The Role of Altered Antigen Receptor Signaling in Selection and Homeostasis of Peripheral B cells in Wiskott-Aldrich Syndrome
Kolhatkar, Nikita Santosh
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Humoral immunity and the ability to recognize and protect against a broad spectrum of pathogens is dependent on the range of receptor diversity within the B cell compartment. An inherent problem associated with generating a highly diverse B cell repertoire is the risk of selecting B cell receptors (BCRs) specific for self-antigens. To reduce the threat of autoimmunity, there are several tolerance checkpoints throughout B cell development aimed at purging self-reactive B cells from entering the mature repertoire. We have established a role for dual BCR and TLR signaling in modulating both B cell tolerance and homeostasis in autoimmune-prone settings using the murine model of Wiskott-Aldrich Syndrome. 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 both the establishment and homeostasis of the mature, naïve BCR repertoire. We evaluated the naïve B cell repertoire in both WASp-deficient mice and WAS subjects via high-throughput sequencing and single cell cloning analysis. We found altered heavy chain usage and enrichment for low affinity, self-reactive specificities in the naïve B cell repertoire. Alterations to the naïve repertoire were primarily due to enhanced proliferation of self-reactive transitional cells in vivo mediated by antigen- and Myd88-dependent signals. In addition to modulating positive selection, we also found a role for dual BCR and TLR signals in regulating marginal zone (MZ) B cell homeostasis in WAS. WASp deficiency markedly reduces splenic MZ B cells without impairing MZ B cell development, implying that retention of WAS MZ B cells is abnormal. However, upon deletion of B-cell intrinsic TLR 7 signals or antigen-dependent BCR signals, MZ B cell retention is restored, indicating that dual TLR 7/BCR signals drive spontaneous activation and egress of MZ B cells. 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 both alter B cell tolerance via positive selection of self-reactive transitional B cells as well as to disrupt MZ B cell homeostasis.
- Immunology