Issues

Remembering Richard A. Gatti, MD, a pioneer of clinical immunology and hematopoietic stem cell transplantation, whose landmark contributions—from the first curative bone marrow transplant for primary immunodeficiencies to the discovery of the ATM gene—transformed the diagnosis and treatment of rare immune and DNA repair disorders.

Autoantibodies neutralizing antiviral type I IFNs (AAN-I-IFN) underlie a small but growing number of severe arboviral diseases. These auto-Abs are strong, common, and global determinants of severe arboviral diseases. Genetic defects of type I IFN immunity may underlie other unexplained cases.

22q11.2 deletion syndrome has complex clinical presentations, with congenital malformations of the thymus leading to many immune system changes. These are summarized in the current review.

This review synthesizes human inborn errors of the alternative NF-κB pathway-affecting core components, upstream ligands/receptors, or regulators, or regulatory elements-highlighting their shared and distinct effects on lymphoid development, immune dysregulation, and mTEC-mediated tolerance, which can lead to impaired B and T cell function, the development of neutralizing anti-type I IFN autoantibodies, susceptibility to severe viral diseases, and syndromic features.

Martins-Ferreira and Ballestar review how ICF syndrome serves as a paradigm of epigenetic immunodeficiency. They show how alterations in DNA methylation and chromatin remodeling disrupt genome stability and B cell maturation, highlighting broader principles linking epigenetic regulation to immunity and informing other primary immunodeficiencies.

Freeman et al. provide practical advice on prevention, diagnosis, and management of infections in inborn errors of immunity as well as management of common complications such as bronchiectasis.

We report the same ultra-rare pathogenic noncoding single-nucleotide variant in the promoter of WAS in four male patients from two unrelated kindreds with features of Wiskott-Aldrich syndrome.

Our retrospective study highlights that acute use of nirmatrelvir/ritonavir significantly reduces the risk of post-acute sequelae of SARS-CoV-2 infection (long COVID) in immunodeficient patients, emphasizing the need for clinical trials that include this high-risk population.

Standard newborn screening using T cell receptor excision circles (TRECs) failed to detect delayed-onset ADA deficiency in two cases. Retrospective mass spectrometry (MS/MS) analysis showed diagnostic deoxyadenosine elevation at birth. We advocate integrating MS/MS purine profiling into first-tier screening to enable early diagnosis and timely curative treatment.

We identified six individuals with homozygous truncating variants in the pre-TCRα intracellular tail, revealing hypomorphic and neutral alleles. Functional assays show the tail is largely dispensable for pre-TCR expression and highlight the need for experimental validation of such variants.

We report a case of chronic pulmonary SARS-CoV2 infection caused by impaired B cell–mediated immunity to SARS-CoV-2 in a patient with Good syndrome. Immunoglobulin replacement therapy alone was sufficient to achieve clinical and radiological resolution.

Noninfectious manifestations of CVID have not been formally summarized. This systematic literature review provides a comprehensive summary as a reference point for the field and documents the pervasiveness and negative impact of noninfectious manifestations driven by immune dysregulation.

We report two patients with Whipple’s disease caused by autosomal dominant IRF4 deficiency.

Novel dominant PSMB10 variants cause severe combined immunodeficiency and life-threatening liver disease in three pediatric patients. These mutations impair immunoproteasome assembly through a dominant-negative effect on PSMB9, likely disrupting lymphocyte survival and endothelial function, and are associated with poor outcomes after hematopoietic stem cell transplantation.

Treating patients with ALPS can be challenging. This article examines the efficacy of leniolisib, a selective PI3Kδ inhibitor, in a murine model of ALPS, illustrating a reduction in lymphoproliferation and disease-associated biomarkers such as elevated double-negative T cells.

We evaluated 69 subjects with SCID to assess the neurodevelopmental outcomes following HCT. Compared with the normative population, our subjects performed in the average range. There was no impact of newborn screening, conditioning, or genotype. Families earning <$50,000 had poorer outcomes. Our study provides the most substantial, comprehensive analysis of ND outcomes for SCID.

USIDNET is a suite of resources for clinical immunologists. The registry of patient data utilizes data extraction from electronic health records to minimize burden on participating sites. This has been effective at improving enrollment.

This study explores the use of emapalumab, an interferon gamma inhibitor, in seven children with primary hemophagocytic lymphohistiocytosis. Higher initial doses of emapalumab and combination therapy with JAK inhibitors significantly accelerated disease remission, potentially improving outcomes and the success of subsequent hematopoietic stem cell transplantation.

Kilic et al. reported a child with a homozygous TBK1 mutation previously linked to autoinflammation, suggesting its role in recurrent severe viral infections; the patient died from acute disseminated encephalomyelitis.

Dalvi et al. report on 50 Indian patients with Mendelian susceptibility to mycobacterial disease (MSMD), highlighting its clinical diversity and genetic heterogeneity. The study demonstrates how immunological assays and flow cytometry, combined with genetic testing, enable timely and accurate diagnosis of MSMD, aiding targeted clinical management.