Issues

This Review provides an overview of the discoveries, origins, and complexities of CD21^lo B cells, and how studying inborn errors of immunity can provide a unique window to understand the molecular requirements for generating these cells, as well as mechanisms underpinning their function in health and disease.

Modi et al. review how primary atopic disorders, a group of monogenic inborn errors of immunity, reveal fundamental mechanisms regulating allergic inflammation. These human diseases show how disruptions in barrier integrity, immune signaling, cytoskeletal dynamics, and immune tolerance converge to drive severe type 2 inflammation and inform emerging precision therapies.

Li et al. present a comprehensive clinical framework for diagnosing and managing HA20, an immune dysregulation disease caused by loss-of-function TNFAIP3 variants. The authors outline clinical evaluation strategies, family screening, and phenotype- and biomarker-guided treatment strategies using IL-1, TNF, and JAK inhibitors.

Immune dysregulation is a common yet underrecognized feature of Down syndrome that contributes to infections, autoimmunity, and autoinflammation. Using clinical vignettes, this work highlights the underlying mechanisms and potential treatments for the immune dysregulation in Down syndrome.

The hyper IgE syndrome (formerly also called Job syndrome or Buckley syndrome) is a rare and syndromic primary immunodeficiency. It is an autosomal-dominant disorder caused by heterozygous dominant-negative mutations in the transcription factor STAT3. Here, we propose clinical management guidelines for this multisystem condition based on the experience and management of these patients in the last 25+ years.

This letter highlights diagnostic importance of considering monogenic immune dysregulation in complex allergic and autoimmune diseases. Additionally, the report expands on the clinical spectrum of suppressor of cytokine signaling 1 insufficiency (SOCS1 insufficiency) by identifying severe, treatment-refractory eosinophilic asthma as a novel primary manifestation.

Netea et al. present an infant with macrophage activation syndrome as part of Kawasaki disease, who was first treated with canakinumab, followed by methylprednisolone and IVIG. Despite early treatment, giant coronary artery aneurysms developed transiently, questioning the singular role of IL-1 in KD.

Activated phosphoinositide 3-kinase δ syndrome 1 (APDS1) is a combined immunodeficiency caused by monoallelic gain-of-function mutations in the PIK3CD gene. 556 patients were diagnosed with inborn errors of immunity at our center between February 2017 and October 2025. Five patients had APDS1, confirmed by next-generation sequencing. Their records were analyzed in detail.

The mechanisms underlying thymic dysfunction in the 22q11.2 deletion syndrome are poorly defined. In this study, Hennings et al. integrated spatial transcriptomic and proteomic analyses of thymus tissue from patients with 22q11.2 deletion syndrome to identify fibroblast-driven collagen expansion and alterations in medullary niches.

Gunderman et al. share the second report of X-linked SEPTIN6-related disease in two brothers identified by SCID newborn screening. Findings include congenital neutropenia, absent circulating B cells, marrow mature myeloid, and rare plasma cell accumulation, as well as tetraploidy, with disease reversal following myeloablative HSCT. Xenograft studies implicate SEPTIN6 playing a role in lymphocyte development.

Moreno-Corona et al. identify compound-heterozygous WDR75 variants in a patient with hypogammaglobulinemia and autism spectrum disorder. These variants impair pre-ribosomal RNA processing and trigger nucleolar stress, suggesting a new ribosomopathy.

Longitudinal profiling of 136 newborns shows thymic output peaks at 3–4 mo, correlating with plasma RANKL, lymphotoxin-α, and the TCRD variant rs2204985. In thymic tissue, RANKL tracks medullary—but not cortical—epithelial cellularity, suggesting a microenvironmental basis for thymopoiesis.

Riley, Kotzin et al. screened 43,731 adult exomes and identified six individuals with STING gain-of-function mutations that cause pediatric SAVI. These adults presented with phenotypes ranging from lupus and polychondritis to clinical non-penetrance, none previously diagnosed with SAVI. This establishes AO-SAVI, suggesting that monogenic inborn errors of immunity may be underrecognized in adults.

Griscelli syndrome type 2 typically presents with hypopigmentation and HLH, but some patients retain normal pigmentation. Tanaka et al. functionally characterize compound heterozygous RAB27A variants in Japanese patients, showing allele-specific dissociation of melanosome transport and cytotoxic function, underscoring the need for integrated genetic and functional diagnosis.

CGD is an inborn error of immunity caused by pathogenic variants in genes encoding the phagocyte NADPH oxidase complex. In a multicenter cohort of 39 Colombian patients, we define clinical, microbiological, and genetic features, expanding the regional variant spectrum and highlighting the need for earlier diagnosis and improved access to specialized testing.

In FAS deficiency, lymphoproliferation is driven by FAS-controlled T cells (FCT), yet underlying metabolic programs remain unclear. Using EBV-activated effector T cells as a benchmark, Maccari et al. show that FCT display comparably heightened glycolysis, but a metabolic program uncoupled from T-BET expression and IFNγ production.

Allogeneic processed thymus tissue-agdc (RETHYMIC) is approved therapy for treatment of congenital athymia. Study outcomes include changes in T lymphocyte subsets and T cell function. Immune reconstitution was not associated with T cell function, immune suppression, or HLA matching. Younger age at implantation was associated with improved immune reconstitution.

Suri et al. from PGIMER, Chandigarh, India, report large vessel vasculopathy as a rare, life-threatening, and underrecognized complication of Wiskott–Aldrich syndrome, often mimicking Takayasu arteritis. They implicate immune dysregulation, endothelial injury, and viral triggers, emphasizing early vascular screening and timely definitive therapy to reduce high mortality.

Samra, Sharma, et al. identify biallelic loss-of-function variants in OSMR as the cause of a new human primary atopic disorder characterized by severe early-onset eczema, eosinophilia, and elevated IgE. Loss of OSMRβ surface expression abolishes OSM-dependent STAT signaling, revealing a key role for OSM-OSMR signaling in maintaining cutaneous immune homeostasis.

Patients with STAT2 p.R148Q variant present with life-threatening neuroinflammation, respiratory failure, and high mortality rate. Early genetic recognition and treatment with high-dose JAK inhibitors may improve outcomes in this devastating but potentially treatable interferonopathy.

Karanja-Chege et al. describe a rare case of gastrointestinal tuberculosis in a severely immunosuppressed three-month-old infant presenting with intestinal obstruction in Kenya. Despite surgery and intensive care, life-threatening complications develop. The report underscores the diagnostic challenges, need for early recognition, immunodeficiency evaluation, and clearer management guidance for this severe condition.

CD55 deficiency drives complement hyperactivation, severe gastrointestinal pathology, and disrupted B cell homeostasis. Our findings show that complement inhibition in CHAPLE disease restores serum immunoglobulin levels, re-establishes a normal B cell profile, and enables effective humoral protection and optimal vaccine responses.

This multiple-case study explores the burdens of illness, caregiving, and treatment for five families with children with severe leukocyte adhesion deficiency, type I (LAD-I). It highlights the experiences of nine caregivers and describes the ways their lives are impacted by this rare inborn error of immunity.