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bioRxiv · 10.1101/2024.02.10.579765

Abatacept treatment in LRBA deficient patients results in an increase in circulating FoxP3+ Helios + natural Treg

Donhauser, S.·Salzmann-Manrique, E.·Schubert, R.·Huenecke, S.·Bakhtiar, S.
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Abstract

BackgroundMutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified to cause autoimmunity and immunodeficiency with a broad spectrum of clinical manifestations. Increased lysosomal degradation of the CTLA-4 due to the lack of recylcing by LRBA protein has been described resulting in a reduced suppressive capacity of regulatory T cells (Treg). >ObjectiveWe sought to explore the extended Treg profile of patients with LRBA deficiency (N=6) compared to reference values for Treg subpopulations from an age-matched healthy cohort (N=39) prior and during abatacept treatment as well as after allogeneic haematopoietic stem cell transplantation. In parallel we assessed the feasibility and robustness of the CHAI and the IDDA2.1 scores for this cohort. MethodsUsing a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, we analyzed Treg subsets including CD4+CD25hiFoxP3+ Treg, Helios+ natural Treg, Helios- induced Treg, CD39+ Treg, CD62L+CD45RA+ naive Treg, CD62L+CD45RA- memory Treg, and FoxP3hiCD45RA- effector Treg as well as CD4+CD25hiCD127low Treg. Longitudinal data were collected while patients were receiving abatacept and in three patients after alloHSCT. CHAI and IDDA2.1 scores were performed. ResultsThe healthy cohort including individuals from the ages of 2 to 40 years showed a steady total CD25hiFoxP3+ Treg population around 5%, while there was a significant age-dependent increase in Helios+ natural Treg (P=0.003), Helios- induced Treg (P=0.046), CD62L+CD45RA- memory Treg (P=0.020) with a continuous decrease in CD62L+CD45RA+ naive Treg (P=0.015) and CD4+CD25hiCD127low Treg (P=0.024) over time. LRBA deficient patients showed a significant lack in FoxP3+Helios+ natural Treg (P=0.003), CD62L+CD45RA+ naive Treg (P<0.001), FoxP3hi CD45RA+ effector Treg (P=0.001) and CD4+CD25hiCD127low Treg (P=0.005), while their CD62L+CD45RA+ memory Treg (P=0.016) were significantly elevated. Abatacept treatment led to a significant increase in natural Treg (P=0.003) in patients without having a measurable effect on the other subpopulations. This was accompanied by a decrease in sIL2R levels. The IDDA2.1 score was feasible for this mainly pediatric cohort and correlated with patients clinical course of the disease. ConclusionWithin the Treg subsets in peripheral blood of LRBA deficient patients, there is a significant lack of natural, naive, effector and CD4+CD25hiCD127low Treg, while memory Treg are elevated. During abatacept treatment we observe a significant increase in circulating Helios+ natural Treg levels. IDDA2.1 scoring system is feasible for pediatric patients to assess the severity of their disease and the response to the treatment.

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Donhauser, S., Salzmann-Manrique, E., Schubert, R., Huenecke, S., Bakhtiar, S.. 2024-02-13. Abatacept treatment in LRBA deficient patients results in an increase in circulating FoxP3+ Helios + natural Treg. https://doi.org/10.1101/2024.02.10.579765

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