An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.
In: Blood, Jg. 130 (2017-11-09), Heft 19, S. 2131-2145
academicJournal
Zugriff:
B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graftversus- host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between path ways, we found that BCR-NOTCHactivation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B-cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4-to-IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity. [ABSTRACT FROM AUTHOR]
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An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.
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Autor/in / Beteiligte Person: | Poe, Jonathan C. ; Jia, Wei ; Su, Hsuan ; Anand, Sarah ; Rose, Jeremy J. ; Tata, Prasanthi V. ; Suthers, Amy N. ; Jones, Corbin D. ; Pei Fen Kuan ; Vincent, Benjamin G. ; Serody, Jonathan S. ; Horwitz, Mitchell E. ; Ho, Vincent T. ; Pavletic, Steven Z. ; Hakim, Frances T. ; Owzar, Kouros ; Zhang, Dadong ; Blazar, Bruce R. ; Siebe, Christian W. ; Chao, Nelson J. |
Zeitschrift: | Blood, Jg. 130 (2017-11-09), Heft 19, S. 2131-2145 |
Veröffentlichung: | 2017 |
Medientyp: | academicJournal |
ISSN: | 0006-4971 (print) |
DOI: | 10.1182/blood-2017-05-782466 |
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