Henzler, C. M. | Search bioRxiv

bioRxiv2024

Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 weeks after infection. Therefore, we hypothesized that dysfunctional cell-mediated antibody responses downstream of antibody production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, while natural killer (NK) cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Together, our results reveal dysregulation in antibody-mediated cellular responses unique to MIS-C that likely contribute to the immune pathology of this disease. SummaryMIS-C is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Limited studies tested cellular function ex vivo to understand the aberrant immune response in MIS-C. We found dysregulation in antibody-mediated cellular responses unique to MIS-C that likely contribute to the immune pathology of this disease O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/589585v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@16d9e0dorg.highwire.dtl.DTLVardef@1a37693org.highwire.dtl.DTLVardef@bdb0cforg.highwire.dtl.DTLVardef@1a32604_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

immunology↗

bioRxiv2020

Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia

The transcription factors EBF1 and PAX5 are frequently mutated in B cell acute lymphoblastic leukemia (B-ALL). We demonstrate that Pax5+/- x Ebf1+/- compound heterozygous mice develop highly penetrant leukemia. Similar results were seen in Pax5+/- x Ikzf1+/- and Ebf1+/- x Ikzf1+/- mice for B-ALL, or in Tcf7+/- x Ikzf1+/- mice for T cell leukemia. To identify genetic defects that cooperate with Pax5 and Ebf1 compound heterozygosity to initiate leukemia, we performed a Sleeping Beauty (SB) transposon screen that identified cooperating partners including gain-of-function mutations in Stat5 ([~]65%) and Jak1([~]68%), or loss-of-function mutations in Cblb (61%) and Myb (32%). These findings underscore the role of JAK/STAT5 signaling in B cell transformation and demonstrate unexpected roles for loss-of-function mutations in Cblb and Myb in leukemic transformation. RNA-Seq studies demonstrated upregulation of a PDK1>SGK3>MYC pathway; treatment of Pax5+/- x Ebf1+/- leukemia cells with PDK1 inhibitors blocked proliferation in vitro. Finally, we identified conserved transcriptional variation in a subset of genes between human leukemias and our mouse B-ALL models. Thus, compound haploinsufficiency for B cell transcription factors likely plays a critical role in transformation of human B cells and suggest that PDK1 inhibitors may be effective for treating patients with such defects.

cancer biology↗