Biology subjects

Abram, C. L.

Publications and source records attributed to Abram, C. L..

5 recordsLinked to original sources

bioRxiv2026

Gain-of-function mutation in SKAP2 leads to type 1 diabetes and broader autoimmunity through hyperactive integrin signaling in myeloid cells

Many genetic variants associated with increased type 1 diabetes (T1D) risk are located within the SKAP2 gene; however, the mechanisms by which these variants confer disease risk remain unclear. SKAP2 encodes an adapter protein that functions within the integrin signaling pathway and is found at the highest levels in myeloid leukocytes. We recently identified a de novo gain-of-function SKAP2 mutation in an individual with T1D, leading to hyperactive integrin signaling in myeloid cells. To dissect the mechanisms by which this mutation may lead to T1D, we generated a knock-in mouse line containing the orthologous p.G153R substitution in mouse SKAP2 on the diabetes-prone nonobese diabetic (NOD) genetic background. Both female and male SKAP2G153R/G153R mice developed accelerated T1D. The SKAP2G153R/G153R mice also exhibited a unique spectrum of autoantibodies, leading to immune-complex nephritis. Accelerated infiltration of pancreatic islets by myeloid cells, B lymphocytes, and activated T cells was observed in SKAP2G153R/G153R mice. Single-cell RNA sequencing demonstrated a type 1 IFN{gamma}-driven inflammatory program within the pancreatic islets of SKAP2G153R/G153R mice. Dendritic cells from SKAP2G153R/G153R mice demonstrated increased antigen-presenting capacity, characterized by enhanced adhesion to T cells during immune synapse formation. Macrophages and neutrophils from SKAP2G153R/G153R mice also showed increased integrin signaling responses, with neutrophils expressing high levels of activated {beta}2 integrins on the cell surface. When backcrossed onto the C57BL/6J genetic background, the SKAP2G153R/G153R mice developed spontaneous autoantibody formation and exhibited accelerated autoimmunity, including nephritis, in the pristane-induced model of autoimmune disease. These findings demonstrate that dysregulation of leukocyte integrin signaling, through alterations in SKAP2, may increase the genetic risk for autoimmunity and T1D.

immunology↗

bioRxiv2025

STING activation reshapes the tumor microenvironment leading to tumor regression in osteosarcoma

Osteosarcomas are characterized by a high degree of aneuploidy, chromothripsis and micronuclei, yet these tumors typically have an immunosuppressive, macrophage-rich, T-cell depleted tumor microenvironment. cGAS-STING dysregulation is a possible mechanism by which immune activation in response to tumor genomic instability could be repressed. We identified almost universal repression of cGAS or STING in human osteosarcomas. However, a STING-activation gene signature was predictive of survival in osteosarcoma patients suggesting potential for activation of this pathway in the osteosarcoma tumor microenvironment. Indeed, in immunocompetent osteosarcoma models, systemic STING agonism led to complete regression and induced lasting immunologic memory. Host STING activation is sufficient to promote this anti-tumor immunity even in the absence of tumor STING. These results nominate the cGAS-STING pathway as an important therapeutic target in osteosarcoma, a disease in which no new curative therapies have been developed in the last 40 years. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/684275v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@15b1e5corg.highwire.dtl.DTLVardef@12650aaorg.highwire.dtl.DTLVardef@79ef71org.highwire.dtl.DTLVardef@15704c9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Loss of neutrophil Shp1 produces hemorrhagic and lethal acute lung injury

The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen species in vitro and ameliorated ALI-induced alveolar neutrophilia and NETs in vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.

immunology↗

bioRxiv2023

Validation of a murine proteome-wide phage display library for the identification of autoantibody specificities

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq), to profile mouse autoantibodies. This system and library were validated using seven genetic mouse models across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and MT) were used to model non-specific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor (BCR)-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate three distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities, lending support to the hypothesis that apoptosis is a shared origin of these antigens. Second, serum from non-obese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, enriched peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous auto-antigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 (APS1) carrying recessive mutations in AIRE. Among these were peptides derived from Perilipin-1, a validated autoimmune biomarker of generalized acquired lipodystrophy in humans. Autoreactivity to Perilipin-1 correlated with lymphocyte infiltration in adipose tissue and underscores the approach in revealing previously unknown specificities. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity.

immunology↗

bioRxiv2020

Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β7 integrin expression.

The regulation of integrin expression and function controls interactions of immune cells and targets their trafficking locally and systemically. We show here that the tyrosine phosphatase SHP-1 is required for lymphocyte surface expression of the intestinal immune response-associated integrin {beta}7, but not for {beta}1 or {beta}2 integrins. Viable motheaten mice deficient for SHP-1 have less {beta}7 on T cells and lack {beta}7 on B cells. SHP-1 function is targeted in B cells by the B cell specific lectin CD22 (Siglec-2), suggesting a potential role for CD22 in {beta}7 expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses {beta}7 endocytosis: internalization of {beta}7 but not {beta}1 integrin is accelerated in SHP-1+/- and CD22-/- B cells. Moreover, mutations in CD22 cytoplasmic SHP1-binding ITIM sequences reduce 4{beta}7 comparably, and loss of CD22 lectin activity has an intermediate effect suggesting a model in which the CD22 ITIM sequences recruit SHP-1 to control {beta}7 expression. Integrin 4{beta}7 selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1+/- B cells display reduced {beta}7-dependent homing to gut associated Peyers patches (PP); and CD22-deficiency impairs intestinal but not systemic antibody responses and delays clearance of the gut pathogen rotavirus. The results define a novel role for SHP-1 in the differential control of leukocyte integrins and an unexpected integrin {beta}7-specific role for CD22-SHP-1 interplay in mucosal immunity.

immunology↗