40L expression, recovery of thymopoiesis, normal T cell diversity, and functional outcomes of T and B cell interactions.

Thalhammer et al. report two siblings with hematopoietic protein 1 (HEM1), also named Nck-associated protein 1-like (NCKAP1L), deficiency and varying clinical phenotype and the first case of successful hematopoietic stem cell transplantation for recurrent infections and EBV-induced hemophagocytic lymphohistiocytosis, showing curative potential.

This report by Fréret et al. describes a child with IPEX due to a FOXP3 mutation, presenting with carotid perivasculitis consistent with TIPIC syndrome on multimodal imaging, who achieved clinical and radiologic remission after corticosteroids. This represents the first pediatric case linking TIPIC and immune dysregulation.

Identification of a heterozygous P2RY8 E323G substitution in a father and son with cutaneous lupus and enhanced type I interferon signaling supports a role for P2RY8 in lupus causation and highlights the overlap between Mendelian disease and complex genetic susceptibility.

Garcia-Solis et al. examine genetic testing advances in inborn errors of immunity, highlighting challenges in variant interpretation and the need for standardized approaches. The work emphasizes integrating clinical expertise with genetic research through interdisciplinary collaboration to enable personalized treatment, equitable diagnostic access, and improved outcomes for affected individuals.

There are 30+ papers published on NOD2-autoinflammatory (Yao) syndrome. However, approximately one in five people is heterozygous for Yao-associated variants, so any relationship between variants and clinical phenotypes can only represent extremely low penetrance. Large association studies are needed to prove an association, which have not been done, and the diagnosis should not be used.

Etienne Pays proposes that the lipid-interacting proteins of the APOL families specifically control cellular membrane dynamics involved in processes linked to immunity, like antigen presentation, inflammation, mitophagy, and apoptosis. Dysfunctions in these activities are responsible for diseases such as kidney disease, liver fibrosis, or increased sensitivity to trypanosome infection.

In this Perspective, Casanova discusses the 30-year history and future implications of emerging science showing that monogenetic lesions, and autoimmune disorders targeting the same components of host defense, can underlie the same infection. He elucidates the basic biology and public health possibilities of this provocative idea.

Three studies in this issue of JHI extend our understanding of the genetic, molecular, and clinical characteristics of human disease associated with a gain of TLR7-mediated signaling.