Abstract: Minoxidil induces new hair growth in approximately one-third of patients with androgenetic alopecia after 1 year of treatment. With several conflicting reports in the literature based on small-scale studies, the current study... more
Abstract: Minoxidil induces new hair growth in approximately one-third of patients with androgenetic alopecia after 1 year of treatment. With several conflicting reports in the literature based on small-scale studies, the current study aimed to clarify whether organ culture of human scalp anagen VI hair follicles is a suitable in vitro test system for reproducing, and experimentally dissecting, the recognized in vivo hair-growth-promoting capacity of minoxidil. Hair shaft elongation was studied in terminal anagen VI hair follicles ...
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Hair is a potent cultural signal that when perceived as deficient can invite psychological trauma. Over the past few decades, researchers have successfully dissected several controls for hair follicle development and growth. However, we... more
Hair is a potent cultural signal that when perceived as deficient can invite psychological trauma. Over the past few decades, researchers have successfully dissected several controls for hair follicle development and growth. However, we know relatively little about the genetic controls for hair fiber form and texture, despite wide variability in the expression of hair phenotypes among different, even very closely related, individuals. In this issue, Shimomura et al. present some intriguing insights into the potential role for lipase H in the control of hair form and texture.
Skin pigmentation is directed by epidermal-melanin units, characterized by long-lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously we reported... more
Skin pigmentation is directed by epidermal-melanin units, characterized by long-lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously we reported that MC:KC contact is required for melanosome transfer, that this can be enhanced by filopodial and by UVR/UVA irradiation, which can up-regulate melanosome transfer via Myosin X-mediated control of MC filopodia. Both MC and KC express Ca-dependent E-cadherins. These homophilic adhesion contacts induce transient increases in intra-KC Ca, while ultraviolet radiation (UVR) raises intra-MC Ca via calcium selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca triggers melanin transfer remains unclear, and here we evaluated the role of E-Cadherin in UVR-mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia-associated E-Cadherin, Cdc42, VASP and βcatenin, all of which ...
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Virus-encoded microRNAs are emerging as key regulators of persistent infection and host-cell immune evasion. Merkel cell polyomavirus, the predominant etiological agent of Merkel cell carcinoma, encodes a single microRNA, MCV-miR-M1,... more
Virus-encoded microRNAs are emerging as key regulators of persistent infection and host-cell immune evasion. Merkel cell polyomavirus, the predominant etiological agent of Merkel cell carcinoma, encodes a single microRNA, MCV-miR-M1, which targets the oncogenic Merkel cell polyomavirus large T antigen. MCV-miR-M1 has previously been shown to play an important role in the establishment of long-term infection, however, the underlying mechanism is not fully understood. A key unanswered question is whether, in addition to autoregulating large T antigen, MCV-miR-M1 also targets cellular transcripts to orchestrate an environment conducive to persistent infection. To address this, we adopted an RNA sequencing-based approach to identify cellular targets of MCV-miR-M1. Intriguingly, bioinformatics analysis of transcripts that are differentially expressed in cells expressing MCV-miR-M1 revealed several genes implicated in immune evasion. Subsequent target validation led to the identification ...
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Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny... more
Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs (e.g., beard). Follicle response is epigenetically varied: some remain unaffected (e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors-androgen-activated ...
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Cutaneous science has seen considerable development in the last 25 years, in part due to the Omics revolution, and the appreciation that this organ is hardwired into the body's key neuro-immuno-endocrine axes. Moreover, there is... more
Cutaneous science has seen considerable development in the last 25 years, in part due to the Omics revolution, and the appreciation that this organ is hardwired into the body's key neuro-immuno-endocrine axes. Moreover, there is greater appreciation of how stratification of skin disorders will permit more targeted and more effective treatments. Against this has been how the remarkable extension in the average human life-span, though in the West at least, this parallels worrying increases in lifestyle-associated conditions like diabetes, skin cancer etc. These demographic trends bring greater urgency to finding clinical solutions for numerous age-related deficits in skin function caused by extrinsic and intrinsic factors. Mechanisms for aging skin include the actions of reactive oxygen species (ROS), mtDNA mutations, and telomere shortening, as well as hormonal changes. We have also significantly improved our understanding of how to harness the skin's considerable regenerativ...
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Tattooing has long been practised in various societies all around the world and is becoming increasingly common and widespread in the West. Tattoo ink suspensions unquestionably contain pigments composed of nanoparticles, i.e., particles... more
Tattooing has long been practised in various societies all around the world and is becoming increasingly common and widespread in the West. Tattoo ink suspensions unquestionably contain pigments composed of nanoparticles, i.e., particles of sub-100 nm dimensions. It is widely acknowledged that nanoparticles have higher levels of chemical activity than their larger particle equivalents. However, assessment of the toxicity of tattoo inks has been the subject of little research and ink manufacturers are not obliged to disclose the exact composition of their products. This study examines tattoo ink particles in two fundamental skin components at the nanometre level. We use atomic force microscopy and light microscopy to examine cryosections of tattooed skin, exploring the collagen fibril networks in the dermis that contain ink nanoparticles. Further, we culture fibroblasts in diluted tattoo ink to explore both the immediate impact of ink pigment on cell viability and also to observe the...
In this study, we have shown how particles in carbon black tattoo ink accumulate in the human skin dermis using fine-resolution atomic force microscopy, with which a single ink particle in the collagenous network can be imaged. This... more
In this study, we have shown how particles in carbon black tattoo ink accumulate in the human skin dermis using fine-resolution atomic force microscopy, with which a single ink particle in the collagenous network can be imaged. This information further demonstrates that tattoo inks are nano-particles. Further, we have deposited a commercially available tattoo ink on a glass slide and calculated a range of volumes for single ink particles. © 2015 S. Karger AG, Basel.
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Stem Cells, Aging, Biology, Medicine, Humans, and 4 moreHair, Melanocytes, Hair Follicle, and Hypopigmentation
ABSTRACT JA Hardman, DJ Tobin, I Haslam, Y Al-Nuaimi, B Grimaldi, R Paus
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Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of... more
Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq indivi...
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Biology, Membrane Proteins, Immunohistochemistry, Medicine, Molecular endocrinology, and 15 moreWestern blotting, In Situ Hybridization, Biological Sciences, Progesterone, Humans, Mice, Animals, Male, Leydig cells, Amino Acid Sequence, Base Sequence, Pregnenolone, Gene Expression Regulation, Molecular Sequence Data, and Medical and Health Sciences
The development of hair follicle organ culture techniques is a significant milestone in cutaneous biology research. The hair follicle, or more accurately the “pilo-sebaceous unit”, encapsulates all the important physiologic processes... more
The development of hair follicle organ culture techniques is a significant milestone in cutaneous biology research. The hair follicle, or more accurately the “pilo-sebaceous unit”, encapsulates all the important physiologic processes found in the human body; controlled cell growth/death, interactions between cells of different histologic type, cell differentiation and migration, and hormone responsitivity to name a few. Thus, the value of the hair follicle as a model for biological scientific research goes way beyond its scope for ...
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The dermal papilla (DP) is considered a growth-inducing component of the hair follicle [9] occupying the anagen hair bulb cavity and consisting of connective tissue continuous with that ensheathing the follicle. The cells of the... more
The dermal papilla (DP) is considered a growth-inducing component of the hair follicle [9] occupying the anagen hair bulb cavity and consisting of connective tissue continuous with that ensheathing the follicle. The cells of the vascularized anagen DP lie in an extensive extracellular matrix, rich in basement proteins (laminin, collagen IV), fibronectin and proteoglycans [8]. The DP appears to comprise a constant population of cells [12] which round up and clump during telogen with concomitant vascular collapse. The prominent DP ...
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Background Nitric oxide (NO) is a ubiquitous gaseous lipophilic molecule generated from the conversion of l-arginine to l-citrulline by the NO synthases (NOSs). Ultraviolet radiation (UVR)-induced NO production appears to stimulate... more
Background Nitric oxide (NO) is a ubiquitous gaseous lipophilic molecule generated from the conversion of l-arginine to l-citrulline by the NO synthases (NOSs). Ultraviolet radiation (UVR)-induced NO production appears to stimulate epidermal melanogenesis. However, given their relative protection from UVR, it is unclear whether NO plays a similar role in hair bulb melanocytes. Objectives We aimed to identify the expression profiles of the NOS isoforms endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) and ...
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Deficiency of the lysosomal cysteine protease cathepsin L (Ctsl) in mice results in a phenotype affecting multiple tissues, including thymus, epidermis, and hair follicles, and in the heart develops as a progressive dilated cardiomyopathy... more
Deficiency of the lysosomal cysteine protease cathepsin L (Ctsl) in mice results in a phenotype affecting multiple tissues, including thymus, epidermis, and hair follicles, and in the heart develops as a progressive dilated cardiomyopathy (DCM). To understand the role of Ctsl in the maintenance of regular heart morphology and function, it is critical to determine whether the DCM in Ctsl-/-mice is primarily because of the lack of Ctsl expression and activity in the cardiomyocytes or is caused by the additional extracardiac pathologies. ...
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Alopecia areata is a common disfiguring hair loss disorder that primarily affects the hair follicle as it enters the prolonged growth phase called anagen. The last few years have yielded an explosion of more rigorously obtained data on... more
Alopecia areata is a common disfiguring hair loss disorder that primarily affects the hair follicle as it enters the prolonged growth phase called anagen. The last few years have yielded an explosion of more rigorously obtained data on the etiology and pathogenesis of this disorder. While a consensus is rapidly building in support of an autoimmune pathogenesis, there are still several enigmatic issues to be resolved. These include the possibility that alopecia areata is really a multientity disorder with causes that are ...
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Summary Mice deficient for cathepsin L (CTSL) show epidermal hyperplasia due to a hyperproliferation of basal keratinocytes. Here we show that the critical function of CTSL in the skin is keratinocyte specific. This is revealed by... more
Summary Mice deficient for cathepsin L (CTSL) show epidermal hyperplasia due to a hyperproliferation of basal keratinocytes. Here we show that the critical function of CTSL in the skin is keratinocyte specific. This is revealed by transgenic re-expression of CTSL in the keratinocytes of ctsl-/-mice, resulting in a rescue of the ctsl-/-skin phenotype. Cultivation of primary mouse keratinocytes with fibroblast-and keratinocyte-conditioned media, as well as heterologous organotypic co-cultures of mouse fibroblasts and human keratinocytes, ...
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Biological Sciences, Humans, Keratinocytes, Mice, Animals, and 15 moreSkin, Keratin, Epidermis, Phenotype, Epidermal Growth Factor, Genotype, Time Factors, Cysteine endopeptidases, Cell Proliferation, Growth Factor, Lysosomes, Hair Follicle, Keratins, Cysteine Protease, and Medical and Health Sciences
Abstract: A novel function of NF-{kappa} B in the development of most ectodermal appendages, including two types of murine pelage hair follicles, was detected in a mouse model with suppressed NF-{kappa} B activity (c I {kappa} B... more
Abstract: A novel function of NF-{kappa} B in the development of most ectodermal appendages, including two types of murine pelage hair follicles, was detected in a mouse model with suppressed NF-{kappa} B activity (c I {kappa} B {alpha}{Delta} N). However, the developmental processes regulated by NF-{kappa} B in hair follicles has remained unknown. Furthermore, the similarity between the phenotypes of c I {kappa} BA {Delta} N mice and mice deficient in Eda A1 (tabby) or its receptor EdaR (downless) raised the issue ...
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Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via... more
Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via pathways activated by receptor-dependent and-independent mechanisms, in hormonal, auto-, para-, or intracrine fashion. Because of the multidirectional nature and heterogeneous character of the melanogenesis modifying agents, its controlling factors are not organized into simple ...
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Jump to main content; Jump to navigation; nature.com homepage; Publications AZ index; Browse by subject; SID. My account; Submit manuscript; Register; Subscribe. Advertisement. Login. Journal of Investigative Dermatology homepage Search... more
Jump to main content; Jump to navigation; nature.com homepage; Publications AZ index; Browse by subject; SID. My account; Submit manuscript; Register; Subscribe. Advertisement. Login. Journal of Investigative Dermatology homepage Search Advanced search. Journal home > Archive > Original Articles > Full text. Original Article. Journal of Investigative Dermatology (1995) 104, 13–14; doi:10.1038/jid.1995.35. Immunity to Hair Follicles in Alopecia Areata. Desmond J Tobin and Jean-Claude Bystryn. ...
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Electron Microscopy, Multidisciplinary, Electrocardiography, Echocardiography, Heart Failure, and 13 moreMice, Female, Animals, Male, Dilated cardiomyopathy, Heart valves, Time Factors, Left ventricular hypertrophy, Cysteine endopeptidases, Adaptive Response, Left Ventricular Function, Lysosomes, and Knockout Mice
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The dermal papilla is believed to exert controlling influences on hair growth. This report documents, for the first time, the occurrence of intranuclear rodlets in normal cultured human dermal papilla cells. Intranuclear rodlets have been... more
The dermal papilla is believed to exert controlling influences on hair growth. This report documents, for the first time, the occurrence of intranuclear rodlets in normal cultured human dermal papilla cells. Intranuclear rodlets have been observed predominantly in normal neurons, neural neoplasms, and paraneuromas. Whereas intranuclear rodlets and complex intranuclear bodies have not been identified in dermal papilla cells in vivo, they were observed, by light microscopy and transmission electron microscopy, in primary and subsequent passaged cultures in all 10 individuals examined. Intranuclear rodlets and bodies were not found, however, in parallel cultures of scalp dermal fibroblasts from the same individuals. Rodlet ultrastructure in cultured dermal papilla cells exhibited many features in common with previous reports on rodlets in neuronal and paraneuronal cells. Features that differentiated the rodlets in this study, however, included: doublet/triplet rodlets in the same nucleus; rodlets or crystalline filament bundles within complex nuclear inclusions; close relationship with the nuclear membrane, and their frequent intimate association with intranuclear bodies; and nucleoli and fine chromatin-distinct fibrillar material. Although the function of these true intranuclear inclusions in dermal papilla cells is unknown, it is noteworthy that they were present in these highly metabolically active fibroblasts while absent in comparatively less active dermal fibroblasts, and may indeed be a marker for this fibroblast cell type.
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Abstract The fate of the hair follicle pigmentary unit during the cyclical involution of anagen hair follicles is unknown. Using the C57BL/6 mouse model for hair research, hair follicle melanocytes were examined during the anagen–catagen... more
Abstract The fate of the hair follicle pigmentary unit during the cyclical involution of anagen hair follicles is unknown. Using the C57BL/6 mouse model for hair research, hair follicle melanocytes were examined during the anagen–catagen transformation, comparing spontaneous and pharmacologically induced catagen development. This study shows that both spontaneous catagen and dexamethasone-induced catagen display similar changes in the pigmentary unit. Catagen hair follicles exhibited pigment incontinence in the dermal ...
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Although alopecia areata is suspected to be an autoimmune disease, no direct evidence of an altered immune response to components of the hair follicle has been reported. We studied whether antibodies to normal human anagen scalp hair... more
Although alopecia areata is suspected to be an autoimmune disease, no direct evidence of an altered immune response to components of the hair follicle has been reported. We studied whether antibodies to normal human anagen scalp hair follicles are present in individuals with alopecia areata. Thirty-nine alopecia areata sera and 27 control sera were tested by Western immunoblotting for antibodies to 6 M urea-extractable proteins of normal anagen scalp hair follicles. At serum diluted 1:80, all alopecia areata subjects (100%), but only 44% of control individuals, had antibodies directed to one or more antigens of approximately 57, 52, 50, 47, or 44 kD. The incidence of antibodies to individual hair follicle antigens in alopecia areata was up to seven times more frequent than in control sera and their level up to 13 times greater and was statistically significant for all five antigens. Tissue specificity analysis indicated that these antigens were selectively expressed in hair follicles. These findings indicate that individuals with alopecia areata have abnormal antibodies directed to hair follicle antigens, and support the hypothesis that alopecia areata is an autoimmune disease.
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It is well recognized that alopecia areata (Aa) may preferentially affect pigmented hair and may spare white hair, and that regrowing hair in the disease is often initially white. In addition, there is an association with vitiligo and... more
It is well recognized that alopecia areata (Aa) may preferentially affect pigmented hair and may spare white hair, and that regrowing hair in the disease is often initially white. In addition, there is an association with vitiligo and ocular depigmentation. To date, the pathomechanisms of the melanocyte effects are unclear. We have studied 10 patients with untreated acute alopecia areata, and three normal patients without hair loss. Morphologic changes, studied by conventional light and electron microscopy, in the cytoplasm of affected melanocytes often predated nuclear hyperchromatism. Increased numbers of bizarre melanosomes were found in affected melanocytes compared with normal ones; such melanosomes had incomplete or "aborted" melanization, resulting in poor pigment deposition, and were disrupted, enlarged and rounded, with loss of normal ellipsoidal shape. An unusual outer root sheath (ORS) distribution of hair bulb melanocytes was seen. Other atypical melanosome effects included marked pigment displacement into peribulbar and DP melanophages. In the DP clumped melanin granules formed giant spherical complexes without discernible limiting membranes, which were sometimes associated with lymphocytes. These morphologic changes indicate an active involvement of hair bulb melanocytes in alopecia areata.
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The prime diagnostic feature of acute alopecia areata is the presence of exclamation mark hairs. These characteristic hairs fracture at their distal end and taper proximally towards the scalp, giving them the appearance of an exclamation... more
The prime diagnostic feature of acute alopecia areata is the presence of exclamation mark hairs. These characteristic hairs fracture at their distal end and taper proximally towards the scalp, giving them the appearance of an exclamation mark. Hair morphology was studied in 8 patients with untreated acute alopecia areata and 3 normal adults without hair loss. Light microscopy, transmission and scanning electron microscopy revealed distinct structural differences in the distal end of hairs compared with the remainder of their length and with normal hair shafts. Transverse sections of hairs just below the frayed brush-like tip often displayed asymmetrical cortex disintegration. One side was compact and homogeneous while the other was deeply fissured and/or broken up into discrete heterogeneous-staining fragments of cortical, stratum corneum and cuticular components in addition to apparently degenerate cortex. Many exclamation mark hair tips lacked cuticle and had irregular profiles. Melanin was found in cortical and medullary fragments at the tip, although it was absent in the more degenerate forms of cortex. More proximal sections of these pathognomic telogen hairs revealed nearly normal hair shaft ultrastructure.
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Adolescent, Humans, Child, Hair, Female, and 4 moreMale, Alopecia Areata, Clinical Sciences, and Adult
Melanocytes in human skin reside both in the epidermis and in the matrix and outer root sheath of anagen hair follicles. Comparative study of melanocytes in these different locations has been difficult as hair follicle melanocytes could... more
Melanocytes in human skin reside both in the epidermis and in the matrix and outer root sheath of anagen hair follicles. Comparative study of melanocytes in these different locations has been difficult as hair follicle melanocytes could not be cultured. In this study we used a recently described method of growing hair follicle melanocytes to characterize and compare hair follicle and epidermal melanocytes in the scalp of the same individual. Three morphologically and antigenically distinct types of melanocytes were observed in primary ...
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Both human epidermal melanocytes and keratinocytes have the full capacity for de novo synthesis of 6(R) L-erythro 5,6,7,8, tetrahydrobiopterin, the essential cofactor for the rate limiting step in catecholamine synthesis, via tyrosine... more
Both human epidermal melanocytes and keratinocytes have the full capacity for de novo synthesis of 6(R) L-erythro 5,6,7,8, tetrahydrobiopterin, the essential cofactor for the rate limiting step in catecholamine synthesis, via tyrosine hydroxylase. Catecholamine synthesis has been demonstrated in proliferating keratinocytes of the epidermis in human skin. This study presented herein identified for the first time the expression of tyrosine hydroxylase isozyme I mRNA within the melanocyte. The location of the enzyme was demonstrated in both the cytosol and melanosomes of human epidermal melanocytes, using immunohistochemistry and immunofluorescence double staining as well as immunogold electron microscopy. High-performance liquid chromatography (HPLC) analysis of pure melanosomal extracts from the human melanoma cell line, FM94, confirmed the production of L-dopa within these organelles. In addition, enzyme activities for both tyrosine hydroxylase and tyrosinase were measured in the same preparations, by following the catalytic release of tritiated water from L-[3,5-3H]tyrosine. The melanosomal membrane location of tyrosine hydroxylase together with tyrosinase implies a coupled interaction, where L-dopa production facilitates the activation of tyrosinase. Our results support a direct function for tyrosine hydroxylase in the melanosome via a concerted action with tyrosinase to promote pigmentation.
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The immunology of the hair follicle, its relationship with the 'skin immune system' and its role in hair diseases remain biologically intriguing and clinically important. In this study, we analysed the immunoreactivity... more
The immunology of the hair follicle, its relationship with the 'skin immune system' and its role in hair diseases remain biologically intriguing and clinically important. In this study, we analysed the immunoreactivity patterns of 15 immunodermatological markers to determine the cellular composition and immune privilege of the human hair follicle immune system in anagen VI (growth phase). The most prominent cells located in or around the hair follicle were Langerhans cells, CD4+ or CD8+ T cells, macrophages and mast cells, whereas B cells, natural killer cells and gammadelta T cells were found very rarely. Langerhans cells (CD1a+, major histocompatibility complex, MHC class II+), and T cells (CD4+ or CD8+) were predominantly distributed in the distal hair follicle epithelium, whereas macrophages (CD68+, MHC class II+) and mast cells (Giemsa+) were located in the perifollicular connective tissue sheath. Transmission electron microscopy confirmed low numbers of immune cells in the proximal hair follicle epithelium, and very few macrophages and Langerhans cells were seen in the dermal papilla. Melanophages were observed in the connective tissue sheath and dermal papilla. MHC class I (HLA-A, -B, -C) and beta2-microglobulin immunoreactivity was found on most skin cells, but was substantially reduced on isthmus keratinocytes and virtually absent in the proximal hair follicle epithelium. Apart from the absence of Fas ligand immunoreactivity, the sharply reduced numbers of T cells and Langerhans cells, and the virtual absence of MHC class I expression all suggest that the anagen proximal hair follicle constitutes an area of immune privilege within the hair follicle immune system, whose collapse may be crucial for the pathogenesis of alopecia areata.