RAC2 gain of function variants causing inborn error of immunity drive NLRP3 inflammasome activation

A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here we show that RAC2 activating mutations induce the NLRP3 inflammasome leading to the secretion of IL-1 and IL-18 from macrophages. This induction depends on the RAC2 mutation and in particular their activation state. This suggests that inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.
To investigate in depth the impact of the activating variant RAC2 A59S we performed a single cell RNAseq analysis of blood circulating cells. This analysis showed increased numbers of both classical and non classical monocytes as well as myeloid dendritic cells when compare..., Blood samples were processed for Chromium Single Cell Gene Expression Flex analysis according to manufacturer protocol. Whole blood cells from control (n= 8078 cells) and RAC2 A59S patient (n= 14524 cells) were analyzed.  Raw sequencing data were processed using the 10× Chromium CellRanger \"multi\" analysis pipeline (version 7.0.0). Reads were aligned to the human reference genome (GRCh38-3.0.0) (10x Genomics)., , # Data from: RAC2 gain of function variants causing inborn error of immunity drive NLRP3 inflammasome activation.

[https://doi.org/10.5061/dryad.p8cz8w9zx](https://doi.org/10.5061/dryad.p8cz8w9zx)

Single cell on blood samples were processed for Chromium Single Cell Gene Expression Flex analysis according to manufacturer protocol. Whole blood cells from control (n= 8078 cells) and RAC2 A59S patient (n= 14524 cells) were analyzed.  Raw sequencing data were processed using the 10× Chromium CellRanger \"multi\" analysis pipeline (version 7.0.0). Reads were aligned to the human reference genome (GRCh38-3.0.0) (10x Genomics).

## Description of the data and file structure

The study includes data from a patient carrying the A59S mutation and a representative control. The processed data for these subjects are stored in two separate folders: `filesample_filtered_feature_bc_matrix_A59S` for the patient and `filesample_filtered_feature_bc_matrix_Control` for the control. Containing matrix, featur...