# Borrelia burgdorferi-Induced Autoimmunity in Lyme Disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $503,943

## Abstract

This grant seeks to characterize autoimmune features of a post-infectious Lyme disease (LD)
syndrome called antibiotic-refractory Lyme arthritis (LA), the only post-treatment LD syndrome
for which a specific pathology has been defined. We have previously reported that excessive
inflammation, immune dysregulation of the Teff/Treg cell ratio, up-regulation of certain
microRNAs, and infection-induced autoimmunity are features of this untoward outcome.
Moreover, the greatest genetic risk factor for refractory LA is certain HLA-DR alleles, and we
have identified immunogenic HLA-DR-presented peptides directly from synovial tissue in these
patients. In this way, we have shown that 4 autoantigens, endothelial cell growth factor (ECGF),
MMP-10, apoB-100, and annexin A2, are targets of T and B cell responses in subsets of
patients with each of the manifestations of LD; and nearly half of patients with antibiotic-
refractory LA have autoantibody responses to 1 or more of these autoantigens. Based on RA-
seq data, we report in this grant that the synovial lesion in refractory LA has a highly
inflammatory expression signature, which includes up-regulation of genes associated with IFN-
-responses, MHC class II antigen processing and presentation, cell-mediated cytotoxicity, and
cell proliferation. We now propose that synovial fibroblast-like synoviocytes (FLS), the most
common cell in the lesion, become unconventional antigen presenting cells (uAPC), and CD4+
T cells with cytotoxic potential may be directed against FLS. As detailed in Aim 1, we have
identified two types of CD4+ SLAMF7+ T cells with cytotoxic potential in LA patients, and we will
further determine their phenotype using single-cell RNA-seq. In Aim 2, we will identify a greater
range of HLA-DR-peptides presented to CD4+ T cells by professional APCs or uAPC (FLS),
and we will delineate molecular interactions between CD4+SLAMF7+T cells and FLS in cell
cultures. In Aim 3, we present preliminary data that autoantibodies in refractory LA may
participate in this disease process. In these patients, high levels of IgG4 autoantibodies to
ECGF, MMP-10 and apoB-100 each correlate with marked fibrosis and obliterative microvasular
lesions in synovial tissue. We will assess whether the binding characteristics and glycan
composition of these autoantibodies shift from an anti-inflammatory to a pro-inflammatory
phenotype in refractory patients. Finally, we will determine the utility of autoantibody
determinations as part of a diagnostic platform for early identification of patients with
maladaptive immune responses, which may allow earlier therapy to ameliorate or prevent this
post-infectious syndrome.

## Key facts

- **NIH application ID:** 9980768
- **Project number:** 5R01AI101175-07
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ALLEN C STEERE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $503,943
- **Award type:** 5
- **Project period:** 2013-06-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980768

## Citation

> US National Institutes of Health, RePORTER application 9980768, Borrelia burgdorferi-Induced Autoimmunity in Lyme Disease (5R01AI101175-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9980768. Licensed CC0.

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