Increased expression of Bruton’s tyrosine kinase in peripheral blood is associated with lupus nephritis

Kong, Wei; Deng, Wei; Sun, Yue; Huang, Saisai; Zhang, Zhuoya; Shi, Bingyu; Chen, Weiwei; Tang, Xiaojun; Yao, Genhong; Feng, Xuebing; Sun, Lingyun

doi:10.1007/s10067-017-3717-3

Cited by 42 publications

(30 citation statements)

References 24 publications

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“…Increased peripheral blood expression of BTK is associated with LN in SLE patients, and it is found expressed at high levels within glomeruli of LN patients [17], further emphasizing its potential role in LN. BTK inhibition is a promising treatment option because it would interfere with several of the key pathogenic mechanisms known to be involved in LN.…”

Section: Discussionmentioning

confidence: 99%

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Chalmers

Glynn

Garcia

et al. 2018

Clinical Immunology

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Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton’s tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB×NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8–9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased survival in both strains. BI-BTK-1 treated mice displayed a significant decrease in nephritis-associated inflammatory mediators (e.g. LCN2 and IL-6) in the kidney, combined with a significant inhibition of immune cell infiltration and accumulation. Importantly, BI-BTK-1 treatment resulted in the reversal of established kidney disease. BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen of NZB/W mice. Overall, the significant efficacy of BIBTK-1 in ameliorating multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis provides a strong rationale for BTK inhibition as a promising treatment approach for lupus nephritis.

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Section: Discussionmentioning

confidence: 99%

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Chalmers

Glynn

Garcia

et al. 2018

Clinical Immunology

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“…Btk overexpression resulted in increased numbers of plasma B cells, germinal center B cells, and the production of antinuclear autoantibodies and immune complex deposition in the kidneys . Btk overexpression has also been observed in PBMCs from human SLE patients with active lupus nephritis . Thus, abnormal Btk expression is another example where altered dosage of an X‐linked gene is associated with lupus‐like disease in mouse and human models.…”

Section: The X Chromosome In Autoimmunitymentioning

confidence: 97%

When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity

Syrett

Anguera

2019

Journal of Leukocyte Biology

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Women and men exhibit differences in innate and adaptive immunity, and women are more susceptible to numerous autoimmune disorders. Two or more X chromosomes increases the risk for some autoimmune diseases, and increased expression of some X-linked immune genes is frequently observed in female lymphocytes from autoimmune patients. Evidence from mouse models of autoimmunity also supports the idea that increased expression of X-linked genes is a feature of female-biased autoimmunity. Recent studies have begun to elucidate the correlation between abnormal X-chromosome inactivation (XCI), an essential mechanism female somatic cells use to equalize X-linked gene dosage between the sexes, and autoimmunity in lymphocytes. In this review, we highlight research describing overexpression of X-linked immunity-related genes and female-biased autoimmunity in both humans and mouse models, and make connections with our recent work elucidating lymphocyte-specific mechanisms of XCI maintenance that become altered in lupus patients. K E Y W O R D Slupus, mouse models of lupus disease, sexual dimorphism with immune disease, X-chromosome inactivation, XCI gene escape, Xist RNA important for the development of autoimmunity, and disease results from additive effects of several risk variants, which alone would be insufficient to cause disease. Yet, hundreds of loci have been associated with autoimmune diseases, and some of these immune gene variants are present in different diseases, suggesting that common J Leukoc Biol. 2019;106:919-932.

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“…Similarly, increased Btk expression and phosphorylation correlated with RF antibodies in Sjogren’s syndrome patients ( 138 ). The frequency of Btk + cells in the peripheral blood of SLE patients has been reported to correlate with disease activity, anti-dsDNA antibodies, proteinuria, and C3 levels ( 140 ), but whether this reflects changes in Btk signaling or cell subset distribution is unclear.…”

Section: Btk In Human Autoimmunitymentioning

confidence: 99%

Bruton’s Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus

Satterthwaite

2018

Front. Immunol.

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of adaptive immune tolerance to nucleic acid-containing antigens. The resulting autoantibodies form immune complexes that promote inflammation and tissue damage. Defining the signals that drive pathogenic autoantibody production is an important step in the development of more targeted therapeutic approaches for lupus, which is currently treated primarily with non-specific immunosuppression. Here, we review the contribution of Bruton’s tyrosine kinase (Btk), a component of B and myeloid cell signaling pathways, to disease in murine lupus models. Both gain- and loss-of-function genetic studies have revealed that Btk plays multiple roles in the production of autoantibodies. These include promoting the activation, plasma cell differentiation, and class switching of autoreactive B cells. Small molecule inhibitors of Btk are effective at reducing autoantibody levels, B cell activation, and kidney damage in several lupus models. These studies suggest that Btk may promote end-organ damage both by facilitating the production of autoantibodies and by mediating the inflammatory response of myeloid cells to these immune complexes. While Btk has not been associated with SLE in GWAS studies, SLE B cells display signaling defects in components both upstream and downstream of Btk consistent with enhanced activation of Btk signaling pathways. Taken together, these observations indicate that limiting Btk activity is critical for maintaining B cell tolerance and preventing the development of autoimmune disease. Btk inhibitors, generally well-tolerated and approved to treat B cell malignancy, may thus be a useful therapeutic approach for SLE.

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Increased expression of Bruton’s tyrosine kinase in peripheral blood is associated with lupus nephritis

Cited by 42 publications

References 24 publications

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity

Bruton’s Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus

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