Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus

Jack Hutcheson, Kamala Vanarsa, Anna Bashmakov, Simer Grewal, Deena Sajitharan, Betty Y. Chang, Joseph J. Buggy, Xin J. Zhou, Yong Du, Anne B. Satterthwaite, Chandra Mohan

Research output: Contribution to journalArticle

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Abstract

Introduction: Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice.Methods: B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated.Results: In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.Conclusions: These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.

Original languageEnglish (US)
Article numberR243
JournalArthritis Research and Therapy
Volume14
Issue number6
DOIs
StatePublished - Nov 8 2012

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Autoimmunity
B-Lymphocytes
Nuclear Antigens
Lupus Nephritis
Antigen-Presenting Cells
Transducers
Drinking Water
Systemic Lupus Erythematosus
Autoantibodies
Autoimmune Diseases
Agammaglobulinaemia tyrosine kinase
Cell Differentiation
Chronic Disease
PCI 32765
Neoplasms

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy

Cite this

Hutcheson, J., Vanarsa, K., Bashmakov, A., Grewal, S., Sajitharan, D., Chang, B. Y., ... Mohan, C. (2012). Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus. Arthritis Research and Therapy, 14(6), [R243]. https://doi.org/10.1186/ar4086

Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus. / Hutcheson, Jack; Vanarsa, Kamala; Bashmakov, Anna; Grewal, Simer; Sajitharan, Deena; Chang, Betty Y.; Buggy, Joseph J.; Zhou, Xin J.; Du, Yong; Satterthwaite, Anne B.; Mohan, Chandra.

In: Arthritis Research and Therapy, Vol. 14, No. 6, R243, 08.11.2012.

Research output: Contribution to journalArticle

Hutcheson, J, Vanarsa, K, Bashmakov, A, Grewal, S, Sajitharan, D, Chang, BY, Buggy, JJ, Zhou, XJ, Du, Y, Satterthwaite, AB & Mohan, C 2012, 'Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus', Arthritis Research and Therapy, vol. 14, no. 6, R243. https://doi.org/10.1186/ar4086
Hutcheson, Jack ; Vanarsa, Kamala ; Bashmakov, Anna ; Grewal, Simer ; Sajitharan, Deena ; Chang, Betty Y. ; Buggy, Joseph J. ; Zhou, Xin J. ; Du, Yong ; Satterthwaite, Anne B. ; Mohan, Chandra. / Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus. In: Arthritis Research and Therapy. 2012 ; Vol. 14, No. 6.
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AU - Vanarsa, Kamala

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AU - Grewal, Simer

AU - Sajitharan, Deena

AU - Chang, Betty Y.

AU - Buggy, Joseph J.

AU - Zhou, Xin J.

AU - Du, Yong

AU - Satterthwaite, Anne B.

AU - Mohan, Chandra

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N2 - Introduction: Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice.Methods: B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated.Results: In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.Conclusions: These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.

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