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Defective calcium signaling and disrupted CD20-B-cell receptor dissociation in patients with common variable
Annick A J M van de Ven1, Ewoud B Compeer, Andries C Bloem
1Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht and Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Insights
Impaired B-cell activation in common variable immunodeficiency (CVID) is linked to faulty CD20/B-cell receptor (BCR) dissociation. This defect hinders calcium signaling, potentially contributing to CVID disorders.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Common variable immunodeficiency (CVID) is characterized by impaired immunoglobulin class-switched antibody production.
- B-cell activation involves B-cell receptor (BCR) triggering, leading to signalosome formation and calcium entry.
- CD20, a B-cell surface antigen, associates with BCR in resting cells and dissociates upon signalosome formation.
Purpose of the Study:
- To investigate if CD20 dissociation from BCR during B-cell activation contributes to CVID.
- To evaluate the role of CD20/BCR interaction in early B-cell activation defects observed in CVID.
Main Methods:
- Primary B cells from pediatric CVID patients and healthy controls were analyzed.
- BCR signalosome formation, internalization, and calcium signaling were assessed.
- Gene mutations in key signaling molecules (PLCγ2, BTK) and CD22/calcium channel function were ruled out.
Main Results:
- B cells from many CVID patients showed reduced BCR-triggered calcium entry and impaired plasmablast differentiation.
- Defects were not due to CD22 upregulation or calcium channel issues, nor PLCγ2/BTK mutations.
- Crucially, B cells from CVID patients exhibited reduced dissociation of BCR from CD20.
- BCR or CD20 cross-linking resulted in less BCR internalization and downstream signaling.
Conclusions:
- CD20 dissociation from the BCR signalosome is critical for BCR-mediated calcium signaling.
- Aberrant CD20/BCR signalosome conformation may predispose individuals to CVID disorders.
- This finding highlights a novel mechanism potentially underlying CVID pathogenesis.
Background:
B cells of patients with common variable immunodeficiency (CVID) disorders display impairment in production of immunoglobulin class-switched antibodies, which is possibly contributed to by defects in early B-cell activation. On resting B cells, B-cell receptors (BCRs) are organized in oligomers that are signaling inactive. Their triggering by cognate antigen causes the lateral reorganization of BCRs and associated proteins into signalosomes, resulting in BCR-activated calcium entry. In resting cells the B-cell surface antigen CD20 is associated with the BCR but dissociates on signalosome formation.
Objective:
We sought to determine whether CD20 dissociation from the BCR during early B-cell activation might contribute to the development of CVID disorders.
Methods:
We evaluated BCR signalosome formation, internalization, and signaling in primary B cells of pediatric patients with CVID disorders and healthy control subjects.
Results:
In many pediatric patients with CVID disorders, B cells exhibit significant deficits in BCR triggering-mediated calcium entry in the cytosol, which correlates with impaired plasmablast differentiation in vitro. These alterations did not originate from upregulation of CD22 or defects in calcium channels and did not involve gene mutations in phospholipase Cγ2 or Bruton tyrosine kinase. Instead, B cells from patients with CVID disorders exhibited reduced BCR dissociation from CD20. BCR or CD20 cross-linking induced less BCR internalization, and antibody-mediated CD20 triggering elicited less BCR downstream signaling, as measured based on secondary fluxes.
Conclusions:
We propose that CD20 dissociation from the BCR signalosome is pivotal to BCR-mediated calcium mobilization in the cytosol. Defects in CD20/BCR signalosome conformation might predispose to the spectrum of CVID disorders.
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