Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation.

Abstract

BACKGROUND:

B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA.

OBJECTIVE:

We investigated the role of B cells in XLN pathogenesis.

METHODS:

We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response.

RESULTS:

XLN patients had normal naive B cells and plasmablasts, but reduced IgA+ B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells.

CONCLUSIONS:

Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching.

• Authors: Minghui He, Mezida B Saeed, Julien Record, Marton Keszei, Lia Gonçalves Pinho, Larissa Vasconcelos-Fontes, Roberta D'Aulerio, Rhaissa Vieira, Mariana M S Oliveira, Chiara Geyer, Lena Bohaumilitzky, Meike Thiemann, Ekaterina Deordieva, Lieselot Buedts, Joao Pedro Matias Lopes, Dmitry Pershin, Lennart Hammarström, Yu Xia, Xiaodong Zhao, Charlotte Cunningham-Rundles, Adrian J Thrasher, Siobhan O Burns, Vinicius Cotta-de-Almeida, Chaohong Liu, Anna Shcherbina, Peter Vandenberghe, Lisa S Westerberg
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 149 Issue 3 Pg. 1069-1084 (03 2022) ISSN: 1097-6825 [Electronic] United States
• PMID: 34384840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Immunoglobulin A
• WAS protein, human
• Was protein, mouse
• Wiskott-Aldrich Syndrome Protein

Topics

• Animals
• B-Lymphocytes (cytology)
• Cell Division
• Genetic Diseases, X-Linked
• Humans
• Immunoglobulin A
• Mice
• Neutropenia (genetics)
• Plasma Cells (pathology)
• Wiskott-Aldrich Syndrome Protein (metabolism)