# Role of beta2 integrin in lupus nephritis

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2020 · $480,065

## Abstract

Project Summary
 Lupus nephritis (LN) is a debilitating inflammatory disease that is caused by Systemic Lupus
Erythematosus (SLE, lupus). Poorly defined genetic and environmental factors predispose lupus patients
for renal disease. Approx. 40% of lupus patients show renal impairment and a large percentage develop
end stage renal disease (ESRD). Women, especially young women of childbearing age, are more
susceptible to LN, suggesting role of early glomerular injury in LN. LN is managed by glucocorticoids and
immunosuppressive agents, with many side effects and considerable long-term toxicity. Therefore
improved, targeted treatments are urgently needed. Three single nucleotide polymorphisms (SNPs) in the
coding region of ITGAM gene (coding for CD11b), show strong correlation with the incidence of LN (and
SLE). However, how these nonsynonymous mutations confer SLE risk is not clear, although that they
appear to reduce the biological functions of CD11b. Given that glomerular leukocyte influx in increased in
LN, this is paradoxical, as CD11b is widely considered to play a major role in leukocyte infiltration. Here, we
present data that CD11b activation plays a major role in suppressing Toll like receptor (TLR) signaling
pathways. IFN I is increased in sera of LN patients, and suPAR is a circulating risk factor for glomerular
diseases. Since both biomarkers are generated downstream of the TLR-pathways, we hypothesize that
there is a direct link between coding ITGAM SNPs and the levels of these two biomarkers in LN and that
this is due to the failure of the mutant CD11b protein product to suppress TLR signaling. We also
hypothesize that forced activation of CD11b can reduce TLR signaling, is sufficient to decrease IFN I and
suPAR level, thereby ameliorating disease activity. We also hypothesize that activation of CD11b using a
pharmacologic small molecule LA1 recently discovered in our laboratory, or via genetic mutations, can
rescue the functional deficit of the mutant CD11b protein and suppress TLR-dependent inflammatory
signaling. Therefore, we propose that CD11b activation can be a new therapeutic strategy for the
development of novel therapeutics for LN. In this proposal, we present three specific aims to test our
hypotheses. These studies will help mechanistically connect a common genetic factor associated with SLE
and LN with important clinical biomarkers, and will provide us with an improved understanding of the
disease pathways. More importantly, the studies will also help determine if CD11b activation could be a
novel mechanism to treat LN, as well as define the efficacy of a novel small molecule, LA1, which could
potentially lead to the development of LA1 (or other similar agents) as novel therapeutics to treat LN
patients. This may also lead to the development of a first potential therapy targeting a specific susceptibility
gene (ITGAM) in an autoimmune disease. Thus, this comprehensive translational study has the potential for
making a larg...

## Key facts

- **NIH application ID:** 9838738
- **Project number:** 5R01DK084195-08
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** VINEET GUPTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,065
- **Award type:** 5
- **Project period:** 2011-09-20 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838738

## Citation

> US National Institutes of Health, RePORTER application 9838738, Role of beta2 integrin in lupus nephritis (5R01DK084195-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838738. Licensed CC0.

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