# Age-Associated B cells in Autoimmune Lupus

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $230,145

## Abstract

Abstract
Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against self-
antigens including DNA- and RNA-associated cellular components. Recent work from our lab and several
other groups has shown that the nucleic acid sensing endosomal TLRs, TLR9 and TLR7, are required to break
B cell self tolerance to these antigens and produce anti-DNA or anti-RNA autoantibodies. Despite these
important insights, a great deal remains unknown about the origin of autoantibodies in lupus including the
precise cellular differentiation routes that give rise to autoantibody-forming cells (AFCs). In particular, it
remains unknown to what extent autoantibodies arise directly from the activation and differentiation of naive
autoreactive B cells; whether an autoimmune B cell response can generate a pool of resting autoreactive
memory B cells that can be reactivated over time; or whether both processes occur simultaneously. Recently
a novel population of "age-associated B cells" (ABCs) was defined in mice and humans that are expanded in
human SLE patients and in several murine models of lupus, including MRL/lpr. ABCs have been implicated as
a candidate autoimmune memory B cell population and could be an important source of AFCs in lupus. These
cells lack expression of B subset markers for follicular, marginal zone, transitional or B-1 lineages; express
CD11c and CD11b; and express the transcription factor T-bet. ABCs have been postulated to contain TLR-
dependent autoreactive and antiviral memory B cells, based on the presence of somatic mutations, expression
of memory markers, and other properties. In this proposal, we will use genetic tools available in the MRL/lpr
mouse model of lupus to investigate key questions about ABCs in vivo and to test the hypothesis that these
cells are autoimmune memory and plasmablast precursors that promote lupus disease. In Aim 1, we will
determine the lineage relationships of ABCs relative to naive B cells and plasmablasts, and determine the
kinetics of their formation and activation. In Aim 2, we will test the hypothesis that ABCs are (or include) stable
autoreactive memory B cells, and determine how the gene signature of MRL/lpr ABCs is similar to or different
from that of conventional memory B cells or ABCs generated in normal aging. Finally in Aim 3, using genetic
systems in which ABCs can be specifically targeted for constitutive or inducible depletion, we will test the
hypothesis that ABCs are necessary for the initiation and propagation of lupus disease and evaluate their
potential as a novel target for therapeutic intervention.

## Key facts

- **NIH application ID:** 9882944
- **Project number:** 5R21AI141938-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kevin Nickerson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $230,145
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882944

## Citation

> US National Institutes of Health, RePORTER application 9882944, Age-Associated B cells in Autoimmune Lupus (5R21AI141938-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9882944. Licensed CC0.

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