Rationale for B cell targeting in SLE

Sanz, Iñaki

doi:10.1007/s00281-014-0430-z

Cited by 31 publications

(19 citation statements)

References 101 publications

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“…It is known that B lymphocytes are involved in the pathogenesis of systemic lupus erythematosus (SLE) in autoantibody-dependent mechanisms. While some recent studies suggested that autoantibody-independent mechanisms might be more important, the specific mechanism is still unclear [3–5]. Investigations in the MRL/ lpr mouse model of lupus nephritis have indicated that B cells exert a pathogenic role in the absence of soluble autoantibody production [6].…”

Section: Introductionmentioning

confidence: 99%

Association of Serum CXCL13 with Intrarenal Ectopic Lymphoid Tissue Formation in Lupus Nephritis

Chen

Long

et al. 2016

Journal of Immunology Research

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Aims. To assess the concentrations of serum CXCL13 and intrarenal ectopic lymphoid tissue (ELT) profiles and their correlation in the patients with lupus nephritis (LN). Methods. Serum CXCL13 levels were measured using enzyme-linked immunosorbent assays (ELISA). The expression of CD3, CD20, and CD21 in renal biopsy specimens was tested using immunohistochemical methods. Results. Serum CXCL13 levels were significantly higher in the LN group than those in the SLE group without LN and also in the type III and IV LN patients than in type V LN patients. LN patients with positive CD20 expression (CD20+ LN) had a longer disease course and poorer response to combination therapy and higher serum CXCL13 levels than CD20− LN patients. Moreover, the serum CXCL13 level was positively correlated with the number of B cells/HP in the renal tissue of LN patients. The coexpression patterns of CD3, CD20, and CD21 in the renal tissue of LN patients with different WHO pathological types were significantly different. Serum CXCL13 levels were significantly higher in ELT-2 type LN patients than in 0 or 1 type LN patients. Conclusions. This study suggested that increased serum levels of CXCL13 might be involved in renal ELT formation and renal impairment process in LN.

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Section: Introductionmentioning

confidence: 99%

Association of Serum CXCL13 with Intrarenal Ectopic Lymphoid Tissue Formation in Lupus Nephritis

Chen

Long

et al. 2016

Journal of Immunology Research

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“…Abnormal B cell activation contributes to SLE pathogenesis through both antibody-dependent and independent fashions [1, 54, 79–81]. In addition to the impaired B cell survival, B cell-specific deletion of PKK also resulted in significant reduction of activated CD4 + T cells in Sle mice (Figure 5), and PKK-deficient Sle B cells fail to efficiently up-regulate the critical T cell-costimulatory molecules CD80 and CD86 in response to BCR stimulation (Figure 6C).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that B cells play a central role in autoimmune diseases through their unique functions including auto-antibody production and antibody-independent functions such as antigen presentation to T cells and cytokine production [1–6]. The deregulation of B cell development pathways, such as alterations in B cell receptor (BCR) signaling, can lead to the development of lupus [7–11].…”

Section: Introductionmentioning

confidence: 99%

PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B- lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.

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“…Anti-CD20 mAbs efficiently deplete mature naïve and memory B cells [36]. However, B cells in the early developmental stages, as well as the majority of plasma cells, are largely resistant to depletion by anti-CD20 because these B-cell subsets do not express detectable CD20 on the cell surface [36].…”

Section: Rationale For Targeting Cd19 and The Development Of Inebimentioning

confidence: 99%

“…However, B cells in the early developmental stages, as well as the majority of plasma cells, are largely resistant to depletion by anti-CD20 because these B-cell subsets do not express detectable CD20 on the cell surface [36]. In contrast, CD19 has a broader expression during B-cell development than does CD20 [37,38].…”

Section: Rationale For Targeting Cd19 and The Development Of Inebimentioning

confidence: 99%

Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies

Chen

Gallagher²,

Monson

et al. 2016

JCM

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Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS) has stimulated the development of novel B-cell-targeting therapies with the potential for improved efficacy. CD19 has emerged as a promising target for the depletion of B cells as well as CD19-positive plasmablasts and plasma cells. Inebilizumab (MEDI-551), an anti-CD19 antibody with enhanced antibody-dependent cell-mediated cytotoxicity against B cells, is currently being evaluated in MS and neuromyelitis optica. This review discusses the role of B cells in autoimmune neurological disorders, summarizes the development of inebilizumab, and analyzes the recent results for inebilizumab treatment in an autoimmune encephalitis mouse model. The novel insights obtained from these preclinical studies can potentially guide future investigation of inebilizumab in patients.

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Rationale for B cell targeting in SLE

Cited by 31 publications

References 101 publications

Association of Serum CXCL13 with Intrarenal Ectopic Lymphoid Tissue Formation in Lupus Nephritis

Association of Serum CXCL13 with Intrarenal Ectopic Lymphoid Tissue Formation in Lupus Nephritis

PKK deficiency in B cells prevents lupus development in Sle lupus mice

Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies

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