Issues

A broader scope for the Journal of Human Immunity.

PGM3 deficiency is a multisystem disorder characterized by recurrent infections, chronic severe neutropenia, and virus-associated malignancies, often leading to premature mortality in early adulthood. These features strongly support early consideration of hematopoietic stem cell transplantation in affected individuals.

Children with bronchiolitis exhibit a unique immunophenotype. We identify a significant difference in plasmacytoid dendritic cells and eosinophils in hospitalized patients as compared to controls, as well as cytokines involved in airway inflammation that are significantly different in hospitalized patients as compared to controls.

We present a patient harboring the TLR7 F507S mutation who initially presented with refractory thrombocytopenia that evolved into SLE with subtle neurologic features, accompanied by hypertriglyceridemia. Both hematological and metabolic features responded to ruxolitinib, thereby expanding the phenotypic spectrum and therapeutic understanding of TLR7 GOF disease.

Groen et al. identify neutralizing interferon-λ2/3 autoantibodies in 11.8% of individuals with cystic fibrosis, a greater than 10-fold higher prevalence than in control individuals. Autoantibody-containing plasmas enhanced respiratory virus replication in vitro, and associated with allergic rhinitis in patients, suggesting that interferon-λ2/3 autoantibodies have the potential to impact mucosal pathology.

We report vasculitis and interstitial lung disease in two siblings with a novel C1QB pathogenic variant. Patients responded to rituximab + tacrolimus or baricitinib. This report broadens the genotypic and phenotypic landscape of C1Q deficiency and extends on the similarities with other type 1 interferonopathies.

Cook et al. report a novel de novo heterozygous N236K mutation in PSTPIP1, identified in a patient with neonatal-onset PAMI that was ultimately fatal. The N236K mutation showed increased binding to pyrin and enhanced inflammasome formation. The authors also identify blood transcriptome changes in PAMI patients with both N236K and the more common E250K mutation.

Akalu et al. report new and long-term follow-up cases of human TBK1 deficiency, revealing that, beyond systemic autoinflammation, affected individuals are also vulnerable to severe viral encephalitis. Their findings highlight the dual nature of TBK1 deficiency—combining autoinflammatory disease with impaired antiviral defense—and emphasize the need for antiviral vigilance in care.

We describe a novel CTLA-4 p.Tyr218* variant associated with immune dysregulation across four generations. The mutation truncates the cytoplasmic tail, reducing CTLA-4 stability and transendocytosis, consistent with haploinsufficiency and autoimmunity. These findings suggest an important role for the C-terminal domain of CTLA-4 in maintaining immune homeostasis.

Here, Lønskov et al. describe a child homozygous for a deleterious variant in PARK7/DJ-1 presenting with RSV infection, brain inflammation, and seizures and explore the pathophysiology of PARK7 deficiency, underscoring the importance of PARK7 in human immune regulation and homeostasis.

The immune dysregulation in SARS-CoV-2–related multisystem inflammatory syndrome in adults (MIS-A) is not fully characterized. In this work, Khoryati et al. identify a T cell receptor Vβ21.3 signature in MIS-A similar to that previously reported in children (MIS-C), suggesting a shared immune-related mechanism between the two conditions.

This study identifies a novel TLR7 variant causing monogenic lupus, recurrent infections, and neuroinflammation. The phenotype resembles type I interferonopathies, with neuroinflammation emerging as a core feature, with sustained interferon pathway activation.

Inflammatory complications occur in many subjects with common variable immunodeficiency. We show that microbial bacterial 16S ribosomal DNA, significantly increased in the serum of these subjects, is associated with loss of IgA, leading to excess IFN-γ and increased serum B cell–activating factor (BAFF), both of which promote autoimmunity and inflammation.

Here, Jensen and colleagues studied type I interferon (IFN-I) neutralizing autoAbs in people with HIV, and found that the prevalence does not significantly differ from that in the general population. While hepatitic C and IFN therapy likely contribute to the development of IFN-I autoAbs, these may predispose to mucocutaneous herpesvirus infections and HPV-related neoplasia.

X-linked MCTS1 deficiency causes susceptibility to mycobacterial disease. Four new patients carried three previously undescribed truncating or loss-of-expression variants, presenting with BCG disease or M. abscessus infection. Functional testing showed complete or partial loss of MCTS1 activity, expanding the clinical and genetic spectrum of this disorder.

Moratti et al. exemplify how an effective management of IEI-related LPD demands close collaboration among immunologists, hematologists, and pathologists—integrating clinical presentation with serology, histology, immunohistochemistry, clonality assays, EBV status, and genetics. Reliance on histopathology alone risks misclassification, and atypical cases should prompt re-biopsy and multidisciplinary genetic reassessment to avoid overtreatment.

TREC-based NBS detects many secondary findings and additional causes for T cell lymphopenia other than SCID. The clinical follow-up of these newborns poses a new challenge for pediatric immunologists. We present clinical follow-up data of 6.5 years of NBS for SCID, underscoring the importance of preventing overtreatment and avoiding unnecessary prolonged follow-up.

Guarnieri et al. report long-term outcomes after HSCT in children with chronic granulomatous disease. While survival is excellent, a wide range of autoimmune and organ-specific late effects emerge, highlighting the significance of extended multidisciplinary follow-up to optimize patient care.

Hemorrhage detected on imaging may predict poor outcomes in acute necrotizing encephalopathy associated with COVID-19. RANBP2 mutations have been identified in some cases, suggesting a genetic contribution to disease susceptibility and highlighting the need for further research.

The history of the ESID registry is described with the help of original documents of the precursor EGID going back to 1994.