Tu133 - Mass Cytometry Demonstrates an Extrafollicular T and B cell Signature that Correlates with Disease Activity in Pediatric Lupus Nephritis

Tuesday, June 21, 2022

6:15 PM – 7:45 PM PT

Presenting Author(s)

RB

Ryan Baxter, MS

University of Colorado School of Medicine, Dept. of Immunology
Aurora, Colorado, United States

Co-Author(s)

CW

Christine Wang, MD

Department of Pediatrics, Section of Rheumatology, Children’s Hospital Colorado
Aurora, Colorado, United States
JC

Jennifer Cooper, MD/DO

Department of Pediatrics, Section of Rheumatology, Children’s Hospital Colorado
Aurora, Colorado, United States
MS

Mia J. Smith, PhD, DVM

Department of Immunology and Microbiology, University of Colorado, School of Medicine
Aurora, Colorado, United States
Elena WY Hsieh, MD

Associate Professor
Department of Immunology and Microbiology, Department of Pediatrics, Section of Allergy and Immunology, University of Colorado, School of Medicine
Aurora, Colorado, United States
PR

Pratyadipta Rudra, PhD

Department of Statistics, Oklahoma State University
Stillwater, Oklahoma, United States
TG

Tusharkanti Ghosh, PhD

Department of Biostatistics and Informatics, University of Colorado, School of Public Health
Aurora, Colorado, United States
DP

Debdas Paul, PhD

Clinical Bioinformatics & Machine Learning, University Hospital
Tubingen, Baden-Wurttemberg, Germany
MC

Manfred Claasen, PhD

Clinical Bioinformatics & Machine Learning, University Hospital
Tubingen, Baden-Wurttemberg, Germany
DG

Debashis Ghosh, PhD

Department of Biostatistics and Informatics, University of Colorado, School of Public Health
Aurora, Colorado, United States

Systemic lupus erythematosus (SLE) is a multi-organ rheumatologic disease with heightened severity in children. A majority of childhood-onset SLE (cSLE) patients develop lupus nephritis (LN), resulting in significant morbidity and mortality. Current diagnostics are inadequate for detecting incipient renal disease or anticipating severe manifestations. Incomplete knowledge regarding immune dysregulation in LN poses a significant hurdle for the development of biomarkers to monitor disease activity and/or guide specific therapy.

We performed mass cytometry (CyTOF) on peripheral blood from cSLE patients (n=22, 7 with LN). These single-cell immune phenotypic and functional data were complemented by whole blood gene expression and clinical data. We applied traditional supervised and novel unsupervised analytical tools to identify immunological signatures common to cSLE, and those unique to LN.

cSLE patients exhibit a broadly activated immune system, with an increased interferon gene expression signature and increased pro-inflammatory CD14hi monocyte cytokine production. Their T cells exhibit an activation/exhaustion phenotype with an increased frequency of T follicular and peripheral helper cells (Tfh and Tph). Consistent with an increase in these T cell subsets, there is an increased frequency of plasmablasts, memory B cells, and extrafollicular B cells contained within the anergic and age-associated B cell subsets—supporting a complementary B cell activation state. For LN patients, SLEDAI score correlates with i) Tph frequency and ii) CD38 and PD1 expression on CD8 T cells. These data suggest that extrafollicular T:B interactions are processes unique to LN and may constitute i) biomarkers for disease monitoring; and ii) targets for novel therapeutic approaches.