Stuart G. Tangye

Autosomal-dominant hyper-IgE syndrome (HIES) is characterized by chronic mucocutaneous candidiasis, recurrent sinopulmonary complications, noninflammatory atopic dermatitis, high amounts of serum IgE, and nonimmunological manifestations affecting the musculoskeletal and vascular systems. Most cases are caused by heterozygous loss-of-function, dominant-negative (LOF/DN) variants that affect the DNA binding, SH2, or transactivation domains of STAT3. Here, we report a patient with a unique STAT3 allele affecting the STAT3 N-terminal domain (R31Q), who presented with disseminated invasive aspergillosis affecting the brain and lung, bronchiectasis, and high serum IgE but lacked nonimmune disease manifestations. Biochemical analyses in cell lines demonstrated that R31Q reduced the abundance and transcriptional activity of STAT3 and caused it to exhibit negative dominance on wild-type (WT) STAT3. This was due to preferential STAT3 ^R31Q dimerization with STAT3 ^WT , sequestration of STAT3 ^WT :STAT3 ^R31Q dimers in the cytosol, and a reduction in STAT3 nuclear translocation and transcriptional activity. Lymphocytes from the patient exhibited some typical defects observed in canonical STAT3 ^LOF/DN HIES, such as reduced memory B cells, MAIT cells, and T _H 17 cytokines. However, naïve B cells from this patient had only a partial impairment in immunoglobulin secretion induced by interleukin-21 (IL-21) in vitro, and the patient had normal numbers of T _H 2 cells and circulating T _FH cells. Our findings reveal that the N-terminal domain regulates STAT3 dimer formation and function and provide a previously unknown biochemical mechanism of disease pathogenesis in STAT3 ^LOF/DN HIES.

Validating weak gene–disease associations requires statistical support from large case–control studies. In contrast, strong (e.g., monogenic) gene–disease associations may be established from relatively few affected individuals, when independent orthogonal evidence converges. Here, we examine four publications associating heterozygous variants in five genes—TNIP1, P2RY8, BLK, BANK1, and SH2B3—with autoimmune disease (predominantly systemic lupus erythematosus [SLE]). While we do not dispute the molecular findings of these studies, we do not accept the proposed disease associations, which lack case–control evidence and where high minor allele frequencies in non-disease populations, indicate that the genotypes are far too common to represent Mendelian disease alleles. Additionally, 8 of 18 alleles were searchable in UK Biobank, and none showed enrichment in SLE. Until further evidence emerges, caution is warranted in ascribing disease association to heterozygous genotypes in TNIP1, P2RY8, BLK, BANK1, and SH2B3, and linkage to patients in clinical pedigrees should not be taken as inferring a monoallelic inborn error of immunity.

Inborn errors of immunity (IEIs) are rare monogenic disorders with diverse, often life-limiting manifestations. Next-generation sequencing (NGS) has transformed IEI diagnostics, but data on therapeutic impact remain limited. We conducted a multicenter retrospective study through the Clinical Immunogenomics Research Consortium of Australasia, encompassing 12 hospitals across Australia and New Zealand. Probands with confirmed monogenic IEIs diagnosed by panel, whole-exome, or whole-genome sequencing were included. Among 205 probands with pathogenic variants in 86 genes, NGS findings prompted management changes in 84%: 71.7% major and 12.2% minor. Major changes included recommendation/planning for hematopoietic stem cell transplant (40.8%), initiation of targeted therapies (39.5%), and immunoglobulin replacement or prophylactic antimicrobials (18.4% each). Cascade testing identified 32 affected relatives, including four from probands who themselves did not have a discernible management change, demonstrating the broader impact of molecular diagnosis. Overall, NGS-based diagnosis drove substantial management changes and further defined the Australasian IEI landscape, supporting early genomic testing as a cornerstone of precision care.

Background: Primary immune regulatory disorders (PIRDs) represent a rapidly growing group of inborn errors of immunity (IEIs) characterized by infection susceptibility, autoimmunity, inflammation, and lymphoproliferation. However, the core features of the gene-disease relationships underlying these conditions are often obscured by limitations in available published data. The Clinical Genome Resource (ClinGen) is an international collaborative effort that seeks to address this challenge for PIRDs and other monogenic diseases through a standardized framework for classifying the strength of gene-disease relationships. Objective: We sought to systematically evaluate the evidence for proposed PIRD gene-disease relationships and identify conserved phenotypic features across this heterogeneous group of disorders. Methods: Using the standardized ClinGen framework, the ClinGen PIRD Gene Curation Expert Panel (GCEP) identified potential gene-disease relationships for monogenic conditions characterized predominantly by immune dysregulation. We subsequently curated evidence relevant to these relationships, classified the strength of evidence for these gene-disease relationships, and evaluated clinical patterns among these conditions through standardized phenotyping using the Human Phenotype Ontology (HPO). Results: As of April 2026, the PIRD-GCEP has curated a total of 46 genes corresponding to 49 gene-disease relationships characterized by immune dysregulation. Of these, 28 were categorized as definitive, 2 as strong, 9 as moderate, 7 as limited, and 3 as disputed. Analysis of HPO-based phenotyping revealed 3 major phenotypic clusters corresponding to lymphoproliferation and systemic inflammation, atopic and gastrointestinal inflammation, and combined immune deficiency with autoimmunity. Conclusion: The PIRD-GCEP framework provides validated gene-disease classifications and identifies three distinct phenotypic clusters, facilitating improved diagnosis while revealing genes requiring further investigation to confirm their role in immune regulatory disorders.

We previously reported inherited retinoic acid–related orphan receptor γ T (RORγT) deficiency in seven patients from three ancestries (Chilean, Palestinian, and Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afghan, Indian, Iranian, Japanese, and Sri Lankan), each homozygous for a new loss-of-function RORC variant. All but one patient—the exception receiving early prophylaxis—developed mycobacterial disease due to a near-complete depletion of innate-like adaptive T cells, including mucosa-associated invariant T and invariant natural killer T cells, low counts of adaptive TH1* and CD8+ T cells, and impaired Mycobacterium-induced IFN-γ production by the remaining cells of these subsets, NK cells, conventional CD4+ T, Vδ1, and Vδ2 γδT cells. Most patients also displayed CMC due to their low counts of TH17 and TH1* cells. One patient died from disseminated Bacille Calmette-Guérin vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable at ages of 2 to 20 years. RORγT is essential for protective immunity against mycobacteria and Candida in humans.

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23–dependent IFN-γ production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12Rβ1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-γ production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria.

B cells contribute to many facets of adaptive immunity, including key roles as Ag-presenting cells, cytokine-producing cells, and plasma cells secreting protective antibodies. However, B cell functional dysregulation can result in myriad immune dyscrasias, such as immunodeficiency, chronic infection, autoimmunity, allergy, and malignancy. Thus, it is critical to understand fundamental aspects of human B cell differentiation and effector function. A B cell subset that has attracted much attention over the past 2 decades is a population known by many identities—CD21lo, atypical memory, CD27negIgDneg, age-associated, exhausted—and associated with many diseases, especially humoral immune dysregulation. However, these cells likely also contribute to humoral immunity in the setting of vaccination and natural infection. This Review tries to provide an overview of the discoveries, origins, and complexities of CD21lo 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 function in health and disease.

Nearly 100 individuals have been identified who carry deleterious biallelic germline variants in CARD9 and experience life-threatening, invasive fungal infections caused by Ascomycetes but are otherwise resistant to other infectious agents. CARD9 is an adaptor protein expressed predominantly in myeloid cells, which functions downstream of dectin receptors, pattern recognition receptors for fungal antigens, to activate innate immune responses. The impact of CARD9 deficiency on lymphocytes, however, is less clear. We deciphered the functional consequences and delineated mechanisms of disease in a patient (P1) with a nonsense germline homozygous CARD9 variant (c.673A>T/p.K225*) and invasive Candida disease. P1’s PBMCs expressed truncated CARD9 and showed significantly reduced cytokine production in response to fungal ligands. P1 had reduced frequencies of circulating memory CD4 ⁺ T _H 17-like (CCR6 ⁺ CXCR3 ^– ) cells. In addition, in vitro differentiation of P1’s naive CD4 ⁺ T cells into IL-17A/IL-17F–secreting cells was greatly impaired. Consistent with impaired responses of innate and adaptive immune cells from P1 in vitro, proportions of Candida -specific CD4 ⁺ T cells were strongly and selectively diminished. Our findings suggest that the CARD9 variant identified in P1 is pathogenic, affecting not only CARD9-induced immunity mediated by myeloid cells but also CD4 ⁺ T cell–intrinsic IL-17–dependent immunity and Candida -specific T cell responses.

The transcription factor IKAROS plays an important role in lymphocyte development, differentiation, and as a tumor suppressor. To date, >70 IKAROS germ line heterozygous variants have been reported in patients with primary immunodeficiency (PID)/inborn errors of immunity (IEI) and leukemia, and this number continues to grow. Germ line IKAROS loss- and gain-of-function mutations have been linked to immunodeficiency, immune dysregulation, and hematologic malignancies, with a broad spectrum of clinical manifestations. Routine next-generation sequencing approaches in patients with PID/IEI have facilitated the identification of IKAROS variants, including several cases with variants of uncertain significance (VUS). To determine the VUS’ functional behavior, we systematically generated constructs recapitulating those changes and tested IKAROS functions in vitro. We also conducted an in-depth examination of the C-terminal dimerization domain using alanine-scanning mutagenesis to identify amino acids critical for dimerization and other functions. This work provides a comprehensive description of the biologic impact of 81 previously unreported and/or untested IKAROS variants, including 33 patient-detected germ line VUS and 48 laboratory-generated mutations in the dimerization domain. Among them, 15 of the patient-detected variants, primarily mapping to IKAROS DNA-binding or dimerization domains, and at least 21 of the laboratory-generated mutations, impaired IKAROS function and could explain or result in human disease. VUS located in between IKAROS DNA binding and dimerization domains were less likely to be functionally deleterious. Of note, both positive and negative functional data herein generated can be relevant for patients carrying these IKAROS variants, helping to establish a diagnosis and guide treatment decisions.