Anagen stage hair follicles (HFs) exhibit “immune privilege (IP)” from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired ...immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra‐follicular antigen presentation via MHC class I and II molecules, along with prominent expression of “no danger” signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. Perifollicular mast cells, Tregs and other immunocytes may also contribute to HF IP maintenance in healthy human skin. Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro‐inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T‐cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T‐cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. While IP collapse may be induced by exogenous agents, inherent IP deficiencies might confer increased susceptibility to AA for some individuals. Thus, a key goal for effective AA management is the re‐establishment of a functional HF IP, which will also provide superior protection from disease relapse.
Alopecia Areata Gilhar, Amos; Etzioni, Amos; Paus, Ralf
The New England journal of medicine,
04/2012, Letnik:
366, Številka:
16
Journal Article
Recenzirano
This review article synthesizes relevant information about hair-follicle biology and pathobiology and summarizes the clinical presentation and management of this common condition.
The impact of ...certain skin diseases on the lives of those affected tends to be underestimated or even dismissed as simply a “cosmetic problem.” Alopecia areata exemplifies such a condition, owing to its substantial disease burden and its often devastating effects on the patient's quality of life and self-esteem.
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Although alopecia areata is one of the most common autoimmune diseases, the pathobiology of this chronic, relapsing hair-loss disorder is not fully understood, and the available therapies are disappointing.
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This review summarizes the pathogenesis, clinical presentation, and management of alopecia areata and synthesizes relevant background information concerning the biologic . . .
Summary
The role of neurohormones and neuropeptides in human hair follicle (HF) pigmentation extends far beyond the control of melanin synthesis by α‐MSH and ACTH and includes melanoblast ...differentiation, reactive oxygen species scavenging, maintenance of HF immune privilege, and remodeling of the HF pigmentary unit (HFPU). It is now clear that human HFs are not only a target of multiple neuromediators, but also are a major non‐classical production site for neurohormones such as CRH, proopiomelanocortin, ACTH, α‐MSH, ß‐endorphin, TRH, and melatonin. Moreover, human HFs have established a functional peripheral equivalent of the hypothalamic–pituitary–adrenal axis. By charting the author’s own meanderings through the jungle of hair pigmentation research, the current perspectives essay utilizes four clinical observations – hair repigmentation, canities, poliosis, and ‘overnight greying’– as points of entry into the enigmas and challenges of .pigmentary HF neuroendocrinology. After synthesizing key principles and defining major open questions in the field, selected research avenues are delineated that appear clinically most promising. In this context, novel neuroendocrinological strategies to retard or reverse greying and to reduce damage to the HFPU are discussed.
The “thyroid–skin connection” has become a hot frontier in dermatoendocrinology. In this context, the pituitary hormone that controls thyroid hormone production, thyrotropin (TSH), caught the ...attention of skin researchers only after it was reported that the receptor for TSH (TSH-R) is transcribed and translated by selected cultured human skin cell populations and in normal human scalp skin in situ, introducing skin as a nonconventional, peripheral target organ for regulation by TSH. In this issue, Cianfarani et al. present corroborating evidence and raise the old question of whether intracutaneous TSH-R stimulation by autoantibodies contributes to the skin changes seen in autoimmune thyroid disease. This provides a good opportunity to define the questions to be addressed when exploring the thyroid–skin connection.
Abstract
The skin, a self-regulating protective barrier organ, is empowered with sensory and computing capabilities to counteract the environmental stressors to maintain and restore disrupted ...cutaneous homeostasis. These complex functions are coordinated by a cutaneous neuro-endocrine system that also communicates in a bidirectional fashion with the central nervous, endocrine, and immune systems, all acting in concert to control body homeostasis. Although UV energy has played an important role in the origin and evolution of life, UV absorption by the skin not only triggers mechanisms that defend skin integrity and regulate global homeostasis but also induces skin pathology (e.g., cancer, aging, autoimmune responses). These effects are secondary to the transduction of UV electromagnetic energy into chemical, hormonal, and neural signals, defined by the nature of the chromophores and tissue compartments receiving specific UV wavelength. UV radiation can upregulate local neuroendocrine axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis. Similar effects are seen after exposure of the eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.
UV energy triggers skin-protective responses against stress, coordinated by the cutaneous-neuroendocrine system, and activates central neuroendocrine system pathways that regulate global homeostasis.
Frontiers in alopecia areata pathobiology research Gilhar, Amos; Laufer-Britva, Rimma; Keren, Aviad ...
Journal of allergy and clinical immunology,
December 2019, 2019-12-00, 20191201, Letnik:
144, Številka:
6
Journal Article
Recenzirano
Odprti dostop
This current review explores selected and as yet insufficiently investigated frontiers in current alopecia areata (AA) pathobiology research, with an emphasis on potential “new” players in AA ...pathobiology that deserve more systematic exploration and therapeutic targeting. Indeed, new evidence suggests that CD8+ T cells, which have long been thought to be the central players in AA pathobiology, are not the only drivers of disease. Instead, subsets of natural killer (NK) and so-called “unconventional” T cells (invariant NK T cells, γδ T cells, classic NK cells, and type 1 innate lymphoid cells), all of which can produce large amounts of IFN-γ, might also drive AA pathobiology independent of classical, autoantigen-dependent CD8+ T-cell functions. Another important new frontier is the role of regulatory lymphocyte subsets, such as regulatory T cells, γδ regulatory T cells, NKT10 cells, and perifollicular mast cells, in maintaining physiologic hair follicle immune privilege (IP); the extent to which these functions are defective in patients with AA; and how this IP-protective role could be restored therapeutically in patients with established AA. Broadening our AA research horizon along the lines suggested above promises not only to open the door to innovative and even more effective immunotherapy strategies for AA but will also likely be relevant for other autoimmune disorders in which pathobiology, ectopic MHC class I expression, and IP collapse play an important role.
Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells ...within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Hair loss can be a psychologically devastating adverse effect of chemotherapy, but satisfactory management strategies for chemotherapy-induced alopecia remain elusive. In this Review we focus ...on the complex pathobiology of this side-effect. We discuss the clinical features and current management approaches, then draw upon evidence from mouse models and human hair-follicle organ-culture studies to explore the main pathobiology principles and explain why chemotherapy-induced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapy-induced hair-cycle abnormalities, driven by the dystrophic anagen or dystrophic catagen pathway, play important parts in the degree of hair-follicle damage, alopecia phenotype, and hair-regrowth pattern. Additionally, the degree of hair-follicle stem-cell damage determines whether chemotherapy-induced alopecia is reversible. We highlight the need for carefully designed preclinical research models to generate novel, clinically relevant pointers to how this condition may be overcome.
Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate ...circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage. We also review why melatonin promises to be useful in skin cancer prevention, skin photo- and radioprotection, and as an inducer of repair mechanisms that facilitate the recovery of human skin from environmental damage. The fact that human skin and hair follicles not only express functional melatonin receptors but also engage in substantial, extrapineal melatonin synthesis further encourages one to systematically explore how the skin’s melatonin system can be therapeutically targeted in future clinical dermatology and enrolled for preventive medicine strategies.
The immunophilin ligand, cyclosporine A (CsA), which inhibits nuclear factor of activated T cells (NFAT) activity, is a cornerstone of immunosuppressive therapy. Yet, the molecular basis of its ...prominent, nonimmunosuppression-related adverse skin effects, namely drug-induced excessive hair growth (hypertrichosis), is insufficiently understood. Here, we argue that analysis of these adverse effects can uncover clinically important, previously unknown mechanisms of CsA and identify new molecular targets and lead compounds for therapeutic intervention. We exemplify this through our recent discovery that CsA suppresses the potent Wnt inhibitor, secreted frizzled related protein (SFRP)1, in human hair follicles, thereby promoting hair growth and causing hypertrichosis. On this basis, we advocate a new focus on deciphering the molecular basis of the adverse effects of CsA in suitable human model systems as a lead to developing novel therapeutics.
Cyclosporine A (CsA) is a potent immunosuppressant that is required to prevent transplant rejection.CsA treatment leads to a wide range of adverse effects such as hypertrichosis. This adverse effect has served as a blueprint to identify novel strategies to enhance human hair growth.The molecular basis of CsA is thought to occur via canonical nuclear factor of activated T cells (NFAT) inhibition in murine models. However, recent mechanistic work in human tissue reveals nonimmunosuppressive NFAT-independent mechanisms through enhancing Wnt activity.Therefore, it is time to look beyond the NFAT horizon and explore the molecular basis of the complex adverse effects of CsA as a research strategy for identifying novel and well-tolerated therapeutics.
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