Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus

Samantha A. Chalmers, Jing Wen, Jessica Doerner, Ariel Stock, Carla M. Cuda, Hadijat M. Makinde, Harris Perlman, Todd Bosanac, Deborah Webb, Gerald Nabozny, Jay S. Fine, Elliott Klein, Meera Ramanujam, Chaim Putterman

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. Methods: We used a novel inhibitor of Bruton's tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease. Results: We found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus. Conclusions: Directed therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE.

Original languageEnglish (US)
Article number10
JournalArthritis Research and Therapy
Volume20
Issue number1
DOIs
StatePublished - Jan 25 2018

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Brain Diseases
Skin Diseases
Systemic Lupus Erythematosus
Skin
B-Lymphocytes
Macrophages
Central Nervous System
Inbred MRL lpr Mouse
Choroid Plexus
Therapeutics
Autoantibodies
Immunosuppression
Cognition
Autoimmune Diseases
Inhibition (Psychology)
Agammaglobulinaemia tyrosine kinase
Pathology
Cytokines
T-Lymphocytes
Phenotype

Keywords

  • Bruton's tyrosine kinase (BTK)
  • Cutaneous lupus erythematosus (CLE)
  • Neuropsychiatric lupus (NPSLE)
  • Systemic lupus erythematous (SLE)

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

Cite this

Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus. / Chalmers, Samantha A.; Wen, Jing; Doerner, Jessica; Stock, Ariel; Cuda, Carla M.; Makinde, Hadijat M.; Perlman, Harris; Bosanac, Todd; Webb, Deborah; Nabozny, Gerald; Fine, Jay S.; Klein, Elliott; Ramanujam, Meera; Putterman, Chaim.

In: Arthritis Research and Therapy, Vol. 20, No. 1, 10, 25.01.2018.

Research output: Contribution to journalArticle

Chalmers, SA, Wen, J, Doerner, J, Stock, A, Cuda, CM, Makinde, HM, Perlman, H, Bosanac, T, Webb, D, Nabozny, G, Fine, JS, Klein, E, Ramanujam, M & Putterman, C 2018, 'Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus', Arthritis Research and Therapy, vol. 20, no. 1, 10. https://doi.org/10.1186/s13075-017-1500-0
Chalmers, Samantha A. ; Wen, Jing ; Doerner, Jessica ; Stock, Ariel ; Cuda, Carla M. ; Makinde, Hadijat M. ; Perlman, Harris ; Bosanac, Todd ; Webb, Deborah ; Nabozny, Gerald ; Fine, Jay S. ; Klein, Elliott ; Ramanujam, Meera ; Putterman, Chaim. / Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus. In: Arthritis Research and Therapy. 2018 ; Vol. 20, No. 1.
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AU - Cuda, Carla M.

AU - Makinde, Hadijat M.

AU - Perlman, Harris

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AU - Webb, Deborah

AU - Nabozny, Gerald

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AB - Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. Methods: We used a novel inhibitor of Bruton's tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease. Results: We found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus. Conclusions: Directed therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE.

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