# Infections, Microbiome and HLA-DR in the Induction of Lupus Related Auto-antibodies

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $544,950

## Abstract

ABSTRACT
 Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disorder that affects mostly
young females. It causes significant morbidity and mortality. Effective therapies without significant side effects
for induction of remission and prevention of relapses are wanting. Our novel hypothesis that links the HLA-D
region to the pathogenesis of SLE is that autoantibodies (auto-Ab) and auto-reactive T cells are generated by the
activation of T cells cross-reactive with autoantigens (auto-Ag) and enviromental (such as bacterial) Ag in the
HLA-DR restricted manner. Over a period of time accumulation of auto-reactive T cells leads to the production
of complex auto-Ab, resulting in clinical disease in suitable hosts. Remission occurs with reduction of auto-
reactive T cells and of auto-Ab specificities. Relapses occur with repeated stimulation by molecular mimics in
the host. The initial clinical presentation and the relapses depend on the nature of the stimulation by the
molecular mimics. We have extensively mapped the T cell epitopes in a lupus-related Ag, SmD. This auto-Ag has
cross reactive intra- and inter-molecular T cell epitopes. The presence of intra-molecular cross-reactive T cell
epitopes is the reason why they are targeted in SLE. The presence of multiple cross-reactive T cell epitopes
among polypeptides of snRNP provides us the understanding of the mechanism of B cell epitope spreading in
SLE. Multiple T cell antigenic regions have been identified in SmD. Each region appears to induce unique
patterns of auto-Ab specificity. Multiple T cell receptors (TCR) are utilized in responses to immunization with
SmD. Several microbial mimics from commansal flora were identified with the capability of inducing diverse
auto-Ab in a similar manner as the parental peptide. There are cross reactive B cell epitopes between the mimics
and the parental SmD peptides. Cross reactivity between tetenus toxoid (TT) T cell epitopes and those of SmD
have been documented. These results and other preliminary data provide the basis for the current proposal for
us to understand better the role of environmental Ag in the induction of SLE-related auto-Ab. Three specific aims
are proposed: Specific Aim 1: To translate our observations in our DR3 transgenic model to normal individuals
and SLE patients and to relate SLE-related Ab induction to microbiota and tetanus toxoid; Specific Aim 2: To
demonstrate that antibiotic treatments that deplete or modulate the gut microbiota will modulate autoantibody
production and/or disease course with prolonged survival in (NZM2328xNOD)F1, NZM2328 and
NZM2328.DR3; and Specific Aim 3: To derive germ-free mice from NZM2328 and NZM2328.DR3 to show
that lupus nephritis and lupus related auto-Ab will not develop in a germ-free or gnotobiotic environment,
supporting the thesis that microbiota play a crucial role in the development of SLE-related auto-Abs. On the
basic level, the expected results will provide insight to the ...

## Key facts

- **NIH application ID:** 10212946
- **Project number:** 5R01AI139673-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Shu Man Fu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $544,950
- **Award type:** 5
- **Project period:** 2018-08-10 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212946

## Citation

> US National Institutes of Health, RePORTER application 10212946, Infections, Microbiome and HLA-DR in the Induction of Lupus Related Auto-antibodies (5R01AI139673-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10212946. Licensed CC0.

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