Table 1.
Clinical Studies on the role of the Th17/IL-17 axis and associated Imbalances in lupus nephritis.
| References | Year | Biomarker | Patients | Main results |
|---|---|---|---|---|
| Xing et al. (57) | 2012 | Th17, IL-17, and IL-22 | 60 SLE patients and 28 healthy controls (HCs) | Patients with LN had a significant increase in the frequency of Th17 cells in peripheral blood, accompanied by FoxP3+ Treg cells decrease. So, the Th17/Treg ratio was significantly increased along with increased SLEDAI scores. The expression of IL-17 levels in LN patients exhibited a significant increase compared with patients without nephritis and healthy controls. |
| Dong et al. (58) | 2003 | IL-17 | 50 consecutively hospitalized LN patients and 15 adults HC who underwent blood samples to analyze the roles of IL-17 stimulation on the autoantibody's overproduction and IL-6 overexpression in PBMC. | In LN patients, the levels of IgG, anti-dsDNA, and IL-6 were higher in PBMC supernatants under IL-17 stimulation than in a normal culture medium. The increase in IgG, anti-dsDNA, and IL-6 levels, induced by IL-17, was dose-dependent and could be completely blocked by IL-17 monoclonal antibody and partially blocked by dexamethasone. During stimulation with IL-17, IL-6 mRNA levels were higher in LN patients than in HC (mean ± SD: 3.21 ± 0.24 vs. 1.30 ± 0.14, P < 0.05). |
| Cavalcanti et al. (59) | 2017 | IL-17 and IL-6 | 51 childhood-onset SLE patients (11 with LN) and 47 HC. | The levels of serum cytokines were significantly higher during active than inactive disease (mean ± SD: 6.14 ± 6.70 vs. 0.46 ± 1.47 pg/ml; P=0.041; and 13.64 ± 17.13 vs. 1.33 ± 0.86 pg/ml, P = 0.02; for IL-17, and IL-6 respectively). |
| Chen et al. (43) | 2012 | Th17 Cells, Serum and Glomerular IL-17 and IL-23 expression | 24 LN patients (17 with class IV and 7 with class V), 12 HC, and 4 patients with MCD | The median frequency of circulating Th17 cells was significantly higher in LN patients than in HC [median (IQR): 0.68% (0.39–1.10%) vs. 0.12% (0.05–0.18%), p < 0.001]. Serum cytokine levels were significantly higher in LN patients than in HC (median: 7.26 vs. 0.82; 232.60 vs. 34.60; and 37.01 vs. 7.42 pg/ml, for IL-17, IL-6, and IL-23, respectively). The frequencies of circulating Th17-cells correlated positively with poor prognostic factors (SLEDAI, renal SLEDAI, histological activity index, cellular crescent, and endocapillary proliferation). Intraglomerular levels of IL-17 and IL-23 were significantly higher in class IV LN than in MCN patients or HC. Glomerular IL-17 and IL-23 expression levels were positively correlated with renal SLEDAI and histological activity index for LN patients. |
| Galil et al. (52) | 2015 | IL-17 and IL-6 | 72 SLE patients (30 with recent-onset active LN and 42 without renal disease) and 70 sex- and age-matched HC. | SLE patients were found to have significantly higher levels of IL-17 (p < 0.001) and IL-6 (p < 0.001) in relation to HC. Patients with LN had lower levels of both cytokines during periods of remission than in active disease (mean ± SD: 10.78 ± 2.38 vs. 19.54 ± 7.41 and 13.18 ± 2.73 vs. 28.46 ± 8.16, for IL-6 and IL-17, respectively, P < 0.001 for all). Elevated serum levels of both cytokines were associated with active LN, and anemia, and positively correlated with SLEDAI-2k scores (P = 0.025 for IL-17, and P < 0.001 for IL-6). There was a significant positive correlation between IL-6 and IL-17 serum concentrations during disease activity (r = 0.497, P = 0.005), as well as periods of remission of LN (r = 0.662, P < 0.001). |
| Zickert et al. (42) | 2015 | IL-17, IL-23, and other cytokines | 52 patients with active LN who underwent kidney biopsy at baseline and after immunosuppressive treatment and 13 HC. | Baseline levels of IL-6, IL-10, IL-17, IL-23 were increased in patients vs. controls (p < 0.001 for all), as was IFN-γ (p = 0.03). Patients with persisting active nephritis after treatment (WHO III, IV, V) presented higher IL-17 levels at baseline than those who progressed without active nephritis (WHO I-II) (p < 0.03). At follow-up, BILAG-non-responders had higher IL-23 than responders (p < 0.05). This indicates that a subset of LN-patients has a Th17 phenotype that may influence response to treatment. Immunostaining of renal tissue revealed IL-17 expression in inflammatory infiltrates. |
| Susianti et al. (55) | 2015 | Urinary IL-17 (uIL-17) | 50 participants with LN (38 with class III-IV, and 12 with class I-II) and 20 HC | The level of uIL-17 was significantly higher in the severe LN group than in the control group (P < 0.05); and increased with disease severity (mean ± SD: 43.96 ± 24.04, 55.69 ± 33.21, and 124.02 ± 256.74 pg/ml; for HC, class I-II, and class III-IV, respectively). |
| Yazici et al. (49) | 2014 | IL-17 and FOXP3 | Renal tissue samples of 39 LN patients, and normal renal tissue as control (from 20 patients with Wilms' tumor who underwent nephrectomy). | Both IFN-γ (+) and IL-17+ cells were statistically higher in LN tissues when compared with controls (p < 0.01). The cells in the tubulointerstitium were CD3 + CD4+, displaying a Th1 and Th17 phenotype. IL-17 immunostaining correlated with proteinuria, the requirement for pulse steroids, and SLEDAI renal score; and correlated negatively with GFR. Furthermore, glomerular and interstitial IL-17 and IFN-γ stainings were significantly associated with various parameters of histological activity (p < 0.05). |
| Kshirsagar et al. (60) | 2014 | Peripheral Th17 cells, IL-17, and STAT3. | 17 pediatric patients with LN, 5 patients with NS, and 24 age-matched HC | Compared to controls, LN children had a higher frequency of effector IL-17 producing cells in PBMCs, added to enhanced activity of Stat3 in these cells. The mRNA expression of IL-17 and retinoic acid-related orphan receptors was also higher in LN children than in controls.Additionally, Th17 cells from children with LN exhibit enhanced migratory capacity through high Akt activity. |
| Sigdel et al. (56) | 2016 | IL-A7, Th17 cells; and Th1 cytokines | 49 patients with newly diagnosed LN (12 with LN-III; 32 with LN-IV; and 5 LN-V) and 24 HC. | Serum levels of IL-17A were significantly elevated in class IV LN compared to LN-V (p = 0.003) or HC (p = 0.001). IL-6 was increased in LN-IV when compared to LN-III and HC. Th1 cytokines (IFN-γ, IL-18) were also considerably expressed in LN IV patients' serum compared to HC. Additionally, the Th17/Th2 cell cytokines IL-17A/IL-4 ratio was significantly higher in LN-IV when compared with LN-III (p = 0.04), LN-V (p = 0.01), and HC (p < 0.0001). |
| Peliçari et al. (61) | 2015 | IL-17 levels | 67 consecutive childhood-onset SLE patients, 55 first-degree relatives, and 47 age- and sex-matched healthy controls. | The serum IL-17 level was significantly higher in SLE patients than in HC [median (IQR): 36.3 (17.36–105.92) vs. 29.47 (15.16–62.17) pg/mL, p = 0.009]. There was an association between serum IL-17 levels and active nephritis (p = 0.01). Serum IL-17 levels were not associated with disease activity (p = 0.32), cumulative damage (p = 0.34), or medication use (p = 0.63). |
| Saber et al. (53) | 2017 | Peripheral Th17 cells and urinary IL-17 | 45 patients with SLE and 20 matching HC. | Th17 frequency and urinary level of IL-17 were significantly higher in patients than controls. Th17 cell frequencies and uIL-17 levels significantly correlated with renal biopsy classification for LN. Th17 cell frequencies significantly correlated with serum creatinine and SLEDAI; and inversely with C3 (p = 0.003), while uIL-17 significantly correlated with proteinuria and erythrocyte sedimentation rate. |
| AlFadhli et al. (62) | 2016 | Th17-related genes, IL-17A, and IL-17F | 66 SLE patients (14 with LN) and 30 matched HC | Patients with LN had significantly higher serum concentrations of IL-17A (P = 0.002) and IL-17F (P = 0.002) than those without LN.Compared to HC, patients with SLE presented a difference in the expression of 14 Th17- related genes, including IL-17A and IL-17F. |
| Jakiela et al. (63) | 2018 | Th17 and Treg | 33 LN patients and 19 HC. | The percentage of circulating Th17 among CD4+ cells was increased in LN compared to HC [median (IQR): = 1.2 (0.5–1.8) vs. 0.6% (0.32–0.95), P < 0.01]; without significant difference on Treg. Th17 expansion in the patient group was associated with a higher cumulative dose of cyclophosphamide but was not related to LN activity, renal histology, or blood and urine inflammatory biomarkers. |
| Wang et al. (50) | 2018 | Th17 cytokines (IL-17A and IL-21) | 28 LN patients on induction therapy were assessed for serological data at weeks 0, 12, and 24. | There was a progressive decrease in serum concentrations of IL-17A and IL-21 (P < 0.01, P = 0.001, respectively) during induction therapy. The concentration of these cytokines remained higher in the non-remission than in the remission group. Additionally, the concentration of these cytokines at the baseline kept a positive correlation with the severity of proteinuria, ESR, SLEDAI scores, and ANA titers. |
| Edelbauer et al. (64) | 2012 | Th17, IL-17, and IL-23 | 23 patients with definite LN, 12 patients with frequently relapsing NS, and 20 age-matched HC. | There was a significant expansion of Th17 and Th1/Th17 cells in children with LN greater than in HC. Serum IL-17 and IL-23 levels correlated positively with the renal SLEDAI (r = 0.5516, p = 0.0029, and r = 0.6116, p = 0.0007, respectively). |
| Cheng et al. (48) | 2019 | IL-17 | 45 LN patients and 50 HC. | The IL-17 serum levels were significantly higher in LN patients than in the control group (P < 0.001). Serum IL-17 in LN patients was positively correlated with urinary protein (r= 0.436, P < 0.05). IL-17 was an independent risk factor for poor prognosis of LN (P < 0.05) |
| Dedong et al. (45) | 2019 | IL-17 and IL-23 | 80 patients with LN (37 of them accepted immunosuppressive therapy and followed up for 6 months) and 20 HC who underwent blood samples to analyze the roles of IL-17 and IL-23 in monitoring activity and predicting response to treatment in LN. | Baseline IL-17 and IL-23 were higher in patients with active LN than in those with inactive LN or controls (P < 0.001). IL-17 kept an inverse correlation with C3 (r = −0.44, P < 0.001). IL-17 and IL-23 decreased significantly in active LN patients after 6 months of therapy (P < 0.001). The baseline level of IL-23 was a predictor of response to the immunosuppressive treatment in patients with active LN, being lower in the complete response than in the partial response group (P = 0.0015) or non-response group (P = 0.013). IL-17 and IL-23 correlated with SLEDAI (P < 0.001). |
| Nakhjavani et al. (54) | 2019 | Serum IL-17 and TWEAK | 50 lupus patients (25 with LN and 25 without) and 39 HC, who underwent blood samples to evaluate serum IL-17 and TWEAK as biomarkers to detect renal damage. | Increased levels of IL-17 and sTWEAK were observed in SLE patients compared to HC, and in LN compared to non-LN groups. There was a significant positive association between serum IL-17 and TWEAK levels and SLEDAI, proteinuria, nephritis activity index, and other clinical manifestations (P < 0.05). |
| Elkoumi et al. (65) | 2012 | IL-17A gene polymorphisms for three SNPs (rs2275913, rs8193036, and rs3748067). | 320 Egyptian children and adolescents, diagnosed with JSLE (217 with and 103 without LN) and 320 matched HC. | The SNPs of IL-17 rs2275913 were significantly more frequent among JSLE patients than HC (21 vs. 7%, OR: 3.8; and 37 vs. 29%, OR: 1.4, for A/A genotype and A allele, respectively; p < 0.003 for both). No significant difference was found for other SNPs. Patients carrying the IL-17 SNPs rs2275913 were more likely to develop LN (OR: 5.64 and OR = 2.73, for A/A genotype and A allele, respectively). |
| Rastin et al. (66) | 2016 | IL-17, IL-6, IFN-γ, and Foxp3 genes. | 20 patients with LN class IV, 20 sex- and age-matched SLE patients without LN as control who underwent blood samples. | The levels of IL-6, IL-17, IFN-γ, were significantly increased in patients with LN class IV than in those SLE patients without LN. The expression of Foxp3 genes was also significantly increased among class IV LN compared to those without; however, no significant difference was found in TGF-β expression between groups, suggesting the insufficient capacity of Treg to control the pathogenic role of IL-17-producing cells. |
BILAG, British Isles Lupus Assessment Group; ESR, erythrocyte sedimentation rate; HC, healthy controls; IHC, Immunohistochemistry; IQR, interquartile range; JSLE, juvenile systemic lupus erythematosus; LN, lupus nephritis; MCD, minimal change disease; NS, nephrotic syndrome; OR, odds ratio; PBMC, peripheral blood mononuclear cells; SLE, Systemic lupus erythematosus; SLEDAI, Systemic lupus erythematosus disease activity index; SNPs, single-nucleotide polymorphisms; STAT3, Signal transducer and activator of transcription 3; TWEAK, Tumor necrosis factor-like weak inducer of apoptosis; uIL-17, levels of urine interleukin-17; WHO, world health organization.