Genetic polymorphisms in IL-2, IL-10 and FOXP3 are associated with autoimmune neutropaenia in early childhood and autoantibody specificity in a Danish cohort

Kirstine Kløve-Mogensen*, Rudi Steffensen, Tania Nicole Masmas, Andreas Glenthøj, Christina Friis Jensen, Paul Ratcliffe, Petter Höglund, Henrik Hasle, Kaspar René Nielsen, Thure Mors Haunstrup

*Corresponding author for this work

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Abstract

Autoimmune neutropaenia (AIN) in early childhood is characterized by chronic neutropaenia and positivity for human neutrophil antibodies (HNA), resulting in the excessive destruction of neutrophils. The association between regulatory T cells (Tregs) and AIN has been described, and in this study, we investigated three Treg-associated genes, IL-2, IL-10 and FOXP3. The frequencies of three single nucleotide polymorphisms (SNPs) in IL-2 −330T>G (rs2069762), +114G>T (rs2069763) and IVS3-116 A>G (rs2069772), four SNPs in IL-10 −3575T>A (rs1800890), −1082G>A (rs1800896), −819 C>T (rs1800871) and −592 C>A (rs1800872) and three SNPs in FOXP3 –3499 A>G (rs3761547), −3279 C>A (rs3761548) and −924 A>G (rs2232365) were compared between 166 Danish AIN patients and 358 healthy controls. Disease association was observed for IL-2 IVS3-116 GG (p = 0.0081, OR = 0.35 [0.15–0.80]), IL-10 −3575 TT (p = 0.0078, OR = 1.71 [1.16–2.54]) and IL-10 −1082 AA (p = 0.014, OR = 1.76 [1.14–2.72]) in all patients and FOXP3 –924 (p = 0.0005, A OR = 0.41 [0.25–0.68] and G OR = 2.42 [1.46–4.01]) in male patients. None of the associations were linked to antibody specificity. Disease-associated haplotypes were observed in IL-2 and FOXP3. IL-2 −330T/+114 T/IVS3-116A was associated with anti-FcγRIIIb-positive patients (p = 0.012, OR = 2.07 [1.18–3.62]). FOXP3 –3499A/–3279C/−924A was associated with anti-HNA-1a-positive male patients (p = 0.016, OR = 0.41 [0.20–0.83]), and ACG was associated with female patients, both in the combined group (p = 0.006, OR = NA) and the anti-FcγRIIIb-positive group (p = 0.002, OR = NA). We conclude that our findings reveal a correlation between SNP in Treg-associated genes and AIN, indicating that AIN could be driven by dysfunction of immune homeostatic-evolving Tregs.

Original languageEnglish
Article numbere13374
JournalScandinavian Journal of Immunology
Volume100
Issue number2
Number of pages16
ISSN0300-9475
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.

Keywords

  • autoantibody
  • autoimmune neutropaenia
  • FOXP3
  • genetic
  • IL-10
  • IL-2
  • regulatory T cells

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