The association of CD40 polymorphism (rs1883832C/T) and soluble CD40 with the risk of systemic lupus erythematosus among Egyptian patients

Mousa, Taghreed G.; Omar, Hanan Hassan; Emad, Rasha; Salama, Mona I.; Omar, Waleed; Fawzy, Mohamed; Hassoba, Howayda M.

doi:10.1007/s10067-018-4349-y

Cited by 12 publications

(6 citation statements)

References 40 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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“…Rs1883832 was significantly associated with SLE in a Tunisian population (22). However, a study in Egypt population and a study in Korea population did not find significant results (12,23). For RA, there was no association of rs1883832 in Eastern Chinese and Iran population (24,25) and the study published by Liu et al showed that genotype TT versus CC+CT was significant in men (24).…”

Section: Discussionmentioning

confidence: 93%

“…Therefore, dysregulated expression of CD40 may be caused by upregulation of transcription and translation owing to mutated polymorphism. Studies showed that genotype TT, TC of rs1883832 associated with increased CD40 expression in Chinese and Egypt SLE patients (9,23). Genotype GG of rs4810485 was related to increased CD40 expression in Greek and Turkish SLE patients (27,28).…”

Section: Discussionmentioning

confidence: 99%

Association of CD40 Gene Polymorphisms With Systemic Lupus Erythematosus and Rheumatoid Arthritis in a Chinese Han Population

Huang

et al. 2021

Front. Immunol.

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Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases. CD40 participates in inflammatory response, and promotes fibroblast proliferation, leading to occurrence and progression of SLE, RA. This study explores CD40 gene polymorphisms in SLE and RA patients from a Chinese Han population. Two hundred SLE patients, 340 RA patients, and 900 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood, and six polymorphisms of CD40 gene (rs3765456, rs1569723, rs73115010, rs13040307, rs1883832, and rs4810485) were detected by KASP method. Frequencies of rs1569723 genotypes AA, AC, AA+AC were significantly higher in RA patients as compared to those in healthy controls (P = 0.049, P = 0.024, P = 0.022). Frequencies of genotypes CT, CC+CT of rs1883832, and GT, GG+GT of rs4810485 were significantly higher in RA patients as compared to those in healthy controls (P = 0.012, P = 0.018, P = 0.009, P = 0.015). RA patients carrying rs13040307 C allele and rs73115010 T allele showed increased number of swollen joints. Moreover, frequency of allele T of rs13040307 was lower in SLE patients with positive anti-dsDNA and hematuria as compared to that in patients without these parameters (P = 0.038, P = 0.045). There were increased frequencies of genotype TT, allele T for rs13040307 and lower frequencies of genotype TT, allele T for rs73115010 in lupus patients with myositis (all P<0.05). Interestingly, frequencies of rs1569723 A allele, rs4810485 T allele were higher in SLE patients with myositis, and frequencies of rs3765456 A allele, rs1883832 T allele were lower in SLE patients with myositis (All P<0.05). In conclusion, CD40 gene polymorphisms may associate with susceptibility to SLE and RA.

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“…32,33 Therefore, 14 studies met the inclusion criteria. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] One of the eligible studies included data on two different groups that were independently treated 7 (Table 1). Of these studies, six studies together comprised 1884 patients with SLE and 2882 controls, which were evaluated for CD40 rs4810485 polymorphism; three studies for CD40 rs1883832 polymorphism with 898 patients and 1248 controls; and two studies for rs3765456 polymorphism with 916 patients and 1285 controls.…”

Section: Studies Included In the Meta-analysismentioning

confidence: 99%

“…7 Some studies investigating the relationship between CD40 polymorphisms and SLE and between soluble CD40 (sCD40) and soluble CD40L (sCD40L) levels and SLE have found associations with SLE susceptibility. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] Reasons for such disparity may be small sample sizes, low statistical power, and/or clinical heterogeneity. To overcome the limitations of individual studies and resolve inconsistencies, we performed this meta-analysis [21][22][23] to review the systematically available evidence on the associations between CD40 rs4810495, rs1883832, and rs376545 polymorphisms and sCD40/sCD40L levels in patients with SLE and controls.…”

Section: Introductionmentioning

confidence: 99%

Association between CD40 polymorphisms and systemic lupus erythematosus and correlation between soluble CD40 and CD40 ligand levels in the disease: a meta-analysis

Bae

Lee

2019

Lupus

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Objective The aim of this study was to systematically review evidence regarding the association between CD40 polymorphisms and systemic lupus erythematosus and between soluble CD40 (sCD40) and CD40 ligand (sCD40L) levels and systemic lupus erythematosus. Methods We performed a meta-analysis on the association between CD40 rs4810495, rs1883832, and rs376545 polymorphisms and systemic lupus erythematosus risk and sCD40/sCD40L levels in patients with systemic lupus erythematosus and controls. Results Fourteen studies were included. Ethnicity-specific meta-analysis indicated a significant association between the T allele of CD40 rs4810485 polymorphism and systemic lupus erythematosus in Europeans (odds ratio = 0.715, 95% confidence interval = 0.641–0.832, p < 0.001) and a trend toward an association between the T allele and systemic lupus erythematosus in Asians (odds ratio = 1.255, 95% confidence interval = 0.978–1.810, p = 0.074). Furthermore, a significant association was reported between systemic lupus erythematosus and the C allele of CD40 rs1883832 polymorphism (odds ratio = 1.235, 95% confidence interval = 1.087–1.405, p = 0.001) and A allele of CD40 rs3765456 polymorphism and systemic lupus erythematosus in Asians (odds ratio = 1.184, 95% confidence interval = 1.040–1.348, p = 0.011). sCD40 and sCD40L levels were significantly higher in SLE than in controls (standardized mean difference = 1.564, 95% confidence interval = 0.256–2.872, p = 0.019 and standardized mean difference = 1.499, 95% confidence interval = 1.031–1.967, p < 0.001, respectively). Stratification based on ethnicity revealed higher sCD40L levels in the systemic lupus erythematosus group among European, Asian, North American, and Arab populations. Conclusions Our meta-analyses found associations between CD40 rs4810495, rs1883832, and rs376545 polymorphisms and systemic lupus erythematosus susceptibility and significantly higher sCD40 and sCD40L levels in patients with systemic lupus erythematosus than in controls.

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The association of CD40 polymorphism (rs1883832C/T) and soluble CD40 with the risk of systemic lupus erythematosus among Egyptian patients

Cited by 12 publications

References 40 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

Association of CD40 Gene Polymorphisms With Systemic Lupus Erythematosus and Rheumatoid Arthritis in a Chinese Han Population

Association between CD40 polymorphisms and systemic lupus erythematosus and correlation between soluble CD40 and CD40 ligand levels in the disease: a meta-analysis

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