Autoimmune rheumatologic diseases

Oral

cd11b Activation Protects Against Lupus Nephritis by Suppressing Tlr-dependent Ifn Responses

Thursday, June 15
5:45 PM - 7:00 PM

Elevated serum level of IFN I is a heritable risk factor for systemic lupus erythematosus (SLE) and play a pathogenic role. If single-nucleotide polymorphisms (SNPs) in the ITGAM gene (coding for CD11b) are linked to high IFN I and whether CD11b activation could be a therapeutic strategy is studied here. We measured serum IFN I activity in 171 SLE patients and determined their ITGAM genotype to test for a direct link between ITGAM SNPs and the IFN I pathway. We show that three ITGAM SNPs significantly associate with elevated levels of IFN I in SLE. We tested whether partial CD11b activation with small molecule agonist, leukadherin-1 (LA1), reduces IFN I responses and determined the underlying mechanistic pathways. To test the efficacy of LA1 in vivo, we used the MRL/lpr mice that develop IFN I-dependent multi-organ pathology with renal injury. LA1-treated mice had reduced proteinuria, IgG renal immune complex deposition, and glomerular damage as compared to vehicle-treated controls. CD11b activation reduced TLR-dependent pro-inflammatory signaling in leukocytes and suppressed IFN I signaling, via an AKT-FOXO3-IRF7 pathway. TLR-stimulated macrophages from CD11b SNP carriers showed increased basal expression of IRF7 and IFNB and increased nuclear exclusion of FOXO3, which was suppressed by LA1. LA1 suppresses TLR-stimulated overproduction of cytokines in vivo, which have been directly linked to exacerbation of SLE. These findings suggest that pharmacological CD11b activation is a potential novel therapeutic target in SLE, particularly in patients identified as carriers of specific genetic polymorphisms.

Samia Q. Khan

Postdoctoral Research Fellow
Rush University Medical Center

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    Mohd. Hafeez Faridi

    Assistant Professor
    Rush University Medical Center

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      Wenpu Trim

      Research Fellow
      NIAMS/NIH

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        HaWon Lee

        Postdoctoral Research Fellow
        Rush University Medical Center

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          Mehmet Altintas

          Rush University Medical Center

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            Mariana J. Kaplan

            Senior Investigator and Chief, Systemic Autoimmunity Branch
            National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health

            Mariana J. Kaplan, MD is Senior Investigator and Chief of the Systemic Autoimmunity Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. Dr. Kaplan's research has focused on identifying mechanisms of organ damage and premature vascular disease in systemic autoimmunity. More specifically, she investigates how innate immunity promotes end-organ damage in systemic lupus erythematosus, rheumatoid arthritis and other systemic autoimmune diseases. Recently, her research has focused on identifying abnormalities of neutrophil subsets and the role of neutrophil extracellular traps (NETs) in lupus, vasculitis and rheumatoid arthritis, both of which may contribute to the development of autoimmune responses and to end-organ damage. Dr. Kaplan also has an interest in identifying novel therapeutic targets that may prevent premature vascular damage in systemic autoimmunity, as well as the role of environmental triggers in the induction of autoimmunity. Moreover, she has led clinical trials to identify mechanisms that reduce blood vessel dysfunction in autoimmune and chronic inflammatory disorders.

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              Vineet Gupta

              Professor and Vice Chair for Research and Innovation, Department of Internal Medicine
              Rush University Medical Center

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