bims-actimu 2025-12-21 papers

Clin Immunol. 2025 Dec 17. pii: S1521-6616(25)00233-5. [Epub ahead of print] 110658

Clinical spectrum of Wiskott-Aldrich syndrome carriers: Self-reported survey of 193 carriers.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with microthrombocytopenia, eczema, immunodeficiency, autoimmunity and malignancies resulting from WAS pathogenic variants. Prevalence of disease in heterozygous female carriers has not been described previously. An online Qualtrics survey was designed in collaboration with the Wiskott-Aldrich Foundation, the Immune Deficiency Foundation, the Primary Immune Deficiency Treatment Consortium and Emory University to describe the incidence of thrombocytopenia, eczema, infections, autoimmune disorders, malignancies, and psychosocial factors. 193 carriers with a median age of 39 years participated in this survey. Respondents were predominantly White and were mothers of WAS patients. We observed a high prevalence of thrombocytopenia (13 %), eczema (22 %), infections (33 %) and autoimmunity (24 %) in this self-reported survey. No hematological malignancies were reported. Guilt (91 %), anxiety (41 %) and depression (44 %) were very prevalent. Comprehensive clinical and immunologic studies of WAS carriers should be prioritized to define appropriate health screening, preventive approaches, and counselling for carriers. SUMMARY: This self-reported survey describes the disease burden in 193 carriers of X-linked Wiskott-Aldrich syndrome. It highlights the increased incidence of thrombocytopenia, eczema, infections and autoimmunity in WAS carriers and the need for more comprehensive studies of WAS carriers.

Keywords: Carriers; Immune deficiency; Wiskott-Aldrich syndrome

DOI: https://doi.org/10.1016/j.clim.2025.110658

Front Immunol. 2025 ;16 1725282

Mapping the landscape of autoimmunity and autoinflammation in inborn errors of immunity: broad distribution with distinct clustering patterns.

Objective: In this study, we analyzed a large cohort of Algerian patients with inborn errors of immunity (IEI) to delineate the burden, spectrum, and distribution of autoimmune and autoinflammatory manifestations.
Methods: This retrospective cohort study was based on recorded data from 825 Algerian patients with IEI. For each patient, autoimmune and autoinflammatory complications occurring before and/or after IEI diagnosis were systematically assessed and documented.
Results: Autoimmune and/or autoinflammatory manifestations were observed in 217 patients (26.3%) and, notably, represented the initial clinical presentation in nearly half. Autoimmune features were documented in 163 patients (19.8%), including 26 (3.2%) with concurrent autoinflammatory findings, whereas isolated autoinflammatory conditions were observed in 54 patients (6.5%). A broad spectrum was observed, with autoimmune cytopenias predominating (11.4%), followed by gastrointestinal (7.8%), rheumatologic (5.3%), and endocrine (3.4%) disorders. Immune dysregulation was a recurrent theme across all IEI categories, with a distinct, disease-specific, clustering of autoimmunity and autoinflammation. Autoimmune cytopenias predominated in T-cell defects, including hypomorphic RAG and CD3γ deficiencies; Inflammatory bowel disease (IBD) was enriched in ARPC1B, DOCK8, and CD55 deficiencies, as well as in chronic granulomatous disease (CGD); endocrine autoimmunity, while a cardinal feature of APECED and IPEX, also characterized STAT1 gain-of-function; inflammatory granulomatous lung disease was a consistent feature in LRBA deficiency; and granulomatous inflammation, whether confined to the lungs or extending to other organs, was prominent in common variable immunodeficiency.
Conclusion: Recognition of clustering patterns, particularly autoimmune cytopenias, IBD, and endocrine autoimmunity, has direct clinical implications. These manifestations should be regarded as red flags, guiding targeted evaluation and genetic testing. Mapping such associations not only refines our understanding of pathogenesis but also provides a practical framework for earlier diagnosis and tailored management.

Keywords: CD55 deficiency; RAG deficiency; autoimmune cytopenia; autoimmunity; autoinflammation; clustering patterns; inborn errors of immunity; inflammatory bowel disease

DOI: https://doi.org/10.3389/fimmu.2025.1725282

J Hum Immun. 2025 Sep;1(3): e20250041

Intronic branchpoint-to-acceptor variants underlying inborn errors of immunity.

Clinical laboratories searching for pathogenic variants focus mostly on the protein-coding region and corresponding essential splicing sites. Screening for variants in intronic regions requires dedicated bioinformatics tools and detailed experimental studies to confirm deleteriousness and pathogenicity. We report intronic variants in a cohort of eight patients from seven kindreds with unexplained inborn errors of immunity (IEI). Using ad hoc bioinformatics tools, we identified seven kindreds carrying three branchpoint variants at three loci (BTK, SH2D1A, and WAS) and four AG-gain acceptor site variants at another three loci (DOCK8, NFKB1, STXBP2, and UNC13D). The variants were located between positions -9 and -49 relative to the wild-type acceptor site. The deleteriousness and, thus, pathogenicity of these variants were confirmed by exon-captured transcriptome studies and flow cytometry analyses of protein production or function. Our findings indicate that intronic variants should be systematically screened and investigated, even in clinical laboratory settings.

Keywords: Inborn error of immunity; branchpoint; genetics; intronic variants; pathogenicity

DOI: https://doi.org/10.70962/jhi.20250041