Our laboratory has a long-standing interest in B cell antigen receptor (BCR) signaling and how BCR dependent processes regulate specific cell fate decisions. In the bone marrow, we have been working to understand how signals initiated through the pre-BCR, in conjunction with those delivered through the IL-7 receptor, coordinate cell cycle progression with immunoglobulin light chain gene recombination. These studies resulted in discovery of the epigenetic reader BRWD1 as critical for both regulating Ig-kappa accessibility and in coordinating broad transcriptional programs in early and late B lymphopoiesis. Recently, we have demonstrated that the pre-BCR initiates an IRF4-CXCR4 feedforward loop and that it is CXCR4 that directly signals Ig-kappa recombination. These latter findings fundamentally rewrite the canonical model of B lymphopoiesis. Furthermore, they are the first demonstration of a direct and independent role for CXCR4 in driving an important biological process. In the periphery, we have focused on the molecular control of germinal centers (GCs). Recently, we have recently defined two novel B cell populations within the dark zone that both allow compartmentalization of fundamental GC functions and reveal the molecular programs of the GC cycle. This new three population model fundamentally rewrites the GC paradigm. In all these areas, we have derived novel in vivo models, and have performed directed in vitro studies, to obtain definitive insights into these processes.
Our translational studies have focused on how in situ adaptive immune responses drive tubulointerstitial inflammation in human lupus nephritis. For these studies, we have used deep machine learning to develop novel image analysis tools to quantify and identify functional relationships between different T cell and antigen presenting cell populations in situ. Remarkably, this bioinformatics platform approaches the sensitivity and specificity of two-photon excitation microscopy (TPEM). However, unlike TPEM, it can be applied to the study of human disease. We have also used single cell technologies to understand B cell selection at sites of inflammation and determine the interrelationships between transcriptional state and antigenic specificity.
Pseudo-spectral angle mapping for automated pixel-level analysis of highly multiplexed tissue image data.
Pseudo-spectral angle mapping for automated pixel-level analysis of highly multiplexed tissue image data. bioRxiv. 2024 Jan 11.
PMID: 38260318
Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS.
Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS. Cell. 2023 11 22; 186(24):5269-5289.e22.
PMID: 37995656
BRWD1 orchestrates small pre-B?cell chromatin topology by converting static to dynamic cohesin.
BRWD1 orchestrates small pre-B?cell chromatin topology by converting static to dynamic cohesin. Nat Immunol. 2024 Jan; 25(1):129-141.
PMID: 37985858
Corrigendum to "Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu" [J. Autoimmun. 113 (2020) 102469].
Corrigendum to "Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu" [J. Autoimmun. 113 (2020) 102469]. J Autoimmun. 2023 Sep 23; 103116.
PMID: 37748978
Molecular mechanisms insulating proliferation from genotoxic stress in B lymphocytes.
Molecular mechanisms insulating proliferation from genotoxic stress in B lymphocytes. Trends Immunol. 2023 09; 44(9):668-677.
PMID: 37573227
STAT3 signaling in B cells controls germinal center zone organization and recycling.
STAT3 signaling in B cells controls germinal center zone organization and recycling. Cell Rep. 2023 05 30; 42(5):112512.
PMID: 37200190
Antigenic responses are hallmarks of fibrotic interstitial lung diseases independent of underlying etiologies.
Antigenic responses are hallmarks of fibrotic interstitial lung diseases independent of underlying etiologies. medRxiv. 2023 May 11.
PMID: 37214861
The endogenous repertoire harbors self-reactive CD4+ T cell clones that adopt a follicular helper T cell-like phenotype at steady state.
The endogenous repertoire harbors self-reactive CD4+ T cell clones that adopt a follicular helper T cell-like phenotype at steady state. Nat Immunol. 2023 03; 24(3):487-500.
PMID: 36759711
The ion transporter Na+-K+-ATPase enables pathological B cell survival in the kidney microenvironment of lupus nephritis.
The ion transporter Na+-K+-ATPase enables pathological B cell survival in the kidney microenvironment of lupus nephritis. Sci Adv. 2023 02 03; 9(5):eadf8156.
PMID: 36724234
IRF4 expression by lung dendritic cells drives acute but not Trm cell-dependent memory Th2 responses.
IRF4 expression by lung dendritic cells drives acute but not Trm cell-dependent memory Th2 responses. JCI Insight. 2022 11 08; 7(21).
PMID: 36194494