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Patients with congenital ichthyosis show differential activation of IL-23/Th17 pathway among various disease subtypes - A single-centre experience
Corresponding author: Dr. Rahul Mahajan, Department of Dermatology, Venereology and Leprology, Postraduate Institute of Medical Education and Research, Chandigarh, India. drrahulpgi@yahoo.com
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Received: ,
Accepted: ,
How to cite this article: Kumar A, Mahajan R, Srivastava N, Bakshi S, Kaushal L, Karim A, et al. Patients with congenital ichthyosis show differential activation of IL-23/Th17 pathway among various disease subtypes - A single-centre experience. Indian J Dermatol Venereol Leprol. 2026;92:319-27. doi: 10.25259/IJDVL_1749_2024
Abstract
Background
Congenital ichthyosis is a rare genetic skin condition characterised by aberrant keratinisation. This study focused on assessing the differential expression of Th17-related cytokines in different subtypes of ichthyosis and its correlation with clinical features.
Aim
We aimed to compare the gene expression of Th17-related genes and serum levels of IL-17 and IL-23 cytokines of ichthyosis subgroups in the Indian population.
Methods
We analysed blood and skin specimens from consecutively diagnosed patients with congenital ichthyosis along with age/sex-matched healthy controls using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), as well as immunohistochemistry (IHC) for Th17/IL-23 pathway genes. Additionally, IFN-γ (Th1), IL-4 (Th2), and IL-17A (Th17)-dominant cell populations were measured using flow cytometry. Clinical severity was assessed using measures including the overall ichthyosis score (ICH score), which integrates erythema (E), scaling (S), and body surface area (BSA) scores.
Results
This study analysed interleukins in 48 congenital ichthyosis patients and 34 controls. We observed a significant upregulation of IL-17A and IL-23 in all patients, particularly autosomal recessive congenital ichthyosis (ARCI), X-linked recessive ichthyosis (XLRI), and Netherton syndrome (NS) subtypes. Similarly, serum levels of IL-17A were significantly augmented in all ichthyosis subtypes, with ARCI showing the highest increase. Whereas, an increase in IL-23 was only detected in ARCI. NS patients had significantly increased IL-22 levels.
Limitations
Our study included small sample size and lack of mRNA and cytokines expression in skin biopsy samples.
Conclusion
The study highlighted significant immunological alterations in interleukins associated with the Th17 pathway in different subtypes of congenital ichthyosis.
Keywords
Congenital ichthyosis
IL-23/Th17 pathway
immunology
Netherton syndrome
Introduction
Ichthyosis or Mendelian disorders of cornification are a heterogeneous group of genetic skin disorders that result in a defective epidermal barrier, leading to scaling and erythema.1 Recent studies by Paller et al.2 and Malik et al.3 have shown an IL-17-dominant profile in ichthyosis patients. Paller et al.2 described synergistic activation of Th17 pathway-related genes by IL-17A and TNF-α, along with an increase in general inflammatory markers in the ichthyosis patients as compared to the healthy individuals. Furthermore, they discovered a strong positive correlation between inflammatory markers and trans-epidermal water loss in their investigation.2,3 Czarnowicki et al.4 further advanced the understanding of disease pathology and revealed a systemic immune dysregulation. The study also revealed the status of immune profile of different forms of ichthyosis, specifically Netherton syndrome (NS) and congenital ichthyosiform erythroderma (CIE). The level of IL-17 and IL-22 cytokines were revealed to be the highest in NS and CIE patients, suggestive of inflammation and barrier impairment.4
Patients with ichthyosis experience a reduced quality of life, recurrent infections, and pose an economic burden on healthcare.5 Therefore, understanding the underlying disease mechanisms is critical for developing targeted and effective therapies and improving patients’ quality of life. We aimed to compare the gene expression of Th17-related genes and serum levels of IL-17 and IL-23 cytokines of the ichthyosis subgroups in the Indian population.
Methods
Patient characteristics and samples
This prospective study was conducted at a paediatric dermatology clinic and general outpatient clinic of a tertiary care institute after approval by the institutional ethics committee (No.PGI/IEC/000176 dated on 06-02-2019). Regardless of age and sex, 48 patients with a diagnosis of non-syndromic congenital ichthyosis and NS were included in the study. Patients suspected with ichthyosis vulgaris and those with syndromic ichthyosis other than NS were excluded from this study. All patients enrolled in the study were classified according to the standardised nomenclature and classification criteria for inherited ichthyoses, based on the results of genetic screening.6,7 Simultaneously, age-and-sex-matched 34 healthy controls were also recruited. After obtaining written informed consent/assent, a complete physical examination, including estimation of the ichthyosis score (ICH score), was performed and documented in the predesigned proforma. Skin biopsy was done for the analysis of IL-17A expression by immunohistochemistry (IHC). The expression of IL-17A in skin specimens was quantified using the Fiji distribution of the ImageJ software.8 Peripheral blood samples (3 mL per patient) were obtained to establish baseline measurements. Total RNA was isolated from peripheral blood mononuclear cells (PBMCs) obtained from whole blood samples. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to assess the mRNA expression levels of IL-17A, IL-23, IL-22, and IL-21 cytokines. Corresponding protein levels of these cytokines were also quantified in the serum of both patients and healthy controls. Additionally, T-cell subsets secreting IFN-γ (Th1), IL-4 (Th2), and IL-17A (Th17) were analysed in whole blood following stimulation with phorbol 12-myristate 13-acetate (PMA), brefeldin A, and ionomycin using flow cytometry (using FACS CANTO II/Aria, BD Biosciences, USA).9 FACS Canto II and FACS Aria are advanced flow cytometers used for multiparametric analysis of fluorescently labelled cells. While Canto II is mainly for cell analysis, Aria also enables high-speed cell sorting, allowing isolation of specific cell populations for research. Flow graphs were plotted using BD FACS Diva (BD FACSDivaTM Software [Detailed methodology is provided in supplementary file].
Statistical analysis
The data was analysed using GraphPad Prism version 9.0.0 for Windows (GraphPad Software, Boston, Massachusetts, USA). The Kolmogorov-Smirnov test was used to determine the normality of the quantitative data. Depending on the normality of the data, the descriptive data were displayed as mean ± standard deviation (SD) or median interquartile range. qRT-PCR data were analysed using an unpaired t-test to compare the control and ichthyosis patient groups.
IHC was performed to assess IL-17A expression in skin specimens from patients and controls. Fluorescence intensity of the IL-17A protein was graded using a semi-quantitative scoring system. Fluorescence intensity was scored on a 0-3 scale where 0 = no detectable signal, 1 = weak signal slightly above background, 2 = moderate, distinct signal, and 3 = strong, bright fluorescence indicating high protein expression. The mean fluorescence intensities of the IL-17A protein in skin specimens from patients and controls were evaluated using an unpaired t-test. The unpaired t-test was used to compare the Th cell populations in control and patients’ blood samples. Pearson correlation was used to correlate the gene expression levels of Th17 pathway-related genes with the clinical characteristics, using a linear regression model. The P value ≤ 0.05 is represented as*, P ≤ 0.01 as **, P ≤ 0.001 as ***, P ≤ 0.0001 as **** and P > 0.05 as non-significant (ns).
Results
The study included 48 patients with congenital ichthyosis and 34 controls. Among these, 35 patients had autosomal recessive congenital ichthyosis (ARCI), six had NS, three had X-linked recessive ichthyosis (XLRI), two had keratinopathic ichthyosis (KI), including superficial epidermolytic and epidermolytic ichthyosis, and two had other diagnoses (progressive symmetric erythrokeratoderma). The mean age of the patients was 9.71 ± 8.936 years, with an equal male: female ratio. Table 1 summarises the baseline characteristics of the study population.
Analysis of RNA expression of IL-23/Th17 related genes in peripheral blood
The relative mRNA expression levels of various interleukins (IL-17A, IL-21, IL-22, and IL-23) associated with the Th17 pathway in blood samples from individuals with congenital ichthyosis were measured to monitor their differential expression among various disease subgroups or subtypes. We used quantitative PCR to measure the relative mRNA expression levels of various cytokines in each group, and the results were normalised to a reference gene (β-actin) and presented as the fold change relative to the control group, shown in Figures 1a-h.
| Characteristics | Parameter | Controls (n=34) | Patients with ARCI (n = 35) |
Patients with NS (n = 6) |
Patients with XLRI (n =3) | Patients with KI (n = 2) | Patients with others (n = 2) | P value |
|---|---|---|---|---|---|---|---|---|
| Age (y) | Mean ± SD | 17 ± 9.88 | 8.96 ± 9.92 | 6.36 ± 6.13 | 22.67 ± 13.87 | 3.55 ± 4.88 | 7.01 ± 9.88 | 0.1450 |
| Median (age range) | 16 | 4.00 | 9.50 | 4.00 | 3.55 | 7.01 | NA | |
| Gender ratio | Male:Female | 19:15 | 15:20 | 3:3 | 3:0 | 1:1 | 1:1 | 0.7388 |
| Race | South Asian | South Asian | South Asian | South Asian | South Asian | South Asian | South Asian | NA |
| Disease severity scores | Erythema score ± SD | - | 2.29 ± 0.80 | 2.33 ± 0.52 | 1.00 ±0.00 | 1.50 ± 0.71 | 0.50 ± 1.41 | 0.0012 |
| Scaling score ± SD | - | 2.43 ± 0.61 | 2.83 ± 0.41 | 2.00 ± 1.00 | 2.50 ± 2.12 | 3.00 ± 1.41 | 0.3752 | |
| BSA score ± SD | 5.43 ± 0.61 | 5.67 ± 0.52 | 5.00 ± 0.00 | 4.00 ± 0.00 | 3.00 ± 2.83 | <0.0001 | ||
| Induration score ± SD | - | 2.03 ± 0.68 | 1.83 ± 0.41 | 1.33 ± 0.57 | 2.00 ± 0.00 | 1.00 ± 1.41 | <0.001 | |
| ICH score ± SD | - | 25.63 ± 6.14 | 31.33 ± 2.89 | 23.33 ± 5.43 | 12.00 ± 5.43 | 12.00 ± 11.31 | =0.0004 |
Demographic and clinical severity profiles across various ichthyosis subtypes. ARCI: Autosomal recessive congenital ichthyosis, XLRI: X-linked recessive ichthyosis, NS: Netherton syndrome and KI: Keratinopathic ichthyosis, SD: Standard deviation, NA: Not applicable. P-values were calculated using the Kruskal–Wallis test for continuous variables and Fisher’s exact test for categorical variables due to small subgroup sizes, ICH: Ichthyosis score.
Induced levels of inflammatory markers signifying peripheral inflammation in the patients
The relative fold change of IL-17A (fold change = 3.45, p<0.05) cytokines was significantly upregulated in all patients with ichthyosis compared to the control group. However, after closer analysis of subgroups, it was found that individuals with ARCI (fold change = 3.79, p <0.05), XLRI (fold change = 2.20, p<0.01), NS (fold change = 4.09, p<0.01), and other skin conditions (fold change = 2.10, p<0.05) exhibited a significant increase in IL-17A expression levels. Conversely, no significant differences in IL-17A mRNA expression levels were observed in individuals with KI when compared to the control group.
All patients with ichthyosis showed a significant increase in the relative fold change of IL-23 cytokines when compared to the control group. In subgroup analysis, ARCI (fold change = 3.23), XLRI (fold change = 2.13), and NS (fold change = 6.49) groups revealed a significant increase with p < 0.01, while KI and other groups showed a non-significant decrease.
There was a non-significant increase in the relative fold change of the IL-22 cytokine in ichthyosis patients as compared to controls. In the subgroup analysis, expression was raised in a non-significant manner.
In contrast, the relative expression of the IL-21 cytokine was non significantly altered in all the ichthyosis patients, as well as in subgroups of ichthyosis. These data from several ichthyosis subgroups demonstrated varied expression of Th17-related cytokines at the transcriptional level and potentially contribute variably across all subgroups.
Sera level expression of cytokines associated with Th-17 immune cells
Since we observed augmented levels of Th17/Th23-related cytokines at the mRNA level [Figures 1a–h], we further analysed the serum concentrations of cytokines associated with Th-17 type immune cells (IL-17A, IL-21, IL-22, and IL-23) [Figures 1i–n]. These were then compared in different subtypes of ichthyosis patients and healthy individuals.
The serum concentration of IL-17A cytokines was assessed in all subtypes of ichthyosis patients and compared to healthy individuals [Figures 1i and 1l]. As shown in Figure 1l, 16 out of 35 ARCI patients revealed significantly higher expression in the mean serum level of IL-17A (23.77 ± 15.89, p < 0.04) cytokine among other subtypes of ichthyosis as compared to 22 healthy individuals. Patients with other subtypes of ichthyosis revealed a non-significant increase in the IL-17A cytokine expression in comparison to a group of healthy individuals.
The serum concentration of IL-17A cytokines was significantly increased in all subtypes of ichthyosis patients as compared to healthy individuals [Figure 1i]. As shown in Figure 1i, 16 out of 35 ARCI patients revealed significantly higher expression in the mean serum level of IL-17A (23.77 ± 15.89, p < 0.04) cytokine among other subtypes of ichthyosis as compared to 22 healthy individuals. Patients with other subtypes of ichthyosis revealed a non-significant increase in the IL-17A cytokine expression in comparison to a group of healthy individuals.
The serum level of IL-23 cytokines was only detected in four ARCI patients, showing a non-significant increase relative to healthy individuals, whereas in other subtypes, the expression of the same cytokine was undetected (data not given).
All ichthyosis patients in this study showed a non-significant increase in serum IL-22 and IL-21 levels [Figures 1j–k]. Among the subtypes, only the XLRI group demonstrated a statistically significant elevation in IL-22 expression (91 ± 122.26, p < 0.005) compared to healthy controls, while other subtypes showed a non-significant decrease [Figure 1m]. The serum level expression of IL-21 in ARCI (123.64 ± 156.07), NS (155.84 ± 41.97) was non-significantly altered as compared to healthy individuals, while XLRI (20.35 ± 4.51) patients revealed a reduced expression [Figure 1n].
The enhanced expression of IL-17A and IL-23 cytokines in ARCI patients is suggestive of involvement of the IL-23/IL-17 axis-dependent inflammation during disease progression.
Measurements of intracellular cytokine-producing T-helper cells
The percentage of IL-17A (Th17), IL-4 (Th2), and IFN-γ (Th1) producing cells was measured in the whole blood sample of patients and healthy individuals using flow cytometry [Figure 2a-b]. The mean fluorescence intensity (MFI) of IL-17A-producing Th-17 cells (CD4+ - IL17A+) slightly increased in the ichthyosis patients (0.62%) as compared to healthy individuals (0.3%). In the subgroup analysis, the NS group (0.83%, non-significant) revealed the highest increase in the MFI percentage of IL-17A producing cells, followed by ARCI (0.621%, p < 0.05), XLRI (0.45%, non-significant), and another related ichthyosis (0.39%). The MFI percentage of IL-4 producing cells was significantly increased in all the ichthyosis groups: ARCI (1.74%, p < 0.01), XLRI (1.93%, p <0.01), and NS (1.88%, non-significant) patients as compared to healthy individuals (1.15%). The MFI percentage of IFNγ-cytokine-producing cells was non-significantly downregulated in all subgroups (ARCI: 14.17%, XLRI: 11.6%, NS: 5.17%, others: 12.86%) compared to healthy individuals (20.43%). This result revealed variable patterns of immune cell activation among different subgroups of ichthyosis. The measurements of immune cells in ARCI patients have revealed the progression of Th2 cell activation, lowering the population of Th17 cells.
Enhanced cutaneous expression of IL-17A marks the severity of ichthyosis disease in patients
To assess IL-17A expression in skin tissue, biopsy sections from both patients and healthy controls were stained using a human IL-17A primary antibody (catalogue # sc-7927), and MFI was measured. IL-17A was found to be localised in the dermis region of the skin [Figure 3a]. We noticed a significantly increased IL17A expression in the skin sections of ichthyosis patients as compared to healthy controls (270.2 ± 15.75, p< 0.0001) [Figure 3b].
IL-17A correlates with erythema and overall ichthyosis score (ICH score)
Pearson’s correlation analysis was performed to evaluate the relationship between ichthyosis clinical parameters and the mRNA expression of Th17-associated cytokines (IL-17A and IL-23). Scaling score was shown to be non-significantly associated with IL-17A mRNA expression [Figure 4a]. A statistically significant positive correlation was observed between erythema and IL-17A mRNA levels (r = 0.392, p < 0.02) [Figure 4b]. Non-significant positive associations were detected between IL-17A mRNA expression and both BSA and induration scores [Figure 4c and 4d]. The overall ICH severity score also exhibited a positive correlation with IL-17A mRNA expression (r = 0.4911, p < 0.01) [Figure 4e]. In contrast to IL-17A, the scaling score showed a non-significant negative correlation with IL-23 expression [Figure 4f]. Similar to IL-17A, erythema displayed a statistically significant positive correlation with IL-23 mRNA levels (r = 0.336, p < 0.03) [Figure 4g]. Positive but non-significant associations with IL-23 were observed for BSA, induration, and the overall ichthyosis score [Figures 4h, 4i and 4j].
Discussion
Ichthyosis is a group of genetic skin disorders characterised by dry, scaly skin. It affects millions of individuals worldwide.6 Recent research has linked the disease to robust cytokine activation, affecting disease severity and skin barrier function. This study focuses on understanding the immunological aspect of non-syndromic congenital forms of ichthyosis. Non-syndromic congenital ichthyosis refers to a diverse set of genetic skin disorders characterised by the presence of scaling and erythroderma at birth.8,9
Besides the genetic mutations regulating epidermal differentiation and skin barrier function, the patient’s immune response is severely dysregulated. Recent advancements in understanding the inflammation in ichthyosis patients revealed increased expression of various cytokines and discovered a significant positive correlation between IL-17A and Ichthyosis Area and Severity Index (IASI)-erythema and transepidermal water loss (TEWL).6,9-11 In our study, we have explored the immune response in the largest cohort of ichthyosis patients from the Indian population. The present study examines the transcription and translation levels of IL-17A, IL-21, IL-22, and IL-23 cytokines in the peripheral blood of ichthyosis patients and healthy individuals. Moreover, our study also compared the percentage of IL-17A, IL-4, and IFN-γ-producing CD4+ T helper cells.
Among the six structurally related IL-17 isoforms (IL-17A, IL-17B, IL-17C, IL-17D, and IL-17E), IL-17A is predominantly secreted by T-lymphocytes. Additionally, it is produced in smaller amounts by natural killer cells, neutrophils, and mast cells.10 IL-17A cytokine is considered to be a pro-inflammatory cytokine in psoriasis.11,12 Similar to the psoriasis patients, ichthyosis patients tend to demonstrate an increase in an IL-17A dominant skewness. In line with previous studies, our study also highlighted elevated mRNA expression of IL-17A cytokine in all the ichthyosis patients compared with healthy individuals.2-4 In subgroup analysis, expression of IL-17A mRNA and serum IL-17A were significantly elevated in ARCI and NS groups.
Consistent with the earlier studies, the gene expression level of IL23 was upregulated in all the ichthyosis patients as compared to healthy individuals.2,3 In our study, the mRNA level of IL-23 was significantly upregulated in the ARCI and NS patients as compared to other groups of ichthyosis and healthy individuals. The serum level expression of IL-23 cytokines was limited to a few ARCI and NS patients, and quantification of an increase or decrease was beyond analysis due to the limited detection range of the ELISA kit. There was a non-significant increase in mRNA expression of IL-22 cytokine in all the ichthyosis groups except the KI group. The serum level expression of IL-22 cytokine increased only in the XLRI group. Other ichthyosis groups revealed a non-significant reduction in serum level expression of the IL-22 cytokine. The reduced or low expression of IL-22 cytokine in all the groups except XLRI was similar to the earlier study. However, since there is a variable presence of skin-infiltrating immune cell subsets related to IL-22-producing cytokines among paediatric and adult patients, the low expression of IL-22 cytokine in our study is possible. Although transcriptomic and flow cytometry-based studies have shown increased IL-22 expression at the mRNA and cellular levels, its release into the serum has not been studied in detail.4 Cordoro et al.13 revealed low expression of IL-22 cytokines in adult psoriasis patients. Although IL-17 and IL-22 cytokines are co-secreted, their expression and regulation are distinct.14 The combination of cytokines such as IL-6, IL-1β and TGF-β1 stimulate the development of Th17 cell development. Previous studies have shown that stimulation of naïve human T-cells with IL-1β and IL-23 can enhance IL-22 production.15 The expression of IL-22 in human T cells in the context of TGF-β1 is controversial.
Elevated serum levels of the cytokine interleukin-21 (IL-21) have been reported in chronic inflammatory conditions such as AD, where its expression positively correlates with clinical features, including oedema and erythema.16 However, in the present study, as well as in previous reports, IL-21 expression did not exhibit significant alterations. Although current evidence does not directly implicate IL-21 in the pathogenesis of ichthyosis, its role in the regulation of Th17 cells has been shown in other inflammatory diseases.17,18 IL-21, together with IL-6, is crucial for the differentiation process of Th17 cells.3,18 Aberrant IL-21 expression has been linked to changes in inflammatory responses in several chronic inflammatory disorders. The IL-21/IL-21 receptor (IL-21R) signalling axis is capable of establishing a positive feedback loop that enhances tissue inflammation via activation of the STAT3 pathway and sustained cytokine production.
The differentiation of naïve T-cells into intermediate Th17 cells occurs rapidly in the presence of Th17 polarising cytokines. The differentiation of these intermediate Th17 cells does not require TGF-β1 with Th17 cell polarising cytokines. These intermediate cells express the IL-26 cytokine and do not produce IL-17A. In subsequent steps, the IL-26 cytokine induces keratinocyte activation. Activated keratinocytes produce TGF-β1 and help in the maturation of such intermediate Th17 cells into single IL-17A-producing cells in skin tissue. There are contradictory studies related to IL-22 secretion by naïve T-cells upon TGF-β1 stimulation. The expression of IL-17A and IL-22 cytokines was found to be enhanced in the committed Th-17 cells after IL-23 stimulation.19
In concordance with the earlier studies, our study also highlights the increased expression of IL-17A, IL-22, IL-21, and IL-23 cytokines in all the ichthyosis patients. The current study highlights the new advances in understanding the expression of Th-17 cells related cytokines in the context of different ichthyosis forms. Heightened activity of the IL17/IL23 axis was observed in ichthyosis patients with differential expression of related cytokines in different forms of ichthyosis. The observations of enhanced expression of IL-17A, IL-23 cytokines (gene as well as protein level) and positive correlation with erythema and ICH score in ARCI patients are indicative of the Th17-mediated immune responses. The elevated IL-17 levels identified in patients with ARCI and NS provide a rationale for the therapeutic application of anti-IL-17A treatment. Th17-related cytokines were increased non-significantly in XLRI patients, except IL-22. This increase in the IL-22 cytokine might indicate a different source of IL-22 production than Th-17 cells.
In conclusion, our data points to the involvement of Th17-related cytokines in disease progression, specifically in ARCI and NS patients in a racially distinct Indian population.
Limitations
This study had several limitations, including a relatively small sample size for certain ichthyosis subtypes in contrast to the ARCI group. Additionally, the research did not include the analysis of interleukin mRNA and protein expression in affected skin regions, which presents an opportunity for future investigations.
Conclusion
This study highlights the pivotal role of Th17-related cytokines, particularly IL-17A and IL-23, in the pathogenesis of congenital ichthyosis. Elevated transcriptional and serum levels of these cytokines in specific subgroups, notably ARCI and NS, suggest an IL-23/IL-17 axis-driven inflammation. Correlations between IL-17A expression and clinical parameters, such as erythema and disease severity, underscore its potential as a biomarker for disease activity. Despite significant findings, variability in cytokine expression among subgroups suggests distinct immunopathological mechanisms in the Indian patients affected with congenital ichthyosis. These insights provide a foundation for targeted therapies aimed at modulating Th17-related pathways, offering a promising direction for managing inflammation in congenital ichthyosis.
Ethical approval
The research/study was approved by the Institutional Review Board at PGIMER Chandigarh, number PGI/IEC/2019/000176, dated 06-02-2019.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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