Original Research ARTICLE
Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis
- 1Immunology Outpatient Clinic, Austria
- 2University Clinic for Blood Group Serology and Transfusion Medicine, Medical University Vienn, Austria
- 3Department für Gesundheitswissenschaften und Biomedizin, Donau-Universität Krems, Austria
- 4Center for Biomedical Research, Medical University Vienna, Austria
- 5Fakultät für Medizin, Sigmund Freud Privat Universität Wien, Austria
B cell activation via the BCR signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLNK in two unrelated patients that perturb the intrinsic B-cell receptor signaling pathway and lead to selective IgM deficiency, whereas production of other immunoglobulin isotypes and IgG antibody response remain intact. Currently it is unknown how BCR signaling strength affects mature B cell development in humans. Both patients show reduced levels of BCR signalosome phosphorylation as well as impaired BCR-dependent Ca2+ influx, which was accompanied by a marked decreased in IgD+IgM+CD27+ MZ-like B-cells. We further describe reduced expression of essential B cell differentiation factors such as BAFF-R and T-Bet in the patients’ B-cells, which might contribute to the observed deficiency of MZ-like B cells.
MZ-like B cells are known to produce natural IgM antibodies that play an essential role in immune homeostasis. By using surface plasmon resonance (SPR) technology and a synthetic blood group A trisaccharide as antigen we were able to show that both patients lack the presence of anti-blood group A IgM considered to be prototypical natural antibodies whereas IgG levels were normal. Antibody binding dynamics and binding affinity of anti-blood group A IgG were comparable between patients and healthy controls. These results indicate that human IgM deficiency can be associated with signaling defects in the BCR signalosome, defective production of natural IgM antibodies in the blood group A/B/0 system and abnormalities in B cell development.
Keywords: Primary immunodeficiency (PID), B-cell defects, BTK – Bruton's tyrosine kinase, BLNK, selective IgM deficiency
Received: 01 Aug 2018;
Accepted: 04 Dec 2018.
Edited by:WANLI LIU, Tsinghua University, China
Reviewed by:Kishore Alugupalli, Thomas Jefferson University, United States
Lee A. Garrett-Sinha, University at Buffalo, United States
Copyright: © 2018 Geier, Sauerwein, Leiss-Piller, Zmek, Fischer, Eibl and Wolf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Hermann M. Wolf, Immunology Outpatient Clinic, Vienna, Austria, email@example.com