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

Azzeddine Tahiat^1*Souad Touri²Amina Saad-Djaballah³Saliha Hakem⁴Faiza Fernini⁴Samira Aggoune⁵Hayet Belhadj⁶Chafa Bendahmane⁷Linda Mokrane¹Tahar Bencharif Madani⁸Zouleikha Benhacine⁹Souhila Melzi¹⁰Rawda Aboura¹⁰Hassen Messaoudi¹¹Houda Boudiaf¹²Mohamed Samir Ladj¹³Tahar Khelifi Touhami¹⁴Lynda Taibi¹⁵Samira Zobiri¹⁵Rachid Bouhdjila⁹Zahir Bouzerar¹⁰Ouardia Ibsaine⁷Leila Kedji²Abdelghani Yagoubi¹⁶Reda Belbouab⁴Rachida Boukari⁴Leila Smati³Sergio Rosenzweig¹⁷Dusan Bogunovic¹⁸Luigi Daniele Notarangelo¹⁹Kamel Djenouhat¹

• ¹Department of Medical Biology, Rouiba Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ²Department of Pediatrics, Blida University Hospital, University of Blida, Blida, Algeria
• ³Department of Pediatrics, Bologhine Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ⁴Department of Pediatrics, Mustapha University Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ⁵Department of Pediatrics, El-Harrach Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ⁶Department of Pediatrics, Army Mother and Child Hospital, University of Health Sciences, Algiers, Algeria
• ⁷Department of Pediatrics, Ain Taya Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ⁸Department of Pediatrics, Mansourah Hospital, University of Constantine, Constantine, Algeria
• ⁹Department of Pediatrics, Constantine University Hospital, University of Constantine, Constantine, Algeria
• ¹⁰Department of Pediatrics, Bab El-Oued University Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ¹¹Department of Internal Medicine, Rouiba Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ¹²Department of Pediatric Oncology, Mustapha University Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ¹³Department of Pediatrics, Birtraria Hospital El Biar, Algiers University of Health Sciences, Algiers, Algeria
• ¹⁴Private Practitioner, Constantine, Algeria
• ¹⁵Department of Dermatology, Mustapha University Hospital, Algiers University of Health Sciences, Algiers, Algeria
• ¹⁶Pediatric gastroenterology, Centre Algérois de Pédiatrie, Algiers, Algeria
• ¹⁷immunology service, department of laboratory medicine, clinical center, national institutes of health, Bethesda, United States
• ¹⁸Department of Pediatrics, Center for Genetic Errors of Immunity, Columbia University, New York, United States
• ¹⁹National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States

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 (11.3%), 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.