ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome

Amika K Sood; Olivia Francis; Stephen A Schworer; Steven M Johnson; Benjamin D Smith; Paul B Googe; Eveline Y Wu

doi:10.3389/fped.2023.1179788

ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome

Front Pediatr. 2023 May 19:11:1179788. doi: 10.3389/fped.2023.1179788. eCollection 2023.

Authors

Amika K Sood¹, Olivia Francis², Stephen A Schworer^{1

2}, Steven M Johnson³, Benjamin D Smith⁴, Paul B Googe⁵, Eveline Y Wu^{2

6}

Affiliations

¹ Division of Rheumatology, Allergy, and Immunology, Department of Internal Medicine, The University of North Carolina, Chapel Hill, NC, United States.
² Division of Allergy/Immunology, Department of Pediatrics, The University of North Carolina, Chapel Hill, NC, United States.
³ Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, United States.
⁴ Division of Pediatric Radiology, Department of Radiology, The University of North Carolina, Chapel Hill, NC, United States.
⁵ Dermatopathology, Department of Dermatology, The University of North Carolina, Chapel Hill, NC, United States.
⁶ Division of Rheumatology, Department of Pediatrics, The University of North Carolina, Chapel Hill, NC, United States.

Abstract

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a combined immunodeficiency with a broad clinical phenotype, including not only an increased propensity for sinopulmonary and herpesviruses infections but also immune dysregulation, such as benign lymphoproliferation, autoimmunity, and malignancy. Autoimmune complications are increasingly recognized as initial presenting features of immune dysregulation in inborn errors of immunity (IEIs), including APDS, so awareness of the spectrum of autoimmune features inherit within these disorders is critical. We present here a patient vignette to highlight cutaneous antineutrophil cytoplasmic antibody (ANCA) vasculitis as an underrecognized autoimmune manifestation of APDS. The genetic defects underlying APDS result in increased PI3Kδ signaling with aberrant downstream signaling pathways and loss of B- and/or T-cell immunologic tolerance mechanisms, which promote the development of autoimmunity. An understanding of the molecular pathways and mechanisms that lead to immune dysregulation in APDS has allowed for significant advancements in the development of precision-medicine therapeutics, such as leniolisib, to reduce the morbidity and mortality for these patients. Overall, this case and review highlight the need to maintain a high index of suspicion for IEIs, such as APDS, in those presenting with autoimmunity in combination with a dysregulated immune phenotype for prompt diagnosis and targeted intervention.

Keywords: ANCA vasculitis; activated PI3 kinase delta syndrome; autoimmune; immune dysregulation; immunodeficiency; inborn errors of immunity; leniolisib.

Publication types

Review

Grants and funding

Schworer's work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, through Grant T32AI007062. Wu's work was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002490 and through generous donations from the Kioti Tractor Company, the Kim family, and the Smith family. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.