# Endolysosomal transporters and systemic autoimmunity

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $423,500

## Abstract

PROJECT SUMMARY
For several decades, this and other laboratories have extensively investigated the causes and
immune pathogenesis of systemic lupus erythematosus (SLE), the prototypic systemic
autoimmune disease. Despite considerable advances, particularly with regard to abnormalities in
the adaptive immune system, several questions remained unanswered, including why
autoantibodies in this disease are so often directed against nuclear antigens, and what is the initial
trigger for these aberrant responses occurring even under sterile conditions? Emerging knowledge
of a diverse array of mammalian sensors for nucleic acids, and the demonstration by us and others
that these sensors are principal participants in lupus pathogenesis, have now provided new
avenues of inquiry as to how this disease (and possibly many others) is initiated. We recently
observed that congenic lupus-predisposed mice carrying an inactivating mutation of the
proton/histidine transporter SLC15A4 (termed feeble) showed significantly reduced disease
manifestations. The feeble mutation, discovered by others through ENU mutagenesis, has been
shown to extinguish signaling by the endolysosomal TLR7 and TLR9, together with almost
complete absence of production of type I interferons (IFN-I) and other proinflammatory cytokines
by plasmacytoid dendritic cells (pDCs) without affecting the development of these cells. Because
of the apparent potential to therapeutically intervene with the function of SLC15A4, this proposal
will seek to determine how the feeble mutation reduces autoimmunity by defining the functional
characteristics of this molecule, the effects of the feeble mutation in lupus-associated innate and
adaptive pathogenic responses, and ultimately to utilize high-throughput screening systems to
identify pharmacologic inhibitors of this and other molecules necessary for self-nucleic acid
sensing. The insights gained from these studies are certain to provide significant data on the
biology of endolysosomes, TLRs and SLC15A4, and to reveal novel targets for therapeutic
interventions in SLE and other autoimmune diseases.

## Key facts

- **NIH application ID:** 9833495
- **Project number:** 5R01AR068910-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Argyrios N Theofilopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,500
- **Award type:** 5
- **Project period:** 2016-03-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9833495

## Citation

> US National Institutes of Health, RePORTER application 9833495, Endolysosomal transporters and systemic autoimmunity (5R01AR068910-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9833495. Licensed CC0.

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