# Evolution of autoreactive GC and epitope spreading in lupus

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $466,393

## Abstract

EVOLUTION OF AUTOREACTIVE GC AND EPITOPE SPREADING IN LUPUS
 Systemic lupus erythematosus (SLE) is an incurable autoimmune disease and represents a substantial
health problem in the population. Longitudinal studies of patients and murine models of SLE identify
development of autoantibodies against new epitopes over time that correlate with increased pathology. The
phenomena is referred to as epitope spreading, i.e. development of autoantibodies against determinants
other than the initiating self-antigen. While the mechanism underlying epitope spreading remains unclear, we
propose that spontaneous autoreactive GC initiated by a single B cell clone along with T cell help can promote
entry of multiple distinct clones of naïve self-reactive B cells where they can be positively selected and undergo
affinity maturation, compete and differentiate into effector cells leading to epitope spreading.
 In order to characterize the dynamics of spontaneous autoreactive GC in more depth, we developed a
novel mixed bone marrow chimeric model in which bone marrow from a lupus strain is mixed with marrow from
WT mice and transferred into irradiated recipients. In characterization of the chimeras, we found, unexpectedly,
that the self-reactive WT B cells underwent clonal selection and affinity maturation resulting in one or two
clones dominating the GC response much like that observed for foreign antigen. Furthermore, we identified
epitope spreading by the WT B cells (Degn 2017). Thus, in contrast to the predicted negative selection of self-
reactive clones in GC, we found robust positive selection with the generation of pathogenic antibodies specific
for self-antigens distinct from the original nucleolar antigen. In the current proposal, we will characterize further
the events initiating spontaneous autoreactive GC using both radiation chimeras and a parabiosis approach.
Further, we will determine the role of T follicular helper cells in promoting epitope spreading. Three aims are
proposed:
Aim 1. Characterize the dynamics of autoreactive germinal centers leading to epitope spreading.
Aim 2. Characterize Tfh in epitope spreading of self-reactive GC B cells.
Aim 3. Test hypothesis that self-reactive memory B cells cycle through GCs and diversify.

## Key facts

- **NIH application ID:** 9933809
- **Project number:** 5R01AR074105-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Michael Craig Carroll
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,393
- **Award type:** 5
- **Project period:** 2018-07-13 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933809

## Citation

> US National Institutes of Health, RePORTER application 9933809, Evolution of autoreactive GC and epitope spreading in lupus (5R01AR074105-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933809. Licensed CC0.

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