Lori Lee

All Publications

• Impaired innate and adaptive immune responses to BNT162b2 SARS-CoV-2 vaccination in systemic lupus erythematosus. JCI insight Sarin, K. Y., Zheng, H., Chaichian, Y., Arunachalam, P. S., Swaminathan, G., Eschholz, A., Gao, F., Wirz, O. F., Lam, B., Yang, E., Lee, L. W., Feng, A., Lewis, M. A., Lin, J., Maecker, H. T., Boyd, S. D., Davis, M. M., Nadeau, K. C., Pulendran, B., Khatri, P., Utz, P. J., Zaba, L. C. 2024; 9 (5)

  Abstract

  Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.

  View details for DOI 10.1172/jci.insight.176556

  View details for PubMedID 38456511

• Clinical use of shear-wave elastography for detecting liver fibrosis in children and adolescents with cystic fibrosis. Pediatric radiology Levitte, S. n., Lee, L. W., Isaacson, J. n., Zucker, E. J., Milla, C. n., Barth, R. A., Sellers, Z. M. 2021

  Abstract

  Complications from liver cirrhosis are a leading cause of death in children with cystic fibrosis. Identifying children at risk for developing liver cirrhosis and halting its progression are critical to reducing liver-associated mortality.Quantitative US imaging, such as shear-wave elastography (SWE), might improve the detection of liver fibrosis in children with cystic fibrosis (CF) over gray-scale US alone. We incorporated SWE in our pediatric CF liver disease screening program and evaluated its performance using magnetic resonance (MR) elastography.Ninety-four children and adolescents with CF underwent 178 SWE exams, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and platelet measurements. Of these, 27 children underwent 34 MR elastography exams. We evaluated SWE performance using 6-MHz and 9-MHZ point SWE, and 9-MHz two-dimensional (2-D) SWE.The 6-MHz point SWE was the only method that correlated with MR elastography (r=0.52; 95% confidence interval [CI] 0.20-0.74; P=0.003). SWE of 1.45 m/s distinguished normal from abnormal MR elastography (79% sensitivity, 100% specificity, 100% positive predictive value [PPV], 55% negative predictive value [NPV], area under the receiver operating characteristic [AUROC] curve 0.94). SWE of 1.84 m/s separated mild-moderate (3.00-4.77 kPa) from severe (>4.77 kPa) MR elastography (88% sensitivity, 86% specificity, 78% PPV, 93% NPV, AUROC 0.79). Elevations of AST, ALT, GGT and thrombocytopenia were associated with higher SWE. AST-to-platelet ratio index of 0.42, fibrosis-4 of 0.29, and GGT-to-platelet ratio of 1.43 all had >95% NPV for SWE >1.84 m/s.Given its correlation with MR elastography, SWE might be a clinically useful predictor of liver fibrosis. We identified imaging criteria delineating the use of SWE to identify increased liver stiffness in children with CF. With multicenter validation, these data might be used to improve the detection and monitoring of liver fibrosis in children with CF.

  View details for DOI 10.1007/s00247-021-05015-w

  View details for PubMedID 33759025

• New Algorithm for the Integration of Ultrasound Into Cystic Fibrosis Liver Disease Screening. Journal of pediatric gastroenterology and nutrition Sellers, Z. M., Lee, L. W., Barth, R. A., Milla, C. n. 2019; 69 (4): 404–10

  Abstract

  Liver nodularity occurs across the spectrum of cystic fibrosis liver disease (CFLD), from regenerative nodules to cirrhosis, and can occur without liver enzyme abnormalities. Our aims were to determine if incorporating abdominal ultrasound (US) with annual laboratory testing improves the detection of CFLD and establish CF-specific thresholds for liver screening labs.CF patients at least 6 years old who were exocrine pancreatic-insufficient had an US with Doppler and shear wave elastography. Patients were divided into Normal, Echogenic, or Nodular groups, based on US findings. Results were compared with aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, AST to platelet ratio index (APRI), Fibrosis 4 (FIB-4), and gamma-glutamyl transferase (GGT) to platelet ratio (GPR). Receiver operator curve, sensitivity, specificity, positive predictive value, negative predictive value, and optimal cut-off with Youden Index were calculated.From 82 patients, incorporation of US identified more nodular livers than using labs alone. The Nodular group had significantly greater median AST (44), ALT (48), GGT (46), APRI (0.619), FIB-4 (0.286), GPR (1.431). Optimal cut-offs to detect liver nodularity in CF were AST >33, ALT >45, GGT >21, Platelets <230, APRI >0.367, FIB-4 >0.222, GPR >0.682. Using GGT, APRI, and GPR, we generated an algorithm to direct the use of US in CFLD screening.Using modified serum lab thresholds, addition of liver fibrosis indices, and/or abdominal US can increase detection of liver nodularity in CF. A combination of GGT, GPR, and APRI can help direct which CF children should undergo US evaluation. These tools may improve earlier identification of fibrosis and/or cirrhosis in CF patients.

  View details for DOI 10.1097/MPG.0000000000002412

  View details for PubMedID 31181020

• beta 1-Subunit of the calcium-sensitive potassium channel modulates the pulmonary vascular smooth muscle cell response to hypoxia AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Barnes, E. A., Lee, L., Barnes, S. L., Brenner, R., Alvira, C. M., Cornfield, D. N. 2018; 315 (2): L265–L275

  View details for DOI 10.1152/ajplung.00060.2018

  View details for Web of Science ID 000442116600002

• beta1 Subunit of the Calcium-Sensitive Potassium Channel Modulates the Pulmonary Vascular Smooth Muscle Cell Response to Hypoxia. American journal of physiology. Lung cellular and molecular physiology Barnes, E. A., Lee, L., Barnes, S. L., Brenner, R., Alvira, C. M., Cornfield, D. N. 2018

  Abstract

  Accessory subunits associated with the calcium-sensitive potassium channel (BKCa), a major determinant of vascular tone, confer functional and anatomical diversity. The beta1 subunit increases Ca2+-, and voltage-sensitivity of the BKCa channel and is expressed exclusively in smooth muscle cells (SMC). Evidence supporting the physiologic significance of the beta1 subunit includes the observations that murine models with deletion of the beta1 subunit are hypertensive and that humans with a gain-of-function beta1 mutation are at decreased risk of diastolic hypertension, However, whether the beta1 subunit of the BKCa channel contributes to the low tone that characterizes the normal pulmonary circulation or modulates the pulmonary vascular response to hypoxia remains unknown. To determine the role of the BKCa channel beta1 subunit in the regulation of pulmonary vascular tone and the response to acute and chronic hypoxia, mice with deletion of the Kcnmb1 gene that encodes for the beta1 subunit ( Kcnmb1+/+) were placed in chronic hypoxia (10% O2) for 21-24 days. In normoxia, right ventricular systolic pressure (RVSP) did not differ between Kcnmb1+/+ (controls) and Kcnmb1-/- mice. After exposure to either acute or chronic hypoxia, RVSP was higher in Kcnmb1+/+ mice compared to Kcnmb1+/+ mice, without increased vascular remodeling. beta1 subunit expression was predominantly confined to pulmonary artery smooth muscle cells (PASMC) from vessels <150m. Peripheral PASMC contracted collagen gels irrespective of beta1 expression. Focal adhesion expression and Rho kinase activity were greater in Kcnmb1-/- compared to Kcnmb1+/+PASMC. Compromised PASMC beta1 function may contribute to the heightened microvascular vasoconstriction that characterizes pulmonary hypertension.

  View details for PubMedID 29644895

• Disrupted BKCa Channel beta 1 Subunit Gene Contributes to Vascular Dysfunction in Pulmonary Hypertension Barnes, E. A., Chen, C., Lee, L., Barnes, S. L., Cornfield, D. N. FEDERATION AMER SOC EXP BIOL. 2017

  View details for Web of Science ID 000405461402450

• Anti-MDA5-Positive Dermatomyositis Presenting as Fever of Unknown Origin JOURNAL OF GENERAL INTERNAL MEDICINE Lee, L. W., Narang, N. S., Postolova, A., Seminara, N., Kantor, M. A. 2016; 31 (12): 1530-1536

  Abstract

  Dermatomyositis is a chronic systemic autoimmune disease characterized by inflammatory infiltrates in the skin and muscle. The wide variability in clinical and serologic presentation poses a diagnostic challenge for the internist. Appreciation of the clinical variants of dermatomyositis allows for expedient diagnosis and avoidance of diagnostic error. We illustrate these challenges with the case of a 51-year-old Vietnamese-American man who initially presented with fever of unknown origin in the absence of overt skin and muscle manifestations. The diagnosis of dermatomyositis was not evident on several clinical encounters due to the absence of these hallmark symptoms. We review the variable clinical manifestations of a subtype of dermatomyositis associated with an autoantibody against melanoma differentiation-associated protein 5 (anti-MDA5) and suggest consideration of dermatomyositis as a diagnosis in patients presenting with systemic illness and markedly elevated ferritin, even in the absence of elevated muscle enzymes and classic autoantibodies.

  View details for DOI 10.1007/s11606-016-3769-0

  View details for Web of Science ID 000389626600028

  View details for PubMedID 27350281

  View details for PubMedCentralID PMC5130943

• KCNMB1(-/-) Mice as a Model of Pulmonary Arterial Hypertension Barnes, E., Chen, C., Barnes, S., Kim, F., Lee, L., Alvira, C., Cornfield, D. FEDERATION AMER SOC EXP BIOL. 2016

  View details for Web of Science ID 000406444001556

• Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia. American journal of physiology. Lung cellular and molecular physiology Kim, F. Y., Barnes, E. A., Ying, L., Chen, C., Lee, L., Alvira, C. M., Cornfield, D. N. 2015; 308 (4): L368-77

  Abstract

  Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1(flox/flox) mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1(+/+) and ET-1(-/-) mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1(-/-) and SM22α-ET-1(+/+) (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1(-/-) mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.

  View details for DOI 10.1152/ajplung.00253.2014

  View details for PubMedID 25399435

• Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Kim, F. Y., Barnes, E. A., Ying, L., Chen, C., Lee, L., Alvira, C. M., Cornfield, D. N. 2015; 308 (4): L368-L377

  View details for DOI 10.1152/ajplung.00253.2014

  View details for Web of Science ID 000349305400006

  View details for PubMedID 25399435