Loss of ARHGEF1 causes a human primary antibody deficiency

J Clin Invest. 2019 Mar 1;129(3):1047-1060. doi: 10.1172/JCI120572.

Amine Bouafia ¹ ², Sébastien Lofek ¹ ², Julie Bruneau ³, Loïc Chentout ¹ ², Hicham Lamrini ¹ ², Amélie Trinquand ⁴, Marie-Céline Deau ¹ ², Lucie Heurtier ¹ ², Véronique Meignin ⁵, Capucine Picard ² ⁶ ⁷ ⁸, Elizabeth Macintyre ⁴, Olivier Alibeu ⁹, Marc Bras ¹⁰, Thierry Jo Molina ³, Marina Cavazzana ¹ ² ¹¹, Isabelle André-Schmutz ¹ ², Anne Durandy ¹ ², Alain Fischer ² ⁸ ¹² ¹³, Eric Oksenhendler ¹⁴ ¹⁵, Sven Kracker ¹ ²

Affiliations

1 Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France.
2 Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
3 Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4 Hématologie Biologique and INSERM UMR 1151, University Paris Descartes, Sorbonne Paris Cité, Paris, France.
5 Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France.
6 Primary Immunodeficiency Study Center, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
7 Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France.
8 Department of Paediatric Immunology, Hematology and Rheumatology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
9 Genomics Facility, INSERM UMR 1163, Imagine Institute, Paris, France.
10 Bioinformatics Facility, INSERM UMR 1163, University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.
11 Assistance Publique-Hôpitaux de Paris, Department of Biotherapy and Clinical Investigation Centre, Hôpital Necker-Enfants Malades, Paris, France.
12 Collège de France, Paris, France.
13 INSERM UMR 1163, Imagine Institute, Paris, France.
14 Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
15 EA3518, Université Paris Diderot Paris 7, Paris, France.

PMID: 30521495 DOI: 10.1172/JCI120572

Abstract

ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome Sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients' blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients' lymphocytes failed to efficiently restrain Akt phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients' cells corrected the impaired actin polymerization and Akt regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin Cytoskeleton dynamics, restraining PI3K/Akt signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.

Keywords

Adaptive immunity; B cells; Genetic diseases; Immunology.

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