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

Zhang, Shungang; Breidenbach, Joshua D.; Russell, Benjamin; George, Jerrin

doi:10.3390/jcm9113653

Cited by 15 publications

(10 citation statements)

References 139 publications

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“…So far, serum sCD40L levels of MODY5 patients have not been investigated. However, in clinical studies, circulating levels of sCD40L have been reported to be associated with kidney damage in different types of kidney disease (70). Based on this finding, it can be suggested that the level of sCD40L may also be increased in MODY5 patients in relation to nephropathy, but it needs confirmation in studies involving more patients.…”

Section: Discussionmentioning

confidence: 97%

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY)

DIREN¹,

Demirci

Gül

et al. 2022

In Vivo

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Background/Aim: High-sensitivity C-reactive protein (hs-CRP) is used in the differential diagnosis of maturity-onset diabetes of the young (MODY)-3, but other inflammatory markers have not been investigated in MODY patients. We aimed to compare the serum levels of antiinflammatory and proinflammatory cytokines between MODY patients and healthy subjects and show the inflammatory features in MODY subtypes. Patients and Methods: Thirty patients with clinically suspected MODY and 34 healthy controls were included in this study. Nextgeneration sequencing (NGS) was used for the molecular diagnosis of MODY subtypes. Serum levels of cytokines were measured using a multiplexed cytokine assay and hs-CRP concentration was determined by the immunoturbidimetric assay. Results: The hs-CRP levels were higher in both NGSconfirmed (MODY, n=17) (p=0.009) and n=13) patients (p<0.001) than those in controls. However, , , , , and sCD40L (p=0.007) levels of MODY patients and IL-1β (p=0.002), IL-31 (p<0.001), , and sCD40L (p=0.039) levels of non-MODY patients were lower than those of controls. While hs-CRP levels were lower in MODY3 patients than non-MODY3 patients (p=0.009), IL-17A (p=0.006) and IL-23 (p=0.016) levels for the first time in this study were found to be higher in patients with MODY3 than in patients with other MODY subtypes (p<0. 05). Conclusion: MODY patients had lower serum levels of the proinflammatory cytokines IL-1β, IL-6, TNF-α, IL-31, and sCD40L compared to healthy controls. High IL-17A and IL-23 levels along with low hs-CRP levels may be potential markers to distinguish MODY3 from other MODY subtypes.Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes and comprises about 1-5% of total diabetes (1). The prevalence of MODY has been increasing like other forms of diabetes in Turkey (2). The diagnostic criteria specified in the Practice Guideline for MODY in 2018 are evidence of endogenous insulin secretion, diabetes-onset before the age of 25 in at least one family member, presence of diabetes in two consecutive generations, and absence of autoantibodies to pancreatic islet antigens (1, 3). Mutations in genes responsible for beta cells' development and function cause MODY. To date, different mutations in fourteen genes (HNF4A/MODY1, GCK/MODY2, HNF1A/MODY3, PDX1/MODY4, HNF1B/MODY5, NEUROD1/MODY6, KLF11/ MODY7, CEL/MODY8, PAX4/MODY9, INS/MODY10, BLK/ MODY11, ABCC8/MODY12, KCNJ11/MODY13, and APPL1/ MODY14) have been described as responsible for the pathogenesis of MODY subtypes (3, 4). Recent studies have suggested that some possible biomarkers such as urine and serum amino acids, complement 5 and 8, transthyretin, urine glucose, apolipoprotein M (ApoM), lipid profile, D-glycan index, and cystatin C are useful for the differential diagnosis of 2490

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Section: Discussionmentioning

confidence: 97%

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY)

DIREN¹,

Demirci

Gül

et al. 2022

In Vivo

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“…CD40 L (CD154), the natural ligand of CD40, is located at the surface of B and T cells, as well as macrophages, dendritic cells, endothelial cells, fibroblasts, and epithelial cell. Its activation results in the triggering of the PI3K, NF-κB, and p38/ERK cascades, resulting in inflammatory and fibrogenic activity 33 34 . Here again, the downregulation of CD40 L is surprising, but could be associated to the underexpression of IFNγ.…”

Section: Discussionmentioning

confidence: 99%

“…cascades, resulting in inflammatory and fibrogenic activity [33,34]. Here again, the downregulation of CD40L is surprising, but could be associated to the underexpression of IFNγ.…”

Section: Accepted Manuscriptmentioning

confidence: 93%

Mechanisms of esophageal stricture after extensive endoscopic resection: a transcriptomic analysis

et al. 2022

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Introduction: Esophageal stricture is the most frequent adverse event after endoscopic resection for early esophageal neoplasia. Currently available treatments for the prevention of esophageal stricture are poorly effective and associated with major adverse events. Our aim was to identify transcripts specifically overexpressed or repressed in patients who have developed a post endoscopic esophageal stricture, as potential targets for stricture prevention. Patients and methods: We conducted a prospective single-center study in a tertiary endoscopy center. Patients scheduled for an endoscopic resection and considered at risk of esophageal stricture were offered inclusion in the study. The healthy mucosa and resection bed were biopsied at day 0, 14 and 90. A transcriptomic analysis by microarray was performed, and the differences in transcriptomic profile compared between patients with and without esophageal strictures. Results: Eight patients, four with esophageal stricture and four without, were analyzed. The mean ±SD circumferential extension of the mucosal defect was 85±11%. The transcriptomic analysis in the resection bed at day 14 found an activation of the Interleukin-1 group (Z score = 2.159, p = 0.0137), while Interferon γ and NUPR1 were inhibited (Z score = -2.375, p = 0.0022 and Z score =-2.333, p = 0.00131) in the stricture group. None of the activated or inhibited transcripts were still significantly so in any of the groups at day 90. Conclusions: Our data suggest that Interleukin-1 inhibition or Interferon-γ supplementation could constitute promising targets for post-endoscopic esophageal stricture prevention.

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“…In the present study, also tnfr1 and cd40 gene expressions were increased upon CD40 mAb stimulation in liver and to a lesser extent in kidney. CD40 is expressed predominantly on endothelial cells, B lymphocytes and APC [ 5 ] and in various cell types of the diseased kidney, including epithelial cells, podocytes, and immune cells so that CD40 is considered as important mediator in the regulation of inflammatory and fibrotic kidney processes [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

CD40 Agonist Monoclonal Antibody-Mediated Hepatitis in TNF-Receptor 1 Gene Knockout Mice

et al. 2021

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Tumor necrosis factor-alpha (TNF-α) plays an important role in liver inflammation. CD40-CD40 ligand (CD40-CD40L) is a key receptor–ligand signaling pair involved in the adaptive immune response and pathogenesis of autoimmune diseases. In mice, CD40 activation leads to sickness behavior syndrome (SBS) comprising weight loss, sleep disruption and depression, which can be blocked by administration of the TNF-inhibitor etanercept. In the present study, we assessed the extent of hepatic inflammation in mice devoid of the TNF-receptor 1 (TNFR1)-mediated signaling pathway. The TNFR1-depleted (TNFR1−/−) adult mice and their wild type littermates were given a single intra-peritoneal injection of CD40 agonist monoclonal antibody (mAb) or rat IgG2a isotope control. As described previously, TNFR1−/− mice were protected from SBS upon CD40 mAb treatment. Cd40, tnf and tnfr1 mRNA and Tnf-α peptide were increased in the liver of CD40 mAb-stimulated wild type mice. Serum alanine aminotransferase was elevated in both CD40-activated wild type and TNFR1−/− mice. TNFR1−/− mice showed much less intra-parenchymal infiltrates, hepatocellular necrosis, and perivascular clusters upon CD40 mAb activation than their wild type littermates. A gene expression microarray detected increased activity of metabolic and detoxification pathways and decreased activity of inflammatory pathways. We conclude that immune activation and development of liver inflammation in CD40L interactions depend on TNFR1-mediated signaling pathways and are counteracted by alterations in metabolic pathways.

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

Cited by 15 publications

References 139 publications

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY)

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY)

Mechanisms of esophageal stricture after extensive endoscopic resection: a transcriptomic analysis

CD40 Agonist Monoclonal Antibody-Mediated Hepatitis in TNF-Receptor 1 Gene Knockout Mice

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