Assessment of interleukin-18 gene polymorphism and serum levels in cutaneous lichen planus.

BACKGROUND: Lichen planus (LP) is a chronic inflammatory disease with uncertain etiology. Interleukin-18 (IL-18) is an interferon gamma (INFγ) inducing agent. It is a pro-inflammatory cytokine that was found to play a role in the pathogenesis of some autoimmune disorders. MATERIAL AND METHODS: This study included 50 patients with classic cutaneous lichen planus (CLP) and 50 healthy volunteers serving as controls. Venous blood samples were withdrawn from the study subjects under complete aseptic precautions. Blood samples were examined for single nucleotide polymorphisms (SNPs) of IL-18 gene at promoter -137(G/C) and -656 (G/T) using polymerase chain reaction (PCR) and IL-18 level was assessed using enzyme linked immunosorbent assay (ELISA). RESULTS: The mean level of IL-18 was significantly higher in CLP patients (31.63 ± 4.90) compared to control subjects (13.95 ± 6.82). Significantly high levels of IL-18 were found among patients with diabetes, hypertension (p < 0.01 in both). HCV positive patients and patients with both OLP and CLP also expressed higher levels of IL-18. Genotypic and allelic distribution at position -137(G/C) showed that the genotype GG was present at significantly higher frequency in cases (58%) compared to controls (28.0%). On the other hand the CC genotype at position -137 was significantly higher in the controls (28%) as compared to CLP cases (6%). Polymorphism of IL-18 at position -656(G/T) showed no significant difference between cases and controls. No significant difference could be detected in IL-18 level between different genotypic variants at position -137(G/C) and -656(G/T). CONCLUSION: IL-18 may play important role in pathogenesis of LP. Elevated IL-18 levels could be part of the pro-inflammatory autoimmune process in LP. The presence of OLP, HCV, diabetes and hypertension is associated with higher production of IL-18. IL-18 promotor region -137(G/C) polymorphism might be a factor that increase the risk of development of lichen planus in Egyptian patients.

Gene-Environment Interaction Between CYP1B1 and Oral Contraception on Frontal Fibrosing Alopecia.

Importance: Frontal fibrosing alopecia (FFA) is an increasingly prevalent form of follicular lichen planus, causing irreversible hair loss predominantly in postmenopausal individuals. An earlier genome-wide meta-analysis of female FFA identified risk loci in genes implicated in self-antigen presentation and T-cell homeostasis, including HLA-B*07:02, ST3GAL1, and SEMA4B. However, CYP1B1, which is important for hormone metabolism, was also implicated with the substitution of serine for asparagine at position 453 (c.1358A>G, p.Asn453Ser) exhibiting a protective effect against FFA. Increasing understanding of genetic and environmental variables and their interactions will improve understanding of disease pathogenesis and has the potential to inform risk mitigation strategies. Objective: To investigate whether oral contraceptive pill (OCP) use modulates the protective effect of the common missense variant in CYP1B1 (c.1358A>G, p.Asn453Ser) on FFA risk. Design, Setting, and Participants: This gene-environment interaction study using a case-control design enrolled female patients with FFA from UK-based dermatology clinics. The patients were matched with unrelated age- and ancestry-matched female control individuals derived from UK Biobank in a 1:66 ratio, determined by the first 4 principal components from genome-wide genotypes. Data were collected from July 2015 to September 2017, and analyzed from October 2022 to December 2023. Main Outcome and Measure: The main outcomes were the modulatory effect of OCP use on the contribution of the CYP1B1 missense variant to female FFA risk and a formal gene-environment interaction test evaluated by a logistic regression model with a multiplicative interaction term, under the assumptions of an additive genetic model interaction term, under the assumptions of an additive genetic model. Results: Of the 489 female patients with FFA, the mean (SD) age was 65.8 (9.7) years, and 370 (75.7%) had a history of OCP use. Of the 34 254 age- and ancestry-matched control individuals, the mean (SD) age was 65.0 (8.4) years, and previous OCP use was reported in 31 177 (91.0%). An association between female FFA and the CYP1B1 risk allele was observed in individuals who reported OCP use (odds ratio, 1.90 [95% CI, 1.50-2.40]; P = 8.41 × 10-8) but not in those with no documented exposure to OCPs (odds ratio, 1.16 [95% CI, 0.82-1.64]; P = .39). A full gene-environment interaction model demonstrated a significant additive statistical interaction between c.1358A, p.453Asn, and history of OCP use on FFA risk (OR for interaction, 1.63 [95% CI, 1.07-2.46]; P = .02). Conclusions and Relevance: This gene-environment interaction analysis suggests that the protective effect of the CYP1B1 missense variant on FFA risk might be mediated by exposure to OCPs. The allele that encodes an asparagine at position 453 of CYP1B1 was associated with increased odds of FFA only in participants with OCP history.

Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer.

Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.

Comorbidities in lichen planus by phenome-wide association study in two biobank population cohorts.

BACKGROUND: Lichen planus (LP) is a relatively frequent mucocutaneous inflammatory disease affecting the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx. OBJECTIVES: To estimate the association of LP, with emphasis on dermatological and gastrointestinal conditions, in two large independent population cohorts. MATERIALS AND METHODS: We performed a phenome-wide association study (PheWAS) and examined conditions associated with LP in two unrelated cohorts, i.e. the multicentre, community-based UK Biobank (UKB: 501 381 controls; 1130 LP subjects) and the healthcare-associated Penn Medicine BioBank (PMBB; 42 702 controls; 764 LP subjects). The data were analysed in 2021. The 'PheWAS' R package was used to perform the PheWAS analyses and Bonferroni correction was used to adjust for multiple testing. Odds ratios (ORs) were adjusted for age, sex and body mass index. RESULTS: In the UKB, PheWAS revealed 133 phenome codes (PheCodes) significantly associated with LP and most of them were confirmed in PMBB. Dermatological and digestive PheCodes were the most abundant: 29 and 34 of these disorders, respectively, were significantly overrepresented in LP individuals from both cohorts. The 29 dermatological and 12 oral disorders were often highly enriched, whereas hepatic, gastric, oesophageal and intestinal PheCodes displayed ORs in the range of 1·6-4·5. Several autoimmune disorders also exhibited OR > 5 in both cohorts. CONCLUSIONS: PheWAS in two large unrelated cohorts identified previously unknown comorbidities and may support clinical counselling of patients with LP. What is already known about this topic? Lichen planus (LP) is known to affect the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx. What does this study add? Our data provide the most comprehensive collection of associated dermatological, digestive and autoimmune disorders to date. Our findings are expected to be useful for the evaluation and management of patients with LP.

The Immunogenetics of Lichen Planus.

Lichen planus (LP) is a multifaceted autoimmune disease affecting the skin, nails, hair, and mucous membranes, with several clinical subgroups. Cell-mediated immunity plays a key role in its progression. This chapter reviews the known genetic associations of lichen planus including HLA as well as non-HLA genes.

RNA sequencing of chronic GVHD skin lesions defines shared and unique inflammatory pathways characterizing lichen planus and morphea.

Cutaneous involvement of chronic graft-versus-host disease (cGVHD) has a wide range of manifestations including a lichenoid form with a currently assumed mixed Th1/Th17 signature and a sclerotic form with Th1 signature. Despite substantial heterogeneity of innate and adaptive immune cells recruited to the skin and of the different clinical manifestations, treatment depends mainly on the severity of the skin involvement and relies on systemic, high-dose glucocorticoids alone or in combination with a calcineurin inhibitor. We performed the first study using RNA sequencing to profile and compare the transcriptome of lichen planus cGVHD (n = 8), morphea cGVHD (n = 5), and healthy controls (n = 6). Our findings revealed shared and unique inflammatory pathways to each cGVHD subtype that are both pathogenic and targetable. In particular, the deregulation of IFN signaling pathway was strongly associated with cutaneous cGVHD, whereas the triggering receptor expressed on myeloid cells 1 pathway was found to be specific of lichen planus and likely contributes to its pathogenesis. The results were confirmed at a protein level by performing immunohistochemistry staining and at a transcriptomic level using real-time quantitative polymerase chain reaction.

Evaluation of correlation between transcription factors and IL-17 in oral and cutaneous lichen planus lesions and Leukocytes.

BACKGROUND: Lichen planus (LP) is a chronic autoimmune disease with different clinical subtypes including cutaneous LP (CLP) and oral LP (OLP). We aimed to compare mRNA expression of RORγt and IL-17 in paraffin-embedded blocks of OLP and CLP lesions with normal oral mucosa (NOM), and also its correlation with hematologic parameters. MATERIALS & METHODS: This study included 89 paraffin-embedded blocks contain OLP (44 cases), CLP (45 cases) and NOM from the archive of Mashhad University of Medical Sciences, Mashhad, Iran. The expression of RORγt and IL-17 was evaluated by Real-time RT-PCR method. The result was compared to Leukocyte counts and the other hematological parameters of studied patients. RESULTS: The results of our study showed IL-17 and RORγt expression in OLP lesions were significantly higher than CLP and NOM groups (P = 0.001). Although we found high expression of RORγt and IL-17 in erosive OLP in compared to classic OLP lesion, but this increment was not significant for IL-17 (P = 0.26) and RORγt (P = 0.14). Further, Leukocyte and monocyte counts were substantially high in OLP group in compared to the CLP and NOM groups (P < 0.05). CONCLUSIONS: We concluded that increased expression of RORγt and IL-17 in LP lesions could play role in the pathogenesis of LP. As well, higher expression of RORγt and IL-17 in oral LP more than cutaneous LP might be associated with difference in clinical behavior of the two types of disease and role of these factors in premalignant behavior of OLP lesions.

The inflammation in cutaneous lichen planus is dominated by IFN-ϒ and IL-21-A basis for therapeutic JAK1 inhibition.

Cutaneous lichen planus (CLP) and psoriasis (PSO) are both common chronic inflammatory skin diseases for which development of new treatments requires the identification of key targets. While PSO is a typical Th17/IL-17-disorder, there is some evidence that Th1/IFN-É£ dominate the inflammatory process in CLP. Nonetheless, the immunopathogenesis of CLP is not fully explained and key immunological factors still have to be recognized. In this study, we compared the immune signature of CLP lesions with the well-characterized inflammation present in PSO skin. First, we analysed the histological and immunohistological characteristics of CLP and PSO. Second, we assessed the cytokine expression (IL1A, IL1B, IL4, IL6, IL8, IL10, IL17A, IL19, IL21, IL22, IL23A, IL13, IFNG, TNF, IL12A, IL12B and IL36G) of lesional skin of CLP with PSO by qPCR. Histology revealed a similar epidermal thickness in CLP and PSO. Immunohistochemically, both diseases presented with an inflammatory infiltrate mainly composed by CD3+ CD4+ T cells rather than CD3+ CD8+ . Importantly, mRNA analysis showed a distinct cytokine signature: while levels of IL12B, IL1A, IL6 and IL23 were similar between the two groups, the characteristic PSO-associated cytokines IL8, IL17A, IL22, IL19 and IL36G were expressed at very low levels in CLP. In contrast, CLP lesional skin was dominated by the expression of IFNG, IL21, IL4, IL12A and TNF. Immunohistochemistry confirmed the dominance of IL-21, IFN-É£ and also pSTAT1 in the dermal infiltrate of CLP, while IL-17A was more present in PSO. Collectively, this study improves our understanding of the immunological factors dominating CLP. The dominating cytokines and signalling proteins identified suggest that anti-cytokine therapeutics like JAK inhibitors may be beneficial in CLP.

Lichen planus follicularis tumidus: Immunotyping of the inflammatory infiltrate with focus on plasmacytoid dendritic cells.

Lichen planus follicularis tumidus (LPFT) is a rare clinicopathological variant of lichen planus (LP), clinically presenting with red-to-violaceous plaques studded with comedo-like lesions and keratin-filled milia-like cysts. Histopathologically, LPFT is characterized by cystically dilated follicular infundibula in the dermis, surrounded by a dense lichenoid lymphoid infiltrate with an associated interface reaction. We describe the clinicopathological features of an additional case of LPFT, focusing on the number and distribution of CD123(+) TCF4(+) plasmacytoid dendritic cells (pDCs). In our case, pDCs represented approximately 5% of the total inflammatory infiltrate, predominantly exhibiting a lichenoid distribution around the infundibula with no evidence of cluster formation, thus ruling out cutaneous lupus erythematosus. Our report is the first to describe the number and distribution of pDCs in LPFT. The results of our immunohistochemical analysis corroborate the notion that LPFT should be regarded as a rare variant of LP.

A clinico-demographic study of 344 patients with lichen planus pigmentosus seen in a tertiary care center in India over an 8-year period.

BACKGROUND: Lichen planus pigmentosus (LPP) is an acquired disorder of hyperpigmentation affecting certain racial and ethnic groups. OBJECTIVE: To retrospectively analyze the demographic and clinical characteristics of LPP. METHODS: Clinical and demographic records of all LPP patients attending our pigmentary clinic from January 2011 to June 2018 were reviewed. RESULTS: Data of 344 LPP patients (229 females) were analyzed. Affected females had significantly higher age at onset (P < 0.002) but lesser disease duration at presentation (P < 0.001) as compared to males. Significant positive correlation between body surface area involvement and disease duration was observed (r = 0.72). Personal history of atopy and accompanying autoimmune diseases were observed in 49 (14.24%) and 45 (13.08%) patients, respectively. Observed morphological patterns of LPP included diffuse (n = 193, 56.1%); reticular (n = 45, 13.1%); blotchy (n = 41, 11.9%); and follicular (n = 28, 8.1%). All the patients had a chronic and indolent course of disease with approximately half (49.2%) reporting satisfactory improvement with treatment. CONCLUSION: This is the largest clinico-demographic study till date on LPP. A longer disease duration was associated with more widespread disease. Although the disease improved over time as per patient and physician global assessment, a complete clearance was rarely attained.

IFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus.

Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to CD8+ T cell-mediated cytotoxic responses through MHC class I induction in a coculture model. We show that this process is dependent on Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1), but not JAK1 or STAT2 signaling. Last, using drug prediction algorithms, we identify JAK inhibitors as promising therapeutic agents in LP and demonstrate that the JAK1/2 inhibitor baricitinib fully protects keratinocytes against cell-mediated cytotoxic responses in vitro. In summary, this work elucidates the role and mechanisms of IFN-γ in LP pathogenesis and provides evidence for the therapeutic use of JAK inhibitors to limit cell-mediated cytotoxicity in patients with LP.

Potentially Malignant Oral Disorders and Cancer Transformation.

Cancer in the oral cavity is often preceded by precursor lesions. Nine oral mucosal disorders are known to have an increased risk of malignant transformation. The etiology varies from disorders caused by exogenous factors such as tobacco and autoimmune inflammation to idiopathic or inherited genetic aberrations. In this review, these potentially malignant disorders (PMDs) are described regarding clinical presentation and histopathological architecture. Special attention is paid to the underlying etiologies of PMDs and the potential pathways leading to cancer. The clinical perspective focuses on the importance of accurate and timely diagnosis.

Type I Immune Response Induces Keratinocyte Necroptosis and Is Associated with Interface Dermatitis.

Interface dermatitis is a characteristic histological pattern that occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct type of skin inflammation. Here we investigated the overlap of two different interface dermatitis positive skin diseases, lichen planus and lupus erythematosus. The shared transcriptome signature pointed toward a strong type I immune response, and biopsy-derived T cells were dominated by IFN-γ and tumor necrosis factor alpha (TNF-α) positive cells. The transcriptome of keratinocytes stimulated with IFN-γ and TNF-α correlated significantly with the shared gene regulations of lichen planus and lupus erythematosus. IFN-γ, TNF-α, or mixed supernatant of lesional T cells induced signs of keratinocyte cell death in three-dimensional skin equivalents. We detected a significantly enhanced epidermal expression of receptor-interacting-protein-kinase 3, a key regulator of necroptosis, in interface dermatitis. Phosphorylation of receptor-interacting-protein-kinase 3 and mixed lineage kinase domain like pseudokinase was induced in keratinocytes on stimulation with T-cell supernatant-an effect that was dependent on the presence of either IFN-γ or TNF-α in the T-cell supernatant. Small hairpin RNA knockdown of receptor-interacting-protein-kinase 3 prevented cell death of keratinocytes on stimulation with IFN-γ or TNF-α. In conclusion, type I immunity is associated with lichen planus and lupus erythematosus and induces keratinocyte necroptosis. These two mechanisms are potentially involved in interface dermatitis.

Liquen plano blaschkoide facial como expresión de mosaicismo cutáneo, a propósito de un caso / Lichen planus blaschkoide facial as expression of cutaneous mosaicism, on a case by case

El liquen plano es un trastorno inflamatorio adquirido de etiología desconocida que, excepcionalmente, puede presentarse de forma lineal, debido a la predisposición genética de un clon que se produce durante el desarrollo embrionario. El liquen plano lineal o Blaschkoide de localización facial, es aún más infrecuente, y traduce una mutación genética postcigótica, que así como en otras patologías inflamatorias dermatológicas, aumenta la susceptibilidad de los individuos a desarrollarla.

Lichen planus is an acquired inflammatory disorder of unknown etiology that in exceptional cases can occur linearly. This is due to the genetic predisposition of a clone that occurs during embryonic development. Facial localization of the lichen planus is even more infrequent, and translates to a postcigotic genetic mutation. This mutation increases individual susceptibility, just as in other dermatological inflammatory pathologies.

MicroRNAs in cutaneous lichen planus.

Lichen planus (LP) is a chronic, inflammatory, papulosquamous, autoimmune disease. The pathogenesis of LP appears to be complex, with interactions between genetic, environmental and lifestyle factors. MicroRNAs (miRNAs) are short RNAs encoded in both protein coding and noncoding areas of the genome, and have been found to be involved in the pathogenesis of some inflammatory skin diseases. The aim of this study was to map the levels of miRNA (miR-)-203 and miR-125b in cutaneous LP to evaluate their possible role in the pathogenesis of the disease. In total, 40 patients with classic cutaneous LP and 40 age- and sex- matched healthy controls (HCs) were enrolled in this study. Punch biopsies (4 mm) were taken from cutaneous LP lesions of patients and from normal skin of HCs. miRNA-203 and miRNA-125b mRNA expression was estimated by reverse transcription PCR. Our analysis revealed a significantly (P < 0.001 for both) lower expression of both miR-203 and miR-125b mRNA in the LP than in the HC biopsies. No relationship was found between expression of miR-203 or miR-125b and either age, sex, presence of mucosal lesions or positivity for HCV antibodies. miR-125b and miR-203 could be involved in the pathogenesis of cutaneous LP.

Studying the association between methylenetetrahydrofolate reductase (MTHFR) 677 gene polymorphism, cardiovascular risk and lichen planus.

BACKGROUND: There is a reported relation between hyperhomocysteinemia and lichen planus (LP). An increase in homocysteine (Hcy) and the risk of cardiovascular disease (CVD) in patients with methylenetetrahydrofolate reductase (MTHFR) mutation has been described. OBJECTIVE: To detect MTHFR (C677T) gene polymorphism, and to find its association with CVD risk, Hcy and folic acid levels in patients with LP. METHODS: This hospital-based case-control study included 110 patients with LP: 70 with cutaneous LP (CLP) and 40 with oral LP (OLP). A total of 120 age- and sex-matched healthy subjects were used as controls. Three millilitre venous blood sample was taken for detection of MTHFR gene polymorphism by PCR-RFLP technique and for measurement of the lipid profile. Hcy and folic acid were measured by ELISA. Hypertension was evaluated. RESULTS: There were significantly higher prevalence of hypertension with higher Hcy, triglycerides and cholesterol levels and lower folic acid and HDL levels among patients' groups. Hypertension with higher Hcy and cholesterol levels together with lower folic acid and HDL levels have been found in OLP when compared to CLP. Patients showed a significant higher percentage of the MTHFR 677 TT genotype (P=.003) and of the MTHFR 677 T allele (P=.042) compared to controls. Moreover, there was a higher prevalence of MTHFR 677 T allele in patients with CLP. CONCLUSION: MTHFR 677 gene polymorphism may be a risk factor for the development of the LP, and to predispose these patients to higher risk of CVD.

MicroRNA in skin diseases.

MicroRNAs are essential regulators of various cellular processes such as cell growth, differentiation, apoptosis, and the immune response, acting as factors for translational repression and/or degradation of target messenger RNA. Currently, microRNAs are considered as promising biomarkers and therapeutic targets for different pathological conditions. Skin may serve as a convenient model for microRNA modulation studies due to the comparatively easy access to targets cells. Cutaneous diseases are characterized by multiple intercellular communication pathways, triggered by diverse stimuli and mediated by heterogenous regulators, including microRNAs. The goal of this article is to summarize the state of research in dermatology concerning the action of microRNAs as epigenetic modulators.