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Bakhtiar, S.

Publications and source records attributed to Bakhtiar, S..

2 recordsLinked to original sources
bioRxiv2024

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

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.

immunology↗
bioRxiv2024

Endosomal LRBA regulates the endo-lysosomal pathway

Deleterious mutations in the LRBA (Lipopolysaccharide Responsive Beige-like Anchor protein) gene cause severe childhood immune dysregulation. The clinical manifestations of LRBA deficiency syndrome are highly variable. Thus, the complexity of the symptoms involving multiple organs and the broad range of unpredictable clinical manifestations complicate the choice of therapeutic interventions. Although LRBA has been linked to Rab11-dependent trafficking of the immune checkpoint protein CTLA-4, its precise cellular role remains elusive. We show that LRBA, however, does not colocalize with Rab11. Instead, LRBA is recruited by members of the small GTPase Arf protein family to the TGN and to Rab4+ endosomes, where it controls intracellular traffic. In patient-derived fibroblasts, loss of LRBA led to defects in the endosomal pathway yielding the accumulation of enlarged endolysosomes. Thus, LRBA appears to regulate flow through the endosomal system on Rab4+ endosomes. Our data strongly suggest functions of LRBA beyond CTLA-4 trafficking and provide a conceptual framework to develop new therapies for LRBA deficiency. SummaryLRBA-deficient patients exhibit enlarged functional endolysosomes due to defects in recycling to the plasma membrane. LRBA localization on Rab4+ endosomes depends on Arf1 and Arf3, and is essential for a functional endosomal-lysosomal pathway. Our results could inform new treatment options.

immunology↗