Loss of ARHGEF1 causes a human primary antibody deficiency

RhoA as a Key Regulator of Innate and Adaptive Immunity

“…Consequently, Gα13-deficient mice developed B cell lymphoma [227]. Recently, Bouafia and co-workers demonstrated that an inherited loss-of-function mutation of RhoA-specific ARHGEF1 in human was the cause for elevated frequencies of transitional B cells, accompanied by a lack of splenic marginal zone B cells and memory B cells [229]. Consequently, patients suffered from impaired antibody production and, hence, recurrent infections.…”

ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function

“…Given the typical complex genetic etiology for PADs, it is noteworthy that Bouafia et al (5) provide compelling evidence that an ARHGEF1 deficiency leads to significant impairment in B and T lymphocyte differentiation, migration, and GPCR-mediated signaling that appears to account for the observed PAD. The identification of ARH-GEF1 deficiency that can lead to a PAD clearly establishes a critical role for ARH-GEF1, and by extension Gα12/13-associated GPCR signaling, in regulating lymphocyte development and function.…”

“…Although B cell frequencies were markedly diminished in both siblings, the MZ and memory B cell populations were more severely affected and likely contributed to the impaired TI antibody responses to S. pneumoniae and reduced Ig serum concentrations. Thus, in consideration of the findings of Bouafia et al (5) and previously characterized mouse mutants, it is clear that ARHGEF1 is not only required for the appropriate development of MZ B cells, but is also required for their ability to mount antibody responses.…”

“…The presence of B lymphocytes was markedly diminished in the peripheral blood of both ARHGEF1-deficient siblings. Consequently, to document signaling abnormalities in ARHGEF1-deficienct lymphocytes isolated from affected siblings, Bouafia et al (5) relied largely on primary T cells and T cell blasts in most of their in vitro experiments; however, transformed mutant B cells had analogous results in some experiments. More precisely, the authors treated ARHGEF1-deficient lymphocytes with agonist ligands for Gα13-associated GPCRs, including sphingosine-1-phosphate (S1P), lysophosphatidic acid (LPA), thromboxane, and CXCL12, and retrovirally introduced GNA13 (encoding Gα13) and ARHGEF1 transgenes into mutant B cells to convincingly demonstrate that loss of ARHGEF1 leads to impaired Gα13-associated GPCR signaling.…”

“…However, in the current era of -omics (genomics, proteomics, lipidomics, and metabalomics), it is now possible to identify genetic lesions that underlie symptoms in affected patients and subsequently characterize the manifestation of these mutations on lymphocyte function. In this issue, Bouafia et al (5) report on their performance and analysis of whole-exome sequencing of siblings presenting with recurrent respiratory tract infection, bronchiectasis, and an inability to mount antigen-specific antibody responses. These analyses led to the identification of two distinct ARHGEF1 mutant alleles that, together as compound heterozygous mutations, resulted in an ARHGEF1 deficiency.…”