Enhanced bioenergetic cellular activity with metabolic switch to aerobic glycolysis in Keloid and Folliculitis Keloidalis Nuchae.

Keloid scars and folliculitis keloidalis nuchae (FKN) are benign fibroproliferative dermal lesions of unknown aetiology and ill-defined treatment, which typically present in genetically susceptible individuals. Their pathognomonic hallmarks include local aggressive invasive behaviour plus high recurrence post-therapy. In view of this, we investigated proliferative and key parameters of bioenergetic cellular characteristics of site-specific keloid-derived fibroblasts (intra(centre)- and peri(margin)-lesional) and FKN compared to normal skin and normal flat non-hypertrophic scar fibroblasts as negative controls.The results showed statistically significant (P < 0.01) and variable growth dynamics with increased proliferation and migration in keloid fibroblasts, while FKN fibroblasts showed a significant (P < 0.001) increase in proliferation but similar migration profile to controls. A statistically significant metabolic switch towards aerobic glycolysis in the fibroblasts from the disease conditions was noted. Furthermore, an increase in basal glycolysis with a concomitant increase in the cellular maximum glycolytic capacity was also demonstrated in perilesional keloid and FKN fibroblasts (P < 0.05). Mitochondrial function parameters showed increased oxidative phosphorylation in the disease conditions (P < 0.05) indicating functional mitochondria. These findings further suggest that Keloids and FKN demonstrate a switch to a metabolic phenotype of aerobic glycolysis. Increased glycolytic flux inhibition is a potential mechanistic basis for future therapy.

Recurrent inverse necrotizing infundibular crystalline folliculitis.

Necrotizing infundibular crystalline folliculitis (NICF) is a rare type of necrotizing folliculitis. The disease typically manifests as folliculocentric papules arising in a seborrheic distribution. Only 23 cases exist in the literature. Most reported cases have arisen spontaneously, but a small number of drug-induced cases in the setting of epidermal-derived growth factor, vascular endothelial-derived growth factor, or PD-1 inhibitor therapy have been reported. Colonization by bacteria and/or yeast occurs frequently. The etiology remains unknown, but some suggest a complex interplay with an aberrant microbiome, sebaceous gland dysfunction, and perturbed EGFR signaling in follicular infundibula. Histopathologic findings include rupture of follicular epithelium, neutrophilic inflammation, and nodular cup-shaped crystal deposits. We present a case of spontaneous, recurrent NICF in an inverse pattern in the inguinal region.

Folliculitis decalvans is characterized by a persistent, abnormal subepidermal microbiota.

Folliculitis decalvans (FD) is a chronic inflammatory disease of unknown aetiology. Although Staphylococcus aureus, frequently found on lesional skin, is thought to play a causal role, the importance of its involvement remains controversial. To examine the role of S aureus, we compared superficial and subepidermal microbiota in 20 FD patients who had S aureus on lesional skin and in 20 healthy controls using culture techniques and genomic identification, before and after an anti-staphylococcal treatment; we also screened for S aureus virulence factors. When present on lesional skin, S aureus colonized non-lesional and subepidermal skin in 80% of cases. These data imply a break in the epidermal barrier integrity and that an abnormal non-lesional skin microbiota persists in FD. S aureus had no superantigenic toxin in 31% of cases and no toxin specificity. Clinical improvement obtained in most cases upon treatment was associated with the disappearance of S aureus in all studied areas, with an incomplete restoration of normal microbiota and a significant increase in negative bacterial samples. This persistent unbalanced, subepidermal microbiota may act as a reservoir of abnormal flora and explain the chronicity of FD, suggesting new avenues of research to restore normal microbiota.

Upregulation of IL-36 cytokines in folliculitis and eosinophilic pustular folliculitis.

BACKGROUND: Members of the interleukin (IL)-36 family, IL-36α, IL-36ß and IL-36γ, are potent chemoattractive cytokines for neutrophils and eosinophils. IL-36 receptor antagonist (IL-36Ra) inhibits IL-36α, IL-36ß and IL-36γ activity. However, the immunohistological expression of IL-36α, IL-36ß, IL-36γ and IL-36Ra has never been addressed in normal follicles, folliculitis or eosinophilic pustular folliculitis (EPF). METHODS: We performed immunohistochemical staining for IL-36α, IL-36ß, IL-36γ and IL-36Ra using 10 cases of EPF, nine of non-specific folliculitis, 10 normal skin samples and 10 samples of normal follicles adjacent to a sebaceous naevus as a control. Two dermatologists, who were blind to the patient records, evaluated all of the slides. RESULTS: The immunoreactive IL-36α was hardly detected in the follicular epithelium and epidermis in the normal skin, folliculitis or EPF. The expression of IL-36ß, IL-36γ and IL-36Ra was augmented in both folliculitis and EPF compared with that in normal follicles. Negative correlations were detected between IL-36ß and IL-36Ra and between IL-36γ and IL-36Ra in normal follicles; however, these were absent in folliculitis. In contrast to normal follicles and folliculitis, a significant positive correlation between IL-36ß/γ and IL-36Ra was shown in EPF. CONCLUSIONS: The overexpression of IL-36ß, IL-36γ and IL-36Ra is an integral part of the inflammatory response of folliculitis and EPF. The coordinated expression of IL-36γ and IL-36Ra may be related to the pathomechanism of EPF.

Sustained obesity reduces litter size by decreasing proteins regulating folliculogenesis and ovulation in rats - A cafeteria diet model.

Global rise in obesity at early age due to overconsumption of energy-dense food is the major health problem which increases the exposure to obesity over longer duration. Recently we reported that the severity of ovarian dysfunction depends on the duration of obesity. In the present study, we examined the consequences of sustained obesity on reproductive outcome and the underlying mechanism. Sprague Dawley female rats (21 days old) were fed ad libitum with a standard diet (control group) and a cafeteria diet (Obese group) for 32 weeks. We observed hypoprolactinemia, sub-fecundity, sub-fertility, delayed conception and macrosomic pups of reduced litter size in sustained obese rats. The observed decrease in the number of ovarian follicles (primordial, primary, secondary and antral follicles) and corpus luteum indicates impairment in folliculogenesis and ovulation. This impairment might be due to decreased level of ovarian proteins (PRLR, AR, GDF-9, OCT-4, COX-2, PPARγ, ER and PR subtypes) in obese rats. We conclude that sustained obesity impaired folliculogenesis and ovulation thereby increased the severity of reproductive deficits.

Facial pustules due to drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report.

Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.

Inflammasome Activation Characterizes Lesional Skin of Folliculitis Decalvans.

Folliculitis decalvans (FD) is a chronic inflammatory disease leading to scarring alopecia with poorly defined pathogenesis. The aim of this study was to investigate the expression of markers associated with the activation of innate immune signals, such as inflammasome (NALP1 and NALP3), interleukin (IL)-1ß and IL-8 and type I interferon (MxA). A retrospective monocentric study was conducted and included 17 patients with FD with available biopsies. Disease activity (stable vs. active) was defined clinically and histologically. Immunostaining was performed using antibodies directed against NALP1, NALP3, IL-1ß, IL-8, and MxA on FD skin biopsies. Results were compared with normal controls and lichen planopilaris. Eleven patients had active disease and 6 had stable disease. NALP1, NALP3, and IL-1ß expression were significantly increased in hair follicles in FD compared with controls and lichen planopilaris. This study highlights the predominant immune signal associated with inflammasome activation in FD, suggesting the use of IL-1ß blockade in FD.

Epidermal psoriasiform hyperplasia, an unrecognized sign of folliculitis decalvans: A histological study of 26 patients.

BACKGROUND: Follicular hyperkeratosis along with hyperplasia of the follicular and interfollicular epithelia are major histopathological characteristics of hidradenitis suppurativa (HS). The presence of an occasional thickening of lesional skin in some folliculitis decalvans (FD) patients and histological similarities between FD and HS led us to look for epidermal hyperplasia and follicular hyperkeratosis in FD patients. PATIENTS AND METHOD: We performed a retrospective histological analysis of 26 patients with FD. OBJECTIVE: We sought to find out whether the presence of hyperplasia of the interfollicular epidermis and of the follicular epithelia could be verified in FD, with reference to the work of von Laffert et al. concerning HS. RESULTS: The main quantitative and qualitative data were: follicular hyperkeratosis (77%), hyperplasia of the interfollicular epidermis (92%) with a psoriasiform aspect (88%), atrophy of the follicular epithelia (85%), plasma cells in infiltrate (92%) in large quantities (42%), follicular microcysts (60%), atrophy of the sebaceous glands (85%) and polytrichia (54%). CONCLUSION: Epidermal hyperplasia, sometimes psoriasiform and follicular microcysts, are significant histological signs of FD, which have been ignored until now although they seem very common.

Should hidradenitis suppurativa/acne inversa best be renamed as "dissecting terminal hair folliculitis"?

Hidradenitis suppurativa/acne inversa is a diverse, enigmatic and distressful disease that has aroused growing interest in specialists from different disciplines. Both names describe its classical manifestations in the intertriginous regions and reflect the historical view of the disease definition, but cause confusions in the understanding of its pathogenesis and classification. In the light of the advance in clinical, histopathological and pathophysiological findings, we propose the term "dissecting terminal hair folliculitis" (DTHF) to characterize its disease nature as folliculitis instead of acneiform disease or apocrine gland disorder. DTHF attacks exclusively the terminal hair follicles in an overwhelming majority of adults, initiating from the fragile acroinfundibulum leading to a non-infectious overreaction of innate immunity system with inflammation that may fiercely dissect and engulf all the surrounding tissues accompanied by secondary bacterial infections. Evidence indicates that perifolliculitis capitis abscedens et suffodiens and pilonidal disease are very likely regional variants of DTHF with the same pathogenesis. Treatment of DTHF remains frustrating. The benefit of biologics in targeting inflammation is so far non-specific, palliative and inconsistent. Hair epilation and photodynamic therapy in treatment of the disease is questionable in consideration of the pathogenesis. Genetic and translational research, especially on the Notch signalling pathways, will yield breakthrough in the development of novel treatment modalities.

Screening of differentially expressed genes in pathological scar tissues using expression microarray.

Pathological scar tissues and normal skin tissues were differentiated by screening for differentially expressed genes in pathologic scar tissues via gene expression microarray. The differentially expressed gene data was analyzed by gene ontology and pathway analyses. There were 5001 up- or down-regulated genes in 2-fold differentially expressed genes, 956 up- or down-regulated genes in 5-fold differentially expressed genes, and 114 up- or down-regulated genes in 20-fold differentially expressed genes. Therefore, significant differences were observed in the gene expression in pathological scar tissues and normal foreskin tissues. The development of pathological scar tissues has been correlated to changes in multiple genes and pathways, which are believed to form a dynamic network connection.

Indomethacin inhibits eosinophil migration to prostaglandin D2 : therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis.

Indomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2 ). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2 and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ(12) -PGJ2 , a plasma metabolite of PGD2 , on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2 -CRTH2 signals play major roles by reducing eosinophil responses to PGD2 .

Expanding the histologic findings in smallpox-related post-vaccinial non-viral folliculitis.

Post-vaccinial non-viral folliculitis has been recognized in the past decade as a new adverse cutaneous reaction to smallpox vaccination. Contrary to more serious smallpox vaccine reactions, post-vaccinial non-viral folliculitis has a benign course and resolves spontaneously within approximately 7 days. We describe additional histopathologic findings associated with post-vaccinial non-viral folliculitis, which has only been described once previously. New findings include the presence of a neutrophilic or lymphohistiocytic infiltrate that is concentrated around the hair follicles. We compare our findings to the follicular nature of varicella and herpes zoster infections, generating the hypothesis of deposition of vaccinia protein within folliculosebaceous units as a potential pathophysiologic mechanism behind post-vaccinial non-viral folliculitis.

Necrotizing infundibular crystalline folliculitis: a clinicopathological study.

BACKGROUND: Necrotizing infundibular crystalline folliculitis (NICF) is a folliculocentric disorder associated with filamentous crystalline deposits, enclosed by parakeratotic columns within the partly necrotic follicular ostium and infundibulum. There are only very few data published about this disorder of unknown origin. OBJECTIVE: We sought to determine the clinicopathological features and pathogenetic aspects of NICF. METHODS: Clinicopathological characterization of 9 patients with NICF and a second group of 7 patients with coincidental findings of NICF in the vicinity of epithelial skin neoplasms was conducted. RESULTS: Clinically, NICF is characterized by multiple waxy papules with predilection for the forehead (56%), neck, and back. Birefringent crystalline deposits were present in the follicular ostia and enclosed by parakeratotic columns in all cases. The necrosis of follicular epithelium was found in 89% and perifollicular neutrophilic infiltrate in 22% of the biopsy specimens. Both yeasts and gram-positive bacteria were identified within the affected follicles in 56% in the first group and 86% in the second group of coincidental NICF. LIMITATION: This was a single-center retrospective study. CONCLUSIONS: NICF is both a distinct entity and an epiphenomenon in the context of other disorders. In regard to the common association with yeasts and gram-positive bacteria in the affected follicles, we hypothesize that NICF is pathogenetically linked to these organisms, which is supported by resolution of the lesions after topical or systemic antimycotic treatment.

The role of inflammation and immunity in the pathogenesis of androgenetic alopecia.

BACKGROUND: Female pattern hair loss affects many women; its pathogenetic basis has been held to be similar to men with common baldness. OBJECTIVE: The objective of this study was to determine the role of immunity and inflammation in androgenetic alopecia in women and modulate therapy according to inflammatory and immunoreactant profiles. MATERIALS AND METHODS: 52 women with androgenetic alopecia (AA) underwent scalp biopsies for routine light microscopic assessment and direct immunofluroescent studies. In 18 patients, serologic assessment for antibodies to androgen receptor, estrogen receptor and cytokeratin 15 was conducted. RESULTS: A lymphocytic folliculitis targeting the bulge epithelium was observed in many cases. Thirty-three of 52 female patients had significant deposits of IgM within the epidermal basement membrane zone typically accompanied by components of complement activation. The severity of changes light microscopically were more apparent in the positive immunoreactant group. Biopsies from men with androgenetic alopecia showed a similar pattern of inflammation and immunoreactant deposition. Serologic assessment for antibodies to androgen receptor, estrogen receptor or cytokeratin 15 were negative. Combined modality therapy with minocycline and topical steroids along with red light produced consistent good results in the positive immunoreactant group compared to the negative immunoreactant group. CONCLUSION: A lymphocytic microfolliculitis targeting the bulge epithelium along with deposits of epithelial basement membrane zone immunoreactants are frequent findings in androgenetic alopecia and could point toward an immunologically driven trigger. Cases showing a positive immunoreactant profile respond well to combined modality therapy compared to those with a negative result.

Imbalance of Th17 to Th1 cells in Behçet's disease.

OBJECTIVES: Behçet's disease (BD) is a helper T cell-mediated autoimmune disease characterised by recurrent orogenital ulcers, uveitis and skin lesions. The helper T cells are divided into Th1, Th2 and Th17 cells according to the pattern of cytokine secretion. Th1 and Th17 cells can contribute to the development of the disease with their respective proinflammatory cytokines, IFN-γ and IL-17. In this study, we investigated the relative role of Th17, Th1 and Th2 cells in BD. METHODS: Peripheral blood mononuclear cells were isolated from 30 patients with BD, for whom the detailed clinical manifestations and medication history were investigated and recorded. Surface markers and intracellular levels of IL-17, IFN-γ and IL-4 in isolated CD4+ T cells were measured using flow-cytometry from these patients and from two control groups, 34 rheumatoid arthritis patients and 24 healthy blood donors to analyse the relationship of Th1, Th17 and Th2 cells in BD. RESULTS: The ratio of Th17/Th1 cells was significantly increased in BD compared to healthy controls (0.16±0.09 vs. 0.10±0.04, p=0.012), while there was no difference in the ratios of Th1/Th2 or Th17/Th2 cells. Th17/Th1 ratio was elevated in BD patients with uveitis or folliculitis compared to those without it (0.21±0.10 vs. 0.13±0.06, p=0.045 for uveitis; 0.18±0.10 vs. 0.12±0.05, p=0.036 for folliculitis). CONCLUSIONS: Our results confirm that TH17 cells are instrumental in Behçet's uveitis and folliculitis. Furthermore, our findings suggest that the role of Th17 cells should be interpreted in the context of their ratio to Th1 cells.