Association of soluble CD40 levels with ‐1 C &gt; T <i>CD40</i> polymorphism and chronic kidney disease in systemic lupus erythematosus

Tapia‐Llanos, Raziel; Muñoz‐Valle, José Francisco; Román-Fernández, Ilce Valeria; Marín‐Rosales, Miguel; Salazar-Camarena, Diana Celeste; Cruz, Álvaro; Orozco‐Barocio, Gerardo; Guareña‐Casillas, Jorge A.; Edith, Oregon-Romero; Palafox‐Sánchez, Claudia Azucena

doi:10.1002/mgg3.1014

Cited by 9 publications

(6 citation statements)

References 49 publications

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“…Consistent with its role in humoral immunity, the CD40-CD40L pathway has been implicated in the pathogenesis of several autoimmune diseases, known to be driven by the production of pathogenic autoantibodies. For example, CD40 polymorphisms, linked to increased CD40 proteins levels, are associated with a higher risk of developing systemic lupus erythematosus (SLE) and Graves' disease [5][6][7][8]. Furthermore, CD40-CD40L interactions have been implicated in the formation of ectopic GCs in salivary glands in Sjogren's syndrome (SjS) and thyroid gland in Graves' disease, and the generation of antibody-producing plasma cells [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

2021

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Background CD40-CD40L is a key co-stimulatory pathway for B cell activation. As such, its blockade can inhibit pathogenic B cell responses in autoimmune diseases, such as Sjogren’s syndrome (SjS) and systemic lupus erythematosus (SLE). In this study, we examined the in vitro effects of KPL-404, a humanized anti-CD40 monoclonal antibody (Ab), on primary human B cells derived from either healthy donors (HD) or autoimmune patients and compared them to the effects of G28-5, a partially antagonistic anti-CD40 antibody. Methods PBMCs from HD or SjS and SLE patients were cultured in high-density cell cultures in the presence of IgG4 isotype control or anti-CD40 Abs KPL-404 or G28-5. Cells were stimulated with anti-CD3/CD28 cross-linking reagent ImmunoCult (IC) to induce CD40L-CD40-mediated B cell responses. B cell proliferation and activation, measured by dilution of proliferation tracker dye and the upregulation of CD69 and CD86, respectively, were assessed by flow cytometry. Anti-CD40 Ab cell-internalization was examined by imaging flow cytometry. Cytokine release in the PBMC cultures was quantified by bead-based multiplex assay. Results KPL-404 binds to CD40 expressed on different subsets of B cells without inducing cell depletion, or B cell proliferation and activation in in vitro culture. Under the same conditions, G28-5 promoted proliferation of and increased CD69 expression on otherwise unstimulated B cells. KPL-404 efficiently blocked the CD40L-CD40-mediated activation of B cells from HD at concentrations between 1 and 10 μg/ml. Treatment with KPL-404 alone did not promote cytokine production and blocked the production of IFNβ in healthy PBMC cultures. KPL-404 efficiently blocked CD40L-CD40-mediated activation of B cells from patients with SjS and SLE, without affecting their anti-IgM responses or affecting their cytokine production. Consistent with the differences of their effects on B cell responses, KPL-404 was not internalized by cells, whereas G28-5 showed partial internalization upon CD40 binding. Conclusions Anti-CD40 mAb KPL-404 showed purely antagonistic effects on B cells and total PBMCs. KPL-404 inhibited CD40L-CD40-mediated B cell activation in PBMC cultures from both healthy controls and autoimmune patients. These data support the therapeutic potential of CD40 targeting by KPL-404 Ab for inhibiting B cell responses in SjS and SLE.

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Section: Introductionmentioning

confidence: 99%

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

2021

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“…Associations between sCD40L and pathological parameters also have been reported in systemic lupus erythematosus (SLE) patients with chronic kidney disease in which sCD40L levels are elevated [43][44][45] and circulating levels of the CD40 receptor are negatively associated with eGFR [45]. Increased circulating sCD40L levels have also been described in patients with Shiga toxin-associated hemolytic uremic syndrome, where sCD40L levels are negatively correlated with levels of urea and creatinine [46].…”

Section: Cd40 and Cd40l As Markers Of Renal Function In Kidney Diseasementioning

confidence: 85%

“…Circulating sCD40L and sCD40 sCD40L levels are elevated [43][44][45] and circulating levels of the CD40 receptor are negatively associated with eGFR [45] Shiga toxin-associated hemolytic uremic syndrome Circulating sCD40L Negatively correlated with levels of urea and creatinine [46] Nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) Serum sCD40L Increased in patients but not correlated with proteinuria and eGFR [47] Renal artery stenosis Circulating sCD40L and sCD40 Lower circulating levels of CD40 receptor (sCD40) are associated with a decline in renal function [4,54]…”

Section: Systemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease

Zhang

Breidenbach

Russell

et al. 2020

JCM

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The cluster of differentiation 40 (CD40) is activated by the CD40 ligand (CD40L) in a variety of diverse cells types and regulates important processes associated with kidney disease. The CD40/CD40L signaling cascade has been comprehensively studied for its roles in immune functions, whereas the signaling axis involved in local kidney injury has only drawn attention in recent years. Clinical studies have revealed that circulating levels of soluble CD40L (sCD40L) are associated with renal function in the setting of kidney disease. Levels of the circulating CD40 receptor (sCD40), sCD40L, and local CD40 expression are tightly related to renal injury in different types of kidney disease. Additionally, various kidney cell types have been identified as non-professional antigen-presenting cells (APCs) that express CD40 on the cell membrane, which contributes to the interactions between immune cells and local kidney cells during the development of kidney injury. Although the potential for adverse CD40 signaling in kidney cells has been reported in several studies, a summary of those studies focusing on the role of CD40 signaling in the development of kidney disease is lacking. In this review, we describe the outcomes of recent studies and summarize the potential therapeutic methods for kidney disease which target CD40.

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“…CD40 is immune-stimulatory molecule important for germinal center formation and antibody class-switching. The SNP lowers translation efficiency and increases the risk for autoimmune diseases such as systemic lupus erythematosus (Jacobson, Concepcion, Oashi, & Tomer, 2005;Tapia-Llanos et al, 2019). The promoter for lactase gene (LCT; green) depends on enhancer sequences (thick dark blue vertical lines) in the upstream intron 13 (gray) of the MCM6 gene.…”

Section: Translational Mutantsmentioning

confidence: 99%

“…CD40 is immune‐stimulatory molecule important for germinal center formation and antibody class‐switching. The SNP lowers translation efficiency and increases the risk for autoimmune diseases such as systemic lupus erythematosus (Jacobson, Concepcion, Oashi, & Tomer, 2005; Tapia‐Llanos et al, 2019).…”

Section: Transcriptional and Translational Mutationsmentioning

confidence: 99%

Two sides of the same medal: Noncoding mutations reveal new pathological mechanisms and insights into the regulation of gene expression

Wachs

Bohne

2020

WIREs RNA

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Noncoding sequences constitute the major part of the human genome and also of pre-mRNAs. Single nucleotide variants in these regions are often overlooked, but may be responsible for much of the variation of phenotypes observed. Mutations in the noncoding part of pre-mRNAs often reveal new and meaningful insights into the regulation of cellular gene expression. Thus, the mechanistic analysis of the pathological mechanism of such mutations will both foster a deeper understanding of the disease and the underlying cellular pathways. Even synonymous mutations can cause diseases, since the primary mRNA sequence not only encodes amino acids, but also encrypts information on RNA-binding proteins and secondary structure. In fact, the RNA sequence directs assembly of a specific mRNP complex, which in turn dictates the fate of the mRNA or regulates its biogenesis. The accumulation of genomic sequence information is increasing at a rapid pace. However, much of the diversity uncovered may not explain the phenotype of a certain syndrome or disease. For this reason, we also emphasize the value of mechanistic studies on pathological mechanisms being complementary to genome-wide studies and bioinformatic approaches.

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Association of soluble CD40 levels with ‐1 C > T CD40 polymorphism and chronic kidney disease in systemic lupus erythematosus

Cited by 9 publications

References 49 publications

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease

Two sides of the same medal: Noncoding mutations reveal new pathological mechanisms and insights into the regulation of gene expression

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