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Cited by 76Immunodeficiency and Autoimmune DisordersT-cell and B-cell ImmunologySystemic Lupus Erythematosus Research

Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome

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Kolhatkar, Nikita S., Brahmandam, Archana, Thouvenel, Christopher D., Becker-Herman, Shirly, Jacobs, Holly M., Schwartz, Marc A., Allenspach, Eric J., Khim, Socheath +8 more·2015·Journal of Experimental Medicine
DOI 10.1084/jem.20150585PMC PMC4577851
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Abstract

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)–deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell–intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells.

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  • During B cell development and BCR editing, defective actin polymerization at immune synapses results in weaker signals, allowing for survival of autoreactive B cells with inherently stronger signals.

    “During B cell development and BCR editing, defective actin polymerization at immune synapses results in weaker signals, allowing for survival of autoreactive B cells with inherently stronger signals [9, 39, 40].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [39]

    The Discussion (page unavailable) says WASp deficiency promotes rather than weakens BCR signaling and favors positive selection of low-affinity autoreactive transitional B cells. The Results section on negative selection (page unavailable) reports essentially identical receptor-editing measurements in deficient and control cells. These findings contradict the proposed weaker-signal, altered-editing mechanism; the cited passages do not establish the immune-synapse mechanism. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Kolhatkar, N. S., Brahmandam, A., Thouvenel, C. D., Becker-Herman, S., Jacobs, H. M., Schwartz, M. A., Allenspach, E. J., Khim, S., Panigrahi, A. K., Luning Prak, E. T., Thrasher, A. J., Notarangelo, L. D., Candotti, F., Torgerson, T. R., Sanz, I., & Rawlings, D. J.
Affiliations
  • University of Washington (US)
  • University of Pennsylvania (US)
  • Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 4
  • University College London (GB)
  • Boston Children's Hospital (US)
  • National Institutes of Health (US)
  • Lowance Center for Human Immunology 8 and 9
Corresponding author
Rawlings, David J.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2015-09-14
Volume
212
Issue
10
Pages
1663-1677
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20150585
PMC
PMC4577851
OpenAlex
W1641024157
Cited by
76
References
0
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 9 · 2018: 8 · 2017: 11 · 2016: 10 · 2015: 1
FWCI
4.43
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Cancer Research Institute
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL075453, P01HL059561)
  • National Institute of General Medical Sciences (T32GM007266)
  • National Institute of Allergy and Infectious Diseases (R01AI084457, R37AI049660, R01AI071163, U19AI110483)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK097672, U01DK070430)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
Keywords
Wiskott-Aldrich syndrome, B cell receptor signaling, Toll-like receptor signaling, positive selection, transitional B cells, naive B cells, B cell tolerance, autoimmunity, MyD88, marginal zone B cells, B cell receptor repertoire, X-linked immunodeficiency
MeSH terms
Adolescent, Adult, Animals, B-Lymphocytes, Child, Child, Preschool, Humans, Infant, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Antigen, B-Cell, Wiskott-Aldrich Syndrome, Case-Control Studies, Mice, Knockout, Cytoprotection, Toll-Like Receptors, Wiskott-Aldrich Syndrome Protein, B-Cell Activating Factor, Myeloid Differentiation Factor 88, Young Adult, High-Throughput Nucleotide Sequencing

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