Natsuho Ito

Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol

The skin and its major appendages are prominent target organs and potent sources of key players along the classical hypothalamic‐pituitary axis, such as corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and α melanocyte stimulating hormone (α‐MSH), and even express key steroidogenic enzymes. Therefore, it may have established local stress response systems that resemble the hypothalamic‐pituitary‐adrenal (HPA) axis. However, functional evidence that this is indeed the case in normal human skin in situ has still been missing. We show that microdissected, organ‐cultured human scalp hair follicles respond to CRH stimulation by up‐regulating proopiomelanocortin (POMC) transcription and immunoreactivity (IR) for ACTH and α‐MSH, which must have been processed from POMC. CRH, α‐MSH, and ACTH also modulate expression of their cognate receptors (CRH‐R1, MC1‐R, MC2‐R). In addition, the strongest stimulus for adrenal cortisol production, ACTH, also up‐regulates cortisol‐IR in the hair follicles. Isolated human hair follicles secrete substantial levels of cortisol into the culture medium, and this activity is further up‐regulated by CRH. CRH also modulates important functional hair growth parameters in vitro (hair shaft elongation, catagen induction, hair keratinocyte proliferation, melanin production). Finally, human hair follicles display HPA axis‐like regulatory feedback systems, since the glucocorticoid receptor agonist hydrocortisone down‐regulates follicular CRH expression. Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops.

Corticotropin-releasing hormone stimulates the in situ generation of mast cells from precursors in the human hair follicle mesenchyme

Hair follicles (HFs) maintain a peripheral, functional equivalent of the hypothalamic-pituitary-adrenal (HPA) axis, whose most proximal element is corticotropin-releasing hormone (CRH). The mast cell (MC)-rich connective-tissue sheath (CTS) of mouse vibrissa HFs harbors MC precursors. Differentiation of these MC precursors into mature MCs can be induced by stem cell factor (SCF). We have investigated whether the MC progenitors of normal human scalp HF CTS respond to stimulation with CRH. Microdissected anagen HFs and full-thickness scalp skin were treated with CRH (10(-7) M). CRH treatment induced the degranulation of CTS MCs, in addition to increasing the number of CTS MCs in full-thickness skin and HF organ cultures in situ. In the latter, cells with characteristic MC features emigrated from the CTS. CRH-receptor protein expression in the CTS was colocalized with Kit expression on some CTS MCs in situ. CRH treatment upregulated SCF mRNA and protein expression within the HF epithelium. In skin organ culture, CRH-induced degranulation of CTS MCs was abolished by anti-SCF antibody. We demonstrate that human skin is an extramedullary reservoir for MC precursors, and we have identified a regulatory loop between CRH and SCF signaling. This highlights a previously unpublished finding about neuroendocrine control of human MC biology.

Immune privilege and the skin

This chapter summarizes the evidence that defined compartments of the hair follicle (HF) and nail epithelium maintain an area of relative immune privilege (IP). HF and nail IP is chiefly characterized by absent or very low level of expression of major histocompatibility complex class Ia antigens, complemented by a number of factors, such as the local production of potent immunosuppressive agents, dysfunction of professional antigen-presenting cells and inhibition of natural killer cell activities. In the hair bulb, IP is seen only in the anagen stage of HF cycling, while the nail apparatus continuously maintains an IP site in its proximal nail matrix, since the nail apparatus does not cycle. Possibly, the (non-cycling) bulge area of human scalp HFs also enjoys some relative, stably maintained IP, even though it is not as pronounced as the IP of the anagen hair bulb. A collapse of HF and nail IP likely plays a key role in the pathogenesis of one of the most common organ-specific autoimmune diseases, alopecia areata. Therefore, the therapeutic restoration of IP collapse promises to be a particularly effective future strategy for the treatment of alopecia areata.

Febrile ulceronecrotic Mucha-Habermann's disease managed with methylprednisolone semipulse and subsequent methotrexate therapies

Febrile ulceronecrotic Mucha-Habermanns disease is an unusual severe form of pityriasis lichenoides et varioliformis acuta characterized by abrupt onset of ulceronecrotic eruption associated with a high fever and systemic symptoms. To our knowledge, 19 cases of this disease have been reported in the literature, and 4 of them were fatal. We report the case of a 12-year-old boy with this disorder who had abdominal pain, hypoproteinemia, and anemia. Although these associated symptoms are considered life-threatening factors according to reported cases, our patient was successfully treated with methylprednisolone semipulse and subsequent methotrexate therapies. From a review of the literature and the present case, we propose that when patients have these systemic symptoms, therapeutic choices include methotrexate, high-dose corticosteroids, and 4,4-diamino-diphenyl-sulfone, which may depress early development of this disease.

Roxithromycin inhibits chemokine-induced chemotaxis of Th1 and Th2 cells but regulatory T cells

BACKGROUND Roxithromycin (RXM), a 14-member macrolide antibiotic, has a variety of bioregulatory functions such as anti-inflammatory effects, anti-oxidant effects, and modulation of immune responses. OBJECTIVES In this study, we analyzed the effect of RXM on chemokine-induced chemotaxis of Th1, Th2, and regulatory T (Treg) cells established from three normal human peripheral blood lymphocytes by the reported methods. METHODS AND RESULTS Incubation with 10 microM RXM for 18 h did not alter the expression profile of CXCR3 on Th1 cells and CCR4 on Th2 and Treg cells. However, upon RXM preincubation, the migration of Th1 cells to IP-10 and Th2 cells to TARC was partially suppressed, although RXM did not influence Treg cell migration. Erythromycin and clarithromycin at the same concentration did not exert such effects. F-actin polymerization and Ca(++) influx induced by IP-10 and TARC in Th1 and Th2 cells, respectively, was down-regulated by RXM pretreatment. CONCLUSION These results imply that RXM exhibits bioregulatory function by influencing chemotaxis of Th1 and Th2 cells while leaving Treg cell migration unaffected.

Roxithromycin antagonizes catagen induction in murine and human hair follicles: implication of topical roxithromycin as hair restoration reagent

Roxithromycin (RXM) is a 14-member macrolide antibiotics, with a variety of bioregulatory functions including anti-apoptotic activity to keratinocytes. Therefore, RXM has been used for many kinds of skin diseases. In this study, human and murine hair follicles were treated with RXM in order to find the possibility to cure hair loss disease such as androgenetic alopecia (AGA). In AGA, dihydrotestosterone signals apoptosis in dermal papilla cells in susceptible individuals, resting in premature termination of anagen and early entry into catagen. Therefore, anti-apoptotitic drug has a possibility of new candidate for AGA. This study revealed RXM antagonized the in vitro inhibitory effect of IFN-γ on proliferation of keratinocytes and induction of apoptosis in murine and human hair bulb. RXM increases hair elongation and inhibits catagen-like changes induced in vitro with IFN-γ in murine and human hair follicles. Furthermore, topical 5% RXM solution effectively restores hair growth in about half of individuals with AGA without any local and systemic adverse effects. Therefore, RXM is new candidate as a hair restoration drug for AGA.

Palpable archiform migratory erythema preceded by B-cell pseudolymphoma in a Japanese man.

Sir, Palpable archiform migratory erythema (PAME) is a rare member of the family of T-cell pseudolymphomas occurring preferentially in adult males (1–5). The clinical picture of PAME is distinctive from other pseudolymphomas because infiltrated annular erythema develops into elevated migrating lesions in the trunk as the predilection site. The aetiology of this condition is unknown and the disease runs a chronic course. We report here a case of PAME in which polyclonal populations of T cells proliferated surrounding a preceding B-cell pseudolymphoma.