The role of IL-17 and Th17 cells in keloid pathogenesis.

Keloids are characterized histologically by excessive fibroblast proliferation and connective tissue deposition, and clinically by scar tissue extending beyond the original site of skin injury. These scars can cause pruritus, pain, physical disfigurement, anxiety, and depression. As a result, keloid patients often have a diminished quality of life with a disproportionate burden on ethnic minorities. Despite advances in understanding keloid pathology, there is no effective Food and Drug Administration (FDA)-approved pharmacotherapy. Recent studies have highlighted the possible pathologic role of T helper (Th)17 cells and interleukin (IL)-17 in keloid formation, as well as their implication in other inflammatory disorders. This systematic review characterizes the role of Th17 cells and IL-17 in keloid pathogenesis, highlighting this pathway as a potential therapeutic target. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search on PubMed, Embase, MEDLINE, and Web of Science databases on June 5, 2024. The search included terms related to Th17 cells, IL-17, and keloids. Thirteen studies met the inclusion criteria, comprising basic science and bioinformatic studies focusing on Th17 cells and IL-17. Key findings include increased Th17 cell infiltration and IL-17 expression in keloids, IL-17's role in amplifying the inflammatory and fibrotic response via the promotion of IL-6 expression, and IL-17's involvement in upregulating fibrotic markers via SDF-1 and HIF-1α pathways. IL-17 also activates the transforming growth factor beta (TGF-ß)/Smad pathway in keloid fibroblasts. Th17 cells and IL-17 significantly contribute to the inflammatory and fibrotic processes in keloid pathogenesis. Therefore, targeting the IL-17 pathway offers a potential new therapeutic target to improve keloid patients' outcomes. Future research could further elucidate the role of Th17 cells and IL-17 in keloid pathogenesis and assess the safety and efficacy of targeting this pathway in human studies.

Identification of novel immune-related signatures for keloid diagnosis and treatment: insights from integrated bulk RNA-seq and scRNA-seq analysis.

BACKGROUND: Keloid is a disease characterized by proliferation of fibrous tissue after the healing of skin tissue, which seriously affects the daily life of patients. However, the clinical treatment of keloids still has limitations, that is, it is not effective in controlling keloids, resulting in a high recurrence rate. Thus, it is urgent to identify new signatures to improve the diagnosis and treatment of keloids. METHOD: Bulk RNA seq and scRNA seq data were downloaded from the GEO database. First, we used WGCNA and MEGENA to co-identify keloid/immune-related DEGs. Subsequently, we used three machine learning algorithms (Randomforest, SVM-RFE, and LASSO) to identify hub immune-related genes of keloid (KHIGs) and investigated the heterogeneous expression of KHIGs during fibroblast subpopulation differentiation using scRNA-seq. Finally, we used HE and Masson staining, quantitative reverse transcription-PCR, western blotting, immunohistochemical, and Immunofluorescent assay to investigate the dysregulated expression and the mechanism of retinoic acid in keloids. RESULTS: In the present study, we identified PTGFR, RBP5, and LIF as KHIGs and validated their diagnostic performance. Subsequently, we constructed a novel artificial neural network molecular diagnostic model based on the transcriptome pattern of KHIGs, which is expected to break through the current dilemma faced by molecular diagnosis of keloids in the clinic. Meanwhile, the constructed IG score can also effectively predict keloid risk, which provides a new strategy for keloid prevention. Additionally, we observed that KHIGs were also heterogeneously expressed in the constructed differentiation trajectories of fibroblast subtypes, which may affect the differentiation of fibroblast subtypes and thus lead to dysregulation of the immune microenvironment in keloids. Finally, we found that retinoic acid may treat or alleviate keloids by inhibiting RBP5 to differentiate pro-inflammatory fibroblasts (PIF) to mesenchymal fibroblasts (MF), which further reduces collagen secretion. CONCLUSION: In summary, the present study provides novel immune signatures (PTGFR, RBP5, and LIF) for keloid diagnosis and treatment, and identifies retinoic acid as potential anti-keloid drugs. More importantly, we provide a new perspective for understanding the interactions between different fibroblast subtypes in keloids and the remodeling of their immune microenvironment.

The role of α7nAchR and PD-L1 in neuroimmune regulation of keloid treatment.

Keloid formation, characterized by aberrant fibroproliferation and immune dysregulation, remains a challenging clinical concern. This study aims to elucidate the neuroimmune mechanisms underlying keloid pathogenesis and explores the efficacy of a combined treatment approach involving modulation of the α7 nicotinic acetylcholine receptor (α7nAchR), a key player in neural transmission, and programmed death ligand 1 (PD-L1), an immune checkpoint molecule, for keloid intervention. A key innovation lies in the identification of signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) as a potential target gene influenced by this dual treatment. We elucidate the underlying mechanism, wherein the hypoxic keloid microenvironment fosters an upsurge in SCUBE3 secretion. Subsequently, SCUBE3 forms complexes with TGF-ß, initiating the activation of the PI3K/AKT/NF-κB signaling pathway. Notably, SCUBE3 is secreted in the form of exosomes, thereby exerting a profound influence on the differentiation of T cells and macrophages within the keloid milieu. This research not only provides a comprehensive understanding of the molecular mechanisms involved but also offers a promising avenue for the development of targeted therapies to address keloid-associated fibrosis and immune dysregulation. In conclusion, the combined inhibition of α7nAchR and PD-L1 represents a promising therapeutic strategy with SCUBE3 as a pivotal molecular target in the complex landscape of keloid pathophysiology.

[Research advances on the influence of poor dietary habits on the development of keloids].

Long-term poor dietary habits can cause changes in the intestinal flora, resulting in the production of a large number of lipopolysaccharide, increase intestinal mucosal permeability, and activate the entrance of a large number of inflammatory factors into the portal vein. In addition, a high carbohydrate diet can increase liver metabolic burden, increase mitochondrial oxidative phosphorylation, leading to oxidative stress, generate new fat during adenosine triphosphate synthesis, and thus resulting in ectopic fat accumulation, which further activate nuclear factor-κB signaling pathway and release inflam- matory factors such as tumor necrosis factor-α, interleukin-1ß (IL-1ß), IL-6, and so on. This leads to obesity and insulin resis- tance, ultimately triggering systemic low-grade inflammation. This article reviews the mechanism of poor dietary habits leading to systemic low-grade inflammation, the clinical and experimental research progress of keloids and systemic low-grade inflammation, the association between dietary habits and keloid constitution, and puts forward the hypothesis that poor dietary habits may lead to the occurrence and development of keloids.

Downregulated cytotoxic CD8+ T-cell identifies with the NKG2A-soluble HLA-E axis as a predictive biomarker and potential therapeutic target in keloids.

Keloids are an abnormal fibroproliferative wound-healing disease with a poorly understood pathogenesis, making it difficult to predict and prevent this disease in clinical settings. Identifying disease-specific signatures at the molecular and cellular levels in both the blood circulation and primary lesions is urgently needed to develop novel biomarkers for risk assessment and therapeutic targets for recurrence-free treatment. There is mounting evidence of immune cell dysregulation in keloid scarring. In this study, we aimed to profile keloid scar tissues and blood cells and found that downregulation of cytotoxic CD8+ T cells is a keloid signature in the peripheral blood and keloid lesions. Single-cell RNA sequencing revealed that the NKG2A/CD94 complex was specifically upregulated, which might contribute to the significant reduction in CTLs within the scar tissue boundary. In addition, the NKG2A/CD94 complex was associated with high serum levels of soluble human leukocyte antigen-E (sHLA-E). We subsequently measured sHLA-E in our hospital-based study cohort, consisting of 104 keloid patients, 512 healthy donors, and 100 patients with an interfering disease. The sensitivity and specificity of sHLA-E were 83.69% (87/104) and 92.16% (564/612), respectively, and hypertrophic scars and other unrelated diseases exhibited minimal interference with the test results. Furthermore, intralesional therapy with triamcinolone combined with 5-fluorouracil drastically decreased the sHLA-E levels in keloid patients with better prognostic outcomes, while an incomplete reduction in the sHLA-E levels in patient serum was associated with higher recurrence. sHLA-E may effectively serve as a diagnostic marker for assessing the risk of keloid formation and a prognostic marker for the clinical outcomes of intralesional treatment.

Multi-Antigen Imaging Reveals Inflammatory DC, ADAM17 and Neprilysin as Effectors in Keloid Formation.

Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.

Integration of Flow Cytometry and Computational Analysis to Dissect the Epidermal Cellular Subsets in Keloids that Correlate with Recurrence.

Keloid disease is a benign skin disease that does not have an effective therapy. More and more research shows that epidermal abnormalities are involved in keloid pathogenesis. Little is known about the relationship between the abnormal epidermal immunophenotype and clinical outcome. Nine-color flow cytometry with computational analysis was performed to detect the altered cellular subpopulation distribution in keloid lesions. Receiver operating characteristic curves were drawn to compare predictive ability between the alteration of cell subgroup frequency and the Vancouver Scar Scale. The frequency of CD49fhi/CD29+/TLR7+ cellular subsets increased in the keloid epidermis compared with that in the healthy control. CD49fmid-hi/CD29+/TLR7+/CD24+ cellular subpopulation level was increased significantly in keloids, whereas CD49flo-mid/CD29‒/TLR7‒/CD24‒ cellular subpopulation frequency was decreased. The CD49flo/CD29‒/TLR7‒/CD24+/CD117+ cellular subpopulation showed an increased frequency during recurrence with a sensitivity of 66.7% and specificity of 91.7%. The area under the curve was 0.806 for cellular subpopulation analysis, which was higher than the area under the curve for the Vancouver Scar Scale (0.583). The alteration of keloid epidermal subpopulation frequency is related to recurrence, which will provide an optional predictive marker for keloid recurrence and a potential target subset for investigating the generation of keloid.

Single-Cell Sequencing Analysis and Weighted Co-Expression Network Analysis Based on Public Databases Identified That TNC Is a Novel Biomarker for Keloid.

Background: The pathophysiology of keloid formation is not yet understood, so the identification of biomarkers for kelod can be one step towards designing new targeting therapies which will improve outcomes for patients with keloids or at risk of developing keloids. Methods: In this study, we performed single-cell RNA sequencing analysis, weighted co-expression network analysis, and differential expression analysis of keloids based on public databases. And 3 RNA sequencing data from keloid patients in our center were used for validation. Besides, we performed QRT-PCR on keloid tissue and adjacent normal tissues from 16 patients for further verification. Results: We identified the sensitive biomarker of keloid: Tenascin-C (TNC). Then, Pseudotime analysis found that the expression level of TNC decreased first, then stabilized and finally increased with fibroblast differentiation, suggesting that TNC may play an potential role in fibroblast differentiation. In addition, there were differences in the infiltration level of macrophages M0 between the TNC-high group and the TNC-low group. Macrophages M0 had a higher infiltration level in low TNC- group (P<0.05). Conclusion: Our results can provide a new idea for the diagnosis and treatment of keloid.

Human CD206+ Macrophages Show Antifibrotic Effects on Human Fibroblasts through an IL-6-Dependent Mechanism In Vitro.

BACKGROUND: Pathologic scarring including keloid and hypertrophic scar causes aesthetic and physical problems, and there are clinical difficulties (e.g., posttreatment recurrence) in dealing with pathologic scarring. Understanding the mechanisms that underlie scar control in wound healing will help prevent and treat pathologic scarring. The authors focused on CD206+ macrophages in the wound-healing process, and hypothesized that CD206+ macrophages have antifibrotic effects on fibroblasts. METHODS: The authors established a co-culture system for CD206+ macrophages and fibroblasts (cell ratio, 1:1). The authors examined the CD206+ macrophages' antifibrotic effects on fibroblasts after a 72-hour culture, focusing on fibrosis-related genes. To identify key factor(s) in the interaction between CD206+ macrophages and fibroblasts, the authors analyzed cytokines in a conditioned medium of the co-culture system. RESULTS: Under co-culture with CD206+ macrophages, expression of the following in the fibroblasts was significantly down-regulated: type 1 (fold change, 0.38) and type 3 collagen (0.45), alpha smooth muscle actin (0.24), connective tissue growth factor (0.40), and transforming growth factor-beta (0.66); the expression of matrix metalloproteinase 1 was significantly up-regulated (1.92). Conditioned medium in the co-culture showed a high interleukin (IL)-6 concentration (419 ± 88 pg/ml). When IL-6 was added to fibroblasts, antifibrotic changes in gene expression (as observed under the co-culture) occurred in the fibroblasts. CONCLUSIONS: The authors' in vitro results revealed that CD206+ macrophages have antifibrotic effects on fibroblasts by means of a paracrine mechanism involving IL-6. Understanding these effects, especially in vivo, will help elucidate the mechanism of scar control in wound healing and contribute to the development of new scar treatments.

The Roles of Inflammation in Keloid and Hypertrophic Scars.

The underlying mechanisms of wound healing are complex but inflammation is one of the determining factors. Besides its traditional role in combating against infection upon injury, the characteristics and magnitude of inflammation have dramatic impacts on the pathogenesis of scar. Keloids and hypertrophic scars are pathological scars that result from aberrant wound healing. They are characterized by continuous local inflammation and excessive collagen deposition. In this review, we aim at discussing how dysregulated inflammation contributes to the pathogenesis of scar formation. Immune cells, soluble inflammatory mediators, and the related intracellular signal transduction pathways are our three subtopics encompassing the events occurring in inflammation associated with scar formation. In the end, we enumerate the current and potential medicines and therapeutics for suppressing inflammation and limiting progression to scar. Understanding the initiation, progression, and resolution of inflammation will provide insights into the mechanisms of scar formation and is useful for developing effective treatments.

RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing.

Keloids are disfiguring, fibroproliferative growths and their pathogenesis remains unclear, inhibiting therapeutic development. Available treatment options have limited efficacy and harbor safety concerns. Thus, there is a great need to clarify keloid pathomechanisms that may lead to novel treatments. In this study, we aimed to elucidate the profile of lesional and non-lesional keloid skin compared to normal skin. We performed gene (RNAseq, qRT-PCR) and protein (immunohistochemistry) expression analyses on biopsy specimens obtained from lesional and non-lesional skin of African American (AA) keloid patients compared to healthy skin from AA controls. Fold-change≥2 and false-discovery rate (FDR)<0.05 was used to define significance. We found that lesional versus normal skin showed significant up-regulation of markers of T-cell activation/migration (ICOS, CCR7), Th2- (IL-4R, CCL11, TNFSF4/OX40L), Th1- (CXCL9/CXCL10/CXCL11), Th17/Th22- (CCL20, S100As) pathways, and JAK/STAT-signaling (JAK3) (false-discovery rate [FDR]<0.05). Non-lesional skin also exhibited similar trends. We observed increased cellular infiltrates in keloid tissues, including T-cells, dendritic cells, mast cells, as well as greater IL-4rα+, CCR9+, and periostin+ immunostaining. In sum, comprehensive molecular profiling demonstrated that both lesional and non-lesional skin show significant immune alternations, and particularly Th2 and JAK3 expression. This advocates for the investigation of novel treatments targeting the Th2 axis and/or JAK/STAT-signaling in keloid patients.

[Examining the pathogenesis and therapeutic strategy of keloids from the perspective of systemic inflammation].

Keloid is a disease that is difficult to cure and has a high recurrence rate. In the past, research on keloid focused on keloid cells themselves and the therapeutic strategy limited to local treatment, whereas the role of systemic factors in the process of occurrence and development of disease was usually neglected. Based on the literature reports and clinical evidence, we propose that the pro-inflammatory constitution of keloid patients can serve as a systemic factor to interact with local factors such as skin lesion, and thus leads to the initiation and development of keloid. The classical theory about close relationship between visceral malfunctions and skin diseases described in traditional Chinese medicine has provided supporting evidence. Therefore, we suggest that systemic anti-inflammatory therapy should be included in the design of future keloid therapeutic strategies and be verified by the clinical trials. Additionally, the therapeutic strategies of traditional Chinese medicine including anti-dampness, detoxing and heating removing can also be employed as a part of systemic treatment of keloids.

Understanding Keloid Pathobiology From a Quasi-Neoplastic Perspective: Less of a Scar and More of a Chronic Inflammatory Disease With Cancer-Like Tendencies.

Keloids are considered as benign fibroproliferative skin tumors growing beyond the site of the original dermal injury. Although traditionally viewed as a form of skin scarring, keloids display many cancer-like characteristics such as progressive uncontrolled growth, lack of spontaneous regression and extremely high rates of recurrence. Phenotypically, keloids are consistent with non-malignant dermal tumors that are due to the excessive overproduction of collagen which never metastasize. Within the remit of keloid pathobiology, there is increasing evidence for the various interplay of neoplastic-promoting and suppressing factors, which may explain its aggressive clinical behavior. Amongst the most compelling parallels between keloids and cancer are their shared cellular bioenergetics, epigenetic methylation profiles and epithelial-to-mesenchymal transition amongst other disease biological (genotypic and phenotypic) behaviors. This review explores the quasi-neoplastic or cancer-like properties of keloids and highlights areas for future study.

Keloid patients have higher peripheral blood endothelial progenitor cell counts and CD34+ cells with normal vasculogenic and angiogenic function that overexpress vascular endothelial growth factor and interleukin-8.

BACKGROUND: One suggested reason for aberrant wound healing in keloid scars is chronic inflammation of the dermis. We hypothesized that excessive blood vessel formation and high capillary density in keloid tissue is caused by dysfunction of endothelial progenitor cells. METHODS: We compared the number of circulating endothelial progenitor cells and vasculogenic and angiogenic capacity, as well as secretory function, of circulating CD34+ cells in keloid patients and healthy individuals. RESULTS: Compared to mononuclear cell cultures from healthy donors, cultures of peripheral blood mononuclear cells obtained from keloid patients showed a more than twofold increase in the number of peripheral blood EPCs (fibronectin-adhering cells that phagocytized acetylated low-density lipoprotein and bound Ulex europaeus agglutinin-I lectin). However, there was no difference in colony-forming ability and participation in in vitro angiogenesis between circulating CD34+ cells isolated from keloid patients and healthy individuals. This means that circulating CD34+ /endothelial progenitor cells in keloid patients have normal vasculogenic and angiogenic function. However, CD34+ cells derived from keloid patients demonstrated a more than sevenfold expression of the interleukin-8 gene and a more than fivefold expression of the vascular endothelial growth factor gene than CD34+ cells derived from healthy individuals. CONCLUSIONS: These results support the role of vascular endothelial growth factor and interleukin-8 in increased recruitment of endothelial progenitor cells in keloid patients.

Skin tissue regeneration for burn injury.

The skin is the largest organ of the body, which meets the environment most directly. Thus, the skin is vulnerable to various damages, particularly burn injury. Skin wound healing is a serious interaction between cell types, cytokines, mediators, the neurovascular system, and matrix remodeling. Tissue regeneration technology remarkably enhances skin repair via re-epidermalization, epidermal-stromal cell interactions, angiogenesis, and inhabitation of hypertrophic scars and keloids. The success rates of skin healing for burn injuries have significantly increased with the use of various skin substitutes. In this review, we discuss skin replacement with cells, growth factors, scaffolds, or cell-seeded scaffolds for skin tissue reconstruction and also compare the high efficacy and cost-effectiveness of each therapy. We describe the essentials, achievements, and challenges of cell-based therapy in reducing scar formation and improving burn injury treatment.

Characterization of CD45RO+ memory T lymphocytes in keloid disease.

BACKGROUND: Memory T cells, a highly effective subset of T lymphocytes, have been reported to be involved in many inflammatory skin disorders. However, the potential role of memory T cells in keloid disease (KD) remains unclear. OBJECTIVES: Due to their important role in regulating inflammation, we investigated the characteristics of CD45RO+ memory T cells in KD. METHODS: Primary cutaneous cells were isolated from keloid scars and normal skin by enzymic digestion. Peripheral blood mononuclear cells were isolated from a related blood sample, and flow cytometry was applied to identify the phenotypic and functional abnormalities of memory T cells in KD. RESULTS: We observed that the majority of T lymphocytes in keloid scars had the memory phenotype, and a greater number of the CD8+ memory T cells in keloid scars produced lower levels of tumour necrosis factor (TNF)-α. This abnormal cytokine production was even more distinct in Forkhead box (FOX)P3-  CD8- memory T cells, with lower TNF-α production and enhanced interferon-γ production. Furthermore, FOXP3+  CD8- memory T cells in keloid scars were abnormal, including showing reduced CD25 and cytotoxic T-lymphocyte-associated antigen 4 expression and interleukin-10 production. In addition, a significant decrease in the number of CD4+  CD25high  FOXP3+ regulatory T cells was identified in patients with multiple keloid scars. We also found that there was significantly increased infiltration of CD103+  CD8+ memory T cells in keloid scars. CONCLUSIONS: Our findings preliminarily elucidate the abnormalities of CD45RO+ memory T cells in keloid scars and provide early evidence that a disrupted T-cell response contributes to the progression of KD.

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology.

Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFß-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

Analysis of Characteristics Similar to Autoimmune Disease in Keloid Patients.

BACKGROUND: Keloid is a fibrotic skin disease for which immune cell infiltration is a primary pathological hallmark. Meanwhile, in autoimmune diseases, triggering of the inflammation response can lead to tissue injury and subsequent organ fibrosis. When the skin is involved in autoimmune disease, skin fibrosis such as that seen in scleroderma can occur. In this study, we propose that keloid possesses features of autoimmune disease. METHODS: To verify whether keloid possesses features of autoimmune disease, immune cell infiltration and immune complex deposits were detected with immunohistochemical staining and immunofluorescence, respectively, in keloid and normal skin tissues. A routine antinuclear antibody profile was tested in sera from 28 keloid patients and 28 healthy controls. Lastly, the anti-hnRNPA2B1 autoantibody in sera was evaluated by enzyme-linked immunosorbent assay. RESULTS: The numbers of CD1α(+) Langerhans cells, CD3(+) T lymphocytes, CD68(+) macrophages, and CD20(+) B lymphocytes increased in keloid tissues compared to normal skin. IgA, IgM, C3, and C1q deposits were found in keloid tissues but not in normal skin, while anti-hnRNPA2B1 levels in sera from keloid patients were elevated. CONCLUSION: The above findings suggest that keloids have some characteristics that are similar to autoimmune disease and might be mediated by autoimmune responses. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Treg-enriched CD4+ T cells attenuate collagen synthesis in keloid fibroblasts.

Keloid is an inflammatory and fibrotic disease with an unknown pathogenesis. Regulatory T cells (Tregs) of CD4+ lineage can suppress other effector CD4+ T cells and modulate the immune response. A relative decrease in the number of Tregs may be involved in the pathogenesis of inflammatory and fibrotic diseases. We therefore investigated the number of Tregs in keloids using immunohistochemistry and examined the interaction between Tregs and keloid fibroblasts (KFs) using a coculture system. It was found that the ratio of Tregs/CD4+ T cells was lower compared with that in other common inflammatory skin conditions. In addition, Treg-enriched CD4+ T cells reduced collagen synthesis by KFs. Our findings suggest that a local imbalance of Tregs contributes to the development of keloids and that correction of this imbalance might represent a novel therapeutic approach to keloid fibrosis.

Mast cell activity in the healing wound: more than meets the eye?

Mast cells (MCs) are an important part of the innate immune system and are abundant in barrier organs such as the skin. They are known primarily for initiating allergic reactions, but many other biological functions have now been described for these cells. Studies have indicated that during wound repair, MCs enhance acute inflammation, stimulate reepithelialization and angiogenesis, and promote scarring. MCs have also been linked to abnormal healing, with high numbers of MCs observed in chronic wounds, hypertrophic scars and keloids. Although MCs have gained attention in the wound healing field, several unique features of MCs have yet to be examined in the context of cutaneous repair. These include the ability of MCs to: (i) produce anti-inflammatory mediators; (ii) release mediators without degranulating; and (iii) change their phenotype. Recent findings highlight the complexity of MCs and suggest that more information is needed to understand their complete range of activities during repair.