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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

Arthritis Research & Therapy 1/2018

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

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 1/2018
Autoren:
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:https://​doi.​org/​10.​1186/​s13075-017-1500-0) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1: Table S1. Antibodies utilized for choroid plexus flow cytometric analysis. (DOCX 12 kb)
13075_2017_1500_MOESM1_ESM.docx
Additional file 2: Figure S1. Flow cytometry gating strategy. Cortical and choroid plexus tissue from MRL/lpr mice treated or not with BI-BTK-1 were analyzed by flow cytometric analysis. Red arrows denote sequential gated population (red boxes). Black arrows denote sequential non-gated population. (DOCX 358 kb)
13075_2017_1500_MOESM2_ESM.docx
Literatur
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